US 20130237454A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2013/0237454 A1 Schutzer (43) Pub. Date: Sep. 12, 2013

(54) DIAGNOSTIC MARKERS FOR Publication Classification NEUROPSYCHIATRIC DISEASE (51) Int. Cl. (76) Inventor: Steven E. Schutzer, Water Mill, NY G0IN 33/68 (2006.01) (US) (52) U.S. CI. CPC ...... G0IN33/6896 (2013.01) (21) Appl. No.: 13/697,417 USPC ..…. 506/12 (22) PCT Filed: May 12, 2011 (57) ABSTRACT Biomarkers for the diagnosis of neuropsychiatric diseases are (86) PCT No.: PCT/US11/00843 presented herein. In particular embodiments, biomarkers are § 371 (c)(1), identified that are useful for diagnosing multiple sclerosis, (2), (4) Date: May 23, 2013 chronic fatigue syndrome, or Neurologic Lyme disease. Also encompassed is a method for diagnosing a patient with a Related U.S. Application Data neuropsychiatric disease, such as multiple sclerosis, chronic e K_f e fatigue syndrome, or Neurologic Lyme disease, by analyzing (60) Provisional application No. 61/395,354, filed on May biological samples isolated from the patient or the patient as 12, 2010. a whole to assess levels of the biomarkers described herein.

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DLAGNOSTIC MARKERS FOR tiple sclerosis is more common in women than men and NEUROPSYCHIATRIC DISEASE generally begins between ages 20 and 40, but can develop at any age. Multiple sclerosis is generally viewed as an autoim FIELD OF THE INVENTION mune syndrome directed against unidentified central nervous [0001] The present invention relates to identifying biologic tissue antigens. The determination of susceptibility to mul markers (biomarkers) that can be used for diagnosis of a tiple sclerosis development is complex and appears to be neuropsychiatric disease. As described herein, neuropsychi governed by both environmental and genetic factors. Some of atric disease may be used to refer to diseases having neuro the symptoms of multiple sclerosis are caused by damage to logic or psychiatric or combined neurologic and psychiatric the myelin sheath, the protective covering that surrounds features. Such neuropsychiatric diseases include, without nerve cells. When this nerve covering is damaged, nerve limitation, multiple sclerosis, chronic fatigue syndrome, and impulses are slowed down or stopped. Ultimately, damage to Neurologic Lyme disease. In particular embodiments, the the myelin sheath results in nerve damage. Multiple sclerosis present invention relates to identifying biomarkers for diag is, moreover, commonly a progressive disease that leads to nosis of multiple sclerosis, chronic fatigue syndrome (CFS: more severe neurologic dysfunction overtime. Nerve damage also referred to hereinas CF), or Neurologic Lyme disease. In may be caused by inflammation that occurs when the body’s a more particular aspect, the invention pertains to the identi immune cells attack the nervous system. Repeated episodes fication of a biomarker signature that is diagnostic for each of of inflammation can occur along any area of the brain and multiple sclerosis, chronic fatigue syndrome, Neurologic spinal cord, which is why the disease is often referred to as Lyme disease. Accordingly, the invention further relates to a one characterized by symptoms and signs over time and method for diagnosing a person or other mammal with a space. neuropsychiatric disease, such as multiple sclerosis, or at risk [0004] Multiple sclerosis is difficult to diagnose because of developing same. The biomarkers and diagnostic signa the progress, severity and specific symptoms of multiple scle tures described herein also identify metabolic/biochemical rosis are quite variable and unpredictable. There are no labo pathways as potential candidates for therapeutic targeting. ratory tests, symptoms or physical findings that can singly The invention further relates to guidance pertaining to appro determine if a person has multiple sclerosis. The differential priate treatment of the person or mammal diagnosed with a diagnosis of multiple sclerosis is quite varied and includes particular neuropsychiatric disease in accordance the meth metabolic, genetic, oncologic, immunologic, and infectious ods described herein. Accurate diagnosis of neuropsychiatric disease assessment. Other diseases that may need to be con disease, particularly with respect to diseases that are difficult sidered in the differential diagnoses, but should be considered to distinguish clinically, should reduce the duration and/or depending on the clinical presentation, include: Acute dis severity of the disease by ensuring that the patient is treated seminated encephalomyelitis, CNS vasculitis, Behçet dis using an appropriate therapeutic regimen. ease, Sjögren syndrome, Sarcoid, neoplasms, CADASIL (ce rebral autosomal dominant arteriopathy with subcortical BACKGROUND OF THE INVENTION infarcts and leukoencephalopathy), Migrainous ischemia, [0002] Knowledge of the entire protein content, the pro Cerebrovascular disease, Progressive multifocal leukoen teome, of normal human cerebrospinal fluid (CSF) would cephalopathy, Inherited white matter diseases, effects of provide a critical standard to allow meaningful comparisons radiation therapy or drugs, CNS lymphoma, Lyme disease, with and between neurologic and psychiatric disorders. CSF HTLV-1 infection, CNS lupus, Mitochondrial encephalopa contains both cellular and soluble components providing thies, Antiphospholipid antibody syndrome, cerebral emboli, insights into processes occurring in the central nervous sys Thrombocytopenic purpura, Progressive multifocal leukoen tem (CNS). As much as 30 to 40% of CSF is formed by the cephalopathy, Mycoplasma encephalopathy, Vitamin B12 extracellular fluid of the brain and spinal cord. CSF contains deficiency, Paraneoplastic syndromes, Psychiatric syn both normal and disease specific components, and provides dromes (Rolak LA, Fleming J O. The Neurologist 2007; 13: an accessible liquid window into the brain. In fact, recent data 57-72). Over the last twenty years, tests such as magnetic suggest CSF may provide more relevant evidence for initial or resonance imaging (MRI), examination of CSF, and evoked propagating pathology than the brain parenchyma itself in response testing have played an increasingly important role in certain neuropsychiatric diseases [Ransohoff (2009) Nature the diagnostic process. In 2005, revised McDonald criteria for 457: 155-156]. Comprehensive characterization of the nor multiple sclerosis were published (Polman et al. Diagnostic mal CSF proteome, furthermore, facilitates identification of Criteria for Multiple Sclerosis: 2005 Revisions to the disease-specific markers [Ekegren et al. (2008) J Mass Spec “McDonald” Criteria. Ann Neurol. (2005) 58:840–846 and trom 43:559–571]. Knowledge of which proteins are present, Polman et al. Ann Neurol (2011) 69:292-302). In addition to absent, or of changed concentrations may lead to diagnostic, the traditional diagnostic tools, the revised criteria provide prognostic, or disease-activity biomarkers as well as provide specific guidelines for using findings of MRI, cerebrospinal insights into disease etiology and pathogenesis. An advantage fluid analysis and visual evoked potentials to support a diag of a full proteome analysis is the ability to identify not just one nosis of multiple sclerosis. However, even with these revised but a multitude of proteins at a single instance. criteria, diagnosis of multiple sclerosis is still challenging and [0003] Multiple sclerosis, for example, is an excellent can frequently takes several months or even years. didate disease for such an approach because it is often a [0005] Rendering a conclusive diagnosis of multiple scle progressive debilitating disease that is difficult to diagnose rosis on an expedited basis would be of great benefit to definitively, especially during the early stages of the disease. patients in light of the potential for recurrence of attacks and Multiple sclerosis is a common demyelinating disease of the progression of the disease. Drugs for the treatment of multiple central nervous system (CNS) that affects up to 0.1% of the sclerosis are now available which slow or prevent progression Caucasian population of northern European descent. Mul of the disease in many patients, and an early diagnosis would, US 2013/0237454 A1 Sep. 12, 2013

therefore, allow early intervention and could significantly tification of at least one of the biomarkers in the biological improve the quality of life for many multiple sclerosis sample indicates a positive diagnosis or is indicative of mul patients. tiple sclerosis in the patient. In an embodiment thereof, the at [0006] It is therefore an object of the present invention to least one biomarker identified in the biological sample is provide an efficient diagnosis system for neuropsychiatric present in the biological sample and set forth in Table 1m, 3m, disease in general, a particular example of which is multiple or 4H-m, and the presence of the at least one biomarker sclerosis, so as to provide biomarkers with which a clinician indicates a positive diagnosis or is indicative of multiple can diagnose or exclude a particular disease in a patient or sclerosis. In another embodiment, the at least one biomarker other mammal. The same reasoning applies to Neurologic identified in the biological sample is absent from the biologi Lyme Disease and Chronic Fatigue syndrome. cal sample and set forth in Table 2m and the absence of the at [0007] The citation of references herein shall not be con least one biomarkerindicates a positive diagnosis oris indica strued as an admission that such is prior art to the present tive of multiple sclerosis. invention. Several publications and patent documents are ref [0012] In yet another aspect, a method for differentially erenced in this application in order to more fully describe the diagnosing a neuropsychiatric disease in a patient is pre state of the art to which this invention pertains. The disclosure sented, wherein the patient exhibits clinical symptoms com of each of these publications and documents is incorporated mon to both Neurologic Lyme disease and Chronic Fatigue by reference herein. Syndrome, the method comprising: a) isolating a biological [0008] Other features and advantages of the invention will sample from the patient; and b) analyzing the biological be apparent from the detailed description, the drawings, and sample for expression of a first panel of biomarkers, wherein the claims. the first panel of biomarkers is set forth in any one of Tables 4H-1, 7L, or 8L, to determineifat least one of the biomarkers SUMMARY OF THE INVENTION listed in any one of Tables 4H-1, 7L, or 8L is identified in the [0009] The present invention is based on the discovery of biological sample, wherein identification of at least one of the biomarkers useful for diagnosing and monitoring neuropsy biomarkers in the biological sample indicates a positive diag chiatric diseases. Neuropsychiatric diseases which may be nosis or is indicative of Neurologic Lyme disease. In an diagnosed or monitored using the biomarkers of the invention embodiment thereof, the at least one biomarker identified in include, without limitation: multiple sclerosis (especially the biological sample is present in the biological sample and focused on first attack multiple sclerosis), Neurologic Lyme set forth in Table 4H-1 or 7L and the presence of the at least Disease, and Chronic Fatigue Syndrome. Biomarkers identi one biomarker indicates a positive diagnosis or is indicative fied for such neuropsychiatric diseases are listed herein in of Neurologic Lyme disease. In another embodiment, the at Tables 1m, 2m, 3, 4H-m, 4H-1, 4H-c, 5c, 6c, 7L, 8L, 9, and least one biomarker identified in the biological sample is 10. As indicated in the tables presented herein, the presence or absent from the biological sample and set forth in Table 8L absence of at least one biomarker in a biological sample and the absence of the at least one biomarker indicates a isolated from a patient is indicative of a positive diagnosis of positive diagnosis or is indicative of Neurologic Lyme dis a neuropsychiatric disease. As indicated herein, the identifi €3Sè. cation of a plurality of biomarkers correlated with a particular [0013] The method may further comprise analyzing the disease may strengthen the confidence level of the diagnostic biological sample for expression of a second panel of biom prediction. Biomarkers identified herein have also been arkers, wherein the second panel of biomarkers is set forth in assessed using software programs (such as, e.g., Ingenuity any one of Tables 4H-c, 5c, or 6c, to determine if at least one Pathway Analysis) to identify metabolic pathways implicated of the biomarkers listed in any one of Tables 4H-c, 5c, or 6c is in disease etiology, maintenance, and/or progression. Mul identified in the biological sample, wherein identification of tiple hits in a particular metabolic pathway underscore the at least one of the biomarkers in the biological sample indi potential importance of the pathway for the disease and direct cates a positive diagnosis or is indicative of Chronic Fatigue therapeutic intervention toward appropriate modulation of Syndrome. In an embodiment thereof, the at least one biom SãIIlê. arker identified in the biological sample is present in the [0010] Accordingly, the present invention is directed to a biological sample and set forth in Table 4H-c or 5c and the method for diagnosing a neuropsychiatric disease in a patient, presence of the at least one biomarker indicates a positive wherein said method comprises isolating a biological sample diagnosis or is indicative of Chronic Fatigue Syndrome. In from the patient and analyzing the biological sample to deter another embodiment, the at least one biomarker identified in mine if at least one of the biomarkers indicative of the pres the biological sample is absent from the biological sample ence of the neuropsychiatric disease is identified in the bio and set forth in Table 6c and the absence of the at least one logical sample, thereby diagnosing the neuropsychiatric biomarker indicates a positive diagnosis or is indicative of disease in the patient. As described herein, the presence or Chronic Fatigue Syndrome. absence of at least one biomarker in a biological sample [0014] In yet another aspect, a method for diagnosing Neu isolated from a patient is indicative of a positive diagnosis of rologic Lyme disease in a patient is presented, the method a neuropsychiatric disease. comprising: a) isolating a biological sample from the patient; [0011] In another aspect, a method for diagnosing multiple and b) analyzing the biological sample for expression of a sclerosis in a patient is presented, the method comprising: a) panel of biomarkers, wherein the panel of biomarkers is set isolating a biological sample from the patient; and b) analyz forth in any one of Tables 4H-1, 7L, or to determine if at least ing the biological sample for expression of a panel of biom one of the biomarkers listed in any one of Tables 4H-1, 7L, or arkers, wherein the panel of biomarkers is set forth in any one 8L is identified in the biological sample, wherein identifica of Tables 1m, 3m, 4H-m or 2m, to determine if at least one of tion of at least one of the biomarkers in the biological sample the biomarkers listed in any one of Tables 1m, 3m, 4H-m or indicates a positive diagnosis or is indicative of Neurologic Table 2m is identified in the biological sample, wherein iden Lyme disease in the patient. In an embodiment thereof, the at US 2013/0237454 A1 Sep. 12, 2013

least one biomarker identified in the biological sample is [0018] In a particular embodiment thereof, a method is present in the biological sample and set forth in Table 4H-1 or presented for diagnosing a neuropsychiatric disease in a 7L, and the presence of the at least one biomarker indicates a patient, wherein the patient exhibits clinical symptoms com positive diagnosis or is indicative of Neurologic Lyme dis mon to both Chronic Fatigue Syndrome and Neurologic ease. In another embodiment, the at least one biomarker iden Lyme disease, the method comprising: a) isolating a biologi tified in the biological sample is absent from the biological cal sample from the patient; b) analyzing the biological sample and set forth in Table 8L and the absence of the at least sample to evaluate expression levels of the biomarkers listed one biomarker indicates a positive diagnosis or is indicative in Table 9 to determine a first level of at least one of the of Neurologic Lyme disease. biomarkers indicative of the presence of the neuropsychiatric disease in the biological sample; and c) comparing the first [0015] In yet another aspect, a method for diagnosing level of the at least one of the biomarkers to a second level of Chronic Fatigue Syndrome in a patient is presented, the the at least one of the biomarkers determined for a subject, method comprising: a) isolating a biological sample from the wherein the subject does not have the neuropsychiatric dis patient; and b) analyzing the biological sample for expression ease, and wherein at least a two-fold difference in the ratio of of a panel of biomarkers, wherein the panel of biomarkers is the first level to the second level indicates a positive diagnosis set forth in any one of Tables 4H-c, 5c, or 6c, to determine if of the neuropsychiatric disease. In an embodiment thereof, at least one of the biomarkers listed in any one of Tables 4H-c, the diagnosis is directed to determining if the patient has 5c, or 6c is identified in the biological sample, wherein iden Chronic Fatigue Syndrome or Neurologic Lyme disease. In a tification of at least one of the biomarkers in the biological particular embodiment, the at least a two-fold difference is at sample indicates a positive diagnosis or is indicative of least a two-fold increase or at least a two-fold decrease. In Chronic Fatigue Syndrome in the patient. In an embodiment another particular embodiment, the subject is a healthy sub thereof, the at least one biomarker identified in the biological ject. sample is present in the biological sample and set forth in [0019) Also encompassed herein are kits for diagnosing Table 4H-c or 5c, and the presence of the at least one biom neuropsychiatric diseases. In a particular aspect, a kit for arkerindicates a positive diagnosis oris indicative of Chronic diagnosing multiple sclerosis is presented, wherein the kit Fatigue Syndrome. In another embodiment, the at least one comprises probes (e.g., antibodies or fragments orderivatives biomarker identified in the biological sample is absent from thereof) for detecting expression of at least one biomarker the biological sample and set forth in Table 6c and the absence listed in Table 1m, 3m, 4H-m, or Table 2m, wherein detect of the at least one biomarker indicates a positive diagnosis or able expression of at least one biomarker listed in Table 1m, is indicative of Chronic Fatigue Syndrome. 3m, or 4H-m is indicative of a positive diagnosis of multiple [0016] In accordance with the methods described herein, sclerosis and wherein an absence of detectable expression of the biological sample may be cerebrospinal fluid, blood or a at least one biomarker listed in Table 2m is indicative of a component thereof (e.g., plasma, serum, cells), tissue or tis positive diagnosis of multiple sclerosis. sue-related fluids, urine, or saliva. [0020] In another aspect, a kit for diagnosing Chronic [0017| Also encompassed herein is a method for diagnos Fatigue Syndrome is presented, wherein the kit comprises ing a neuropsychiatric disease, the method comprising: a) probes (e.g., antibodies or fragments or derivatives thereof) isolating a biological sample from the patient; b) analyzing for detecting expression of at least one biomarker listed in the biological sample to determine a first level of at least one Table 4H-c, 5c, or Table 6c, wherein detectable expression of of the biomarkers indicative of the presence of the neuropsy at least one biomarker listed in Table 4H-c or 5c is indicative chiatric disease in the biological sample; and c) comparing of a positive diagnosis of Chronic Fatigue Syndrome and the first level of the at least one of the biomarkers to a second wherein an absence of detectable expression of at least one level of the at least one of the biomarkers determined for a biomarker listed in Table 6c is indicative of a positive diag subject, wherein the subject does not have the neuropsychi nosis of Chronic Fatigue Syndrome. atric disease, and wherein at least a two-fold difference in the [0021] In yet another aspect, a kit for diagnosing Neuro ratio of the first level to the second level indicates a positive logic Lyme Disease is presented, wherein the kit comprises diagnosis of the neuropsychiatric disease. In a particular probes (e.g., antibodies or fragments or derivatives thereof) embodiment, the at least two-fold difference is an increase, for detecting expression of at least one biomarker listed in which is indicative of a positive diagnosis of the neuropsy Table 7L or Table 8L, wherein detectable expression of at chiatric disease. In an alternative embodiment, the at least least one biomarker listed in Table 7L is indicative of a posi two-fold difference is a decrease, which is indicative of a tive diagnosis of Neurologic Lyme Disease and wherein an positive diagnosis of the neuropsychiatric disease. As absence of detectable expression of at least one biomarker described herein, in certain circumstances the subject is a listed in Table 8L is indicative of a positive diagnosis of healthy subject. In accordance with the invention, the subject Neurologic Lyme Disease. may have a second neuropsychiatric disease, wherein the [0022] As described herein, the kits embodied herein may second neuropsychiatric disease differs from the neuropsy comprise probes for detecting expression of at least 2, 3, 4, 5, chiatric disease for which the instant method is diagnostic. 6, 7, 8, 9, 10, 15, 20, 25, or 30 of the biomarkers listed in any Under such a circumstance, the two-fold difference in the one of Tables 1m, 3m, 4H-m, 2m, 4H-c, 5c, 6c, 7L or 8L, ratio may be used to confer a differential diagnosis between wherein the number of biomarkers listed in any one of Tables the neuropsychiatric disease for which the instant method is 1 m, 3m, 4H-m, 2m, 4H-c, 5c, 6c, 7L or 8L establishes the diagnostic and the second neuropsychiatric disease. This is a upper limit of biomarkers detected by the kit. In other words, particularly useful feature of the present method when the each of the Tables encompasses a maximum number of biom clinical presentation for the neuropsychiatric disease for arkers as indicated therein and the number of biomarkers which the instant method is diagnostic and the second neu listed in the Tables may differ between each Table. In a ropsychiatric disease is similar. particular embodiment, a kit may comprise probes for detect US 2013/0237454 A1 Sep. 12, 2013

ing expression of all of the biomarkers listed in any one of [0026] In one embodiment, the present invention relates to Tables 1m, 3m, 4H-m, 2m, 4H-c, 5c, 6c, 7L or 8L. In particu the identification and use of biomarkers in methods for diag lar embodiments, the probes may be immobilized on a solid nosing multiple sclerosis, particularly diagnosis offirst attack surface. multiple sclerosis. The invention also pertains to the use of [0023] In another aspect, the invention is directed to a these biomarkers in methods for assessing relapse of multiple method for monitoring efficacy of a treatment for a neurop sclerosis patients and disease progression in multiple sclero sychiatric disease in a patient, wherein said method com sis patients. Biomarkers identified in accordance with the prises isolating a first biological sample from the patient prior invention are also useful for identifying treatments for and to initiating the treatment and isolating a second biological monitoring efficacy of treatment of patients with multiple sample from the patient after initiating the treatment, analyz sclerosis. As shown herein, the inventors have identified a ing the biological samples to determine the level of at least plurality of biomarkers whose presence is indicative of mul one of the biomarkers indicative of the presence of the neu ropsychiatric disease in the first and second biological tiple sclerosis; such biomarkers are listed in Tables 1m, 3m, or samples, and comparing the level of the at least one of the 4H-m. The inventors have also identified a plurality of biom biomarkers in the first and second biological samples, arkers whose absence is indicative of multiple sclerosis; such wherein a change in the level of the at least one of the biom biomarkers are listed in Table 2m. arkers reflects the efficacy of the treatment. In one embodi In another embodiment, the present invention relates to the ment, wherein the presence of the at least one biomarker is identification and use of biomarkers in methods for diagnos associated with a positive diagnosis or presence of the dis ing chronic fatigue syndrome (CFS) in patients. Biomarkers ease, a detectable reduction in the level of the at least one identified in accordance with the invention are also useful for biomarker following initiating the treatment indicates that the identifying treatments for and monitoring efficacy of treat treatment is efficacious. In another embodiment, wherein the ment of patients with CFS. As shown herein, the inventors absence of the at least one biomarker is associated with a have identified a plurality of biomarkers whose presence is positive diagnosis or presence of the disease, a detectable indicative of CFS, such biomarkers are listed in Table 4H-c, increase in level in the at least one biomarker following ini and 5c. The inventors have also identified a plurality of biom tiating the treatment indicates that the treatment is effica arkers whose absence is indicative of CFS, such biomarkers C10'llS. are listed in Table 6c. [0024] In another aspect, the invention is directed to a method for monitoring disease progression of a neuropsychi [0027] In yet another embodiment, the present invention atric disease in a patient, wherein said method comprises relates to the identification and use of biomarkers in methods isolating a first biological sample from the patient at an initial for diagnosing Neurologic Lyme disease in patients. Biom or first temporal window and isolating a second biological arkers identified in accordance with the invention are also sample from the patient at a later (e.g., second) temporal useful for identifying treatments for and monitoring efficacy window, analyzing the biological samples to determine the of treatment of patients with Neurologic Lyme disease. As level of at least one of the biomarkers indicative of the pres shown herein, the inventors have identified a plurality of ence of the neuropsychiatric disease in the first and second biomarkers whose presence is indicative of Neurologic Lyme biological samples, and comparing the level of the at least one disease; such biomarkers are listed in Table 7L. The inventors of the biomarkers in the first and second biological samples, have also identified a plurality of biomarkers whose absence wherein a change in the level of the at least one of the biom is indicative of Neurologic Lyme disease; such biomarkers arkers in the first and second biological samples reflects pro are listed in Table 8L. gression of the disease. In one embodiment, wherein the [0028. Also encompassed herein are diagnostic signatures presence of the at least one biomarker is associated with a for neuropsychiatric diseases. Such diagnostic signatures positive diagnosis or presence of the disease, a detectable comprise biomarkers for diagnosing a neuropsychiatric dis increase in the level of the at least one biomarker at the later ease, wherein the presence or absence of at least one biom temporal time window relative to the initial temporal window arker indicates a positive diagnosis of the neuropsychiatric indicates that the disease has progressed or worsened. In disease. In particular aspects, the diagnostic signature is another embodiment, wherein the absence of the at least one indicative of multiple sclerosis, Chronic Fatigue Syndrome, biomarker is associated with a positive diagnosis or presence or Neurologic Lyme Disease. In a particular embodiment, the of the disease, a detectable decrease in the level of the at least diagnostic signature relates to the presence of at least one one biomarker at the later temporal time window relative to biomarker listed in Table 1m, 3m, or 4H-mandis indicative of the initial temporal window indicates that the disease has a positive diagnosis of multiple sclerosis. In another embodi improved. ment, the diagnostic signature relates to the absence of at least [0025] The present invention is, moreover, directed to a one biomarker listed in Table 2m and is indicative of a posi method for diagnosing a neuropsychiatric disease in a patient, tive diagnosis of multiple sclerosis. In yet another embodi wherein said method comprises visualizing or detecting at ment, the diagnostic signature relates to the presence of at least one of the biomarkers indicative of the presence of the least one biomarker listed in Table 4H-c or 5c and is indicative neuropsychiatric disease in the patient, thereby diagnosing of a positive diagnosis of Chronic Fatigue Syndrome. In a the neuropsychiatric disease in the patient. As described further embodiment, the diagnostic signature relates to the herein, the presence or absence of at least one biomarker in a absence of at least one biomarker listed in Table 6c and is patient is indicative of a positive diagnosis of a neuropsychi indicative of a positive diagnosis of Chronic Fatigue Syn atric disease. In accordance with such an embodiment, vari drome. In another embodiment, the diagnostic signature ous detection imaging techniques may be utilized including, relates to the presence of at least one biomarker listed in Table but not limited to, magnetic resonance imaging (MRI), 7L and is indicative of a positive diagnosis of Neurologic positron emission tomography (PET), and CAT scans. Lyme Disease. In yet another embodiment, the diagnostic US 2013/0237454 A1 Sep. 12, 2013

signature relates to the absence of at least one biomarker al. [(2008) J Proteome Res 7: 386-399), using LC-MS/MS, listed in Table 8L and is indicative of a positive diagnosis of reported 798 proteins in a pool of 6 patients with neurologic Neurologic Lyme Disease. complaints that warranted a lumbar puncture, but whose sub sequent clinical CSF laboratory values were reported as nor BRIEF DESCRIPTION OF THE DRAWINGS mal; for the purposes of this application these types of [0029] FIG. 1 shows a Venn diagram revealing the amount patients as referred to as neurologic surrogate-normals. A of overlap of the present dataset with a comparable dataset of notable exception to use of surrogates was the work by Zhang proteins detected in the CSF of “normal clinical value” or et al. [(2005) Neurobiol Aging 26: 207-227], who used “neurologic surrogate-normal” individuals who required a 2D-LC-MS/MS to identify 315 proteins in pools of CSF lumbarpuncture for clinical reasons as reported by Zougman comparing healthy younger versus older individuals. Subse et al. [(2008) J Proteome Res 7: 386-399). The large circle quently, with Xu et al. [(2006) Int Rev Neurobiol 73:29-98], represents the 2630 proteins observed in the present compre they analyzed CSF from the younger group with two different hensive dataset of proteins detected in the CSF of normal LC-MS/MS platforms and identified a combined total of 915 individuals. The small circle represents the 798 proteinsiden proteins. Pan et al., reported a total of 2594 CSF protein tified in the analysis by Zougman et al. [(2008) J Proteome identifications from different combined (cumulative) results Res 7: 386-399). of several CSF studies with a focus on neurodegenerative diseases such as Alzheimer’s disease [(2007) Proteomics 7: DETAILED DESCRIPTION OF THE INVENTION 469-473]. [0030] The present inventors had a unique opportunity to [0032] Towards the principal purpose of establishing a generate what may be the most comprehensive database of comprehensive list or proteome of normal CSF, the present true normal CSF proteins to date. The inventors were able to inventors have prepared CSF samples from healthy normal do this because they had sufficient numbers and total volume people for analysis by using immunoaffinity depletion of of true normal CSF samples to employ immunoaffinity deple abundant proteins (with masking potential) to enhance cov tion, followed by extensive fractionation and high-resolution erage and detection of low abundance proteins [Qian et al. liquid chromatography (LC) separation and mass spectrom (2009).JProteome Res 8:290–299]. It is noteworthy that the etry (MS) analysis. The combination of the normal CSF present inventors also analyzed the abundant sample fraction samples, including a set of serial CSF samples, and advanced in parallel. Samples were then analyzed employing high technology contribute to the uniqueness and value of the throughput, high sensitivity, and high resolution nanocapil present study. Knowledge as to the normal CSF proteome, in lary liquid chromatography-mass spectrometry (LC-MS turn, makes possible a meaningful comparison with disease [Petyuket al. (2007) Genome Res 17:328-336] and LC-MS/ proteomes (i.e., proteomes characteristic of a particular dis MS [Qian et al. (2009) J Proteome Res 8: 290–299]). Pre ease). fractionation (immunoaffinity depletion chromatography) [0031] Until recently, technological limitations have pre and ultra-high resolution nanocapillary LC separations were vented full characterization of the CSF proteome. Compre used to effectively reduce the sample complexity and concen hensive analysis of CSF has been challenged by low protein tration dynamic range (thereby reducing or eliminating the levels (0.3 to 0.7 mg/ml) compared to plasma, protein con “masking” effect [Ramstrom et al. (2005) J Proteome Res 4: centration variability up to twelve orders of magnitude, 410-416]), high efficiency ion transmission technologies potential masking of brain-specific proteins by highly abun (e.g., electrodynamic ion funnel [Shaffer et al. (1997) Rapid dant proteins [Rozek et al. (2007) J Proteome Res 6: 4189 Commun Mass Spectrom 11: 1813-1817]) for highly sensi 4199], and limited access to an adequate number of appropri tive global MS analysis, and the accurate mass and time ate biological samples. Despite some of these limitations, a (AMT) tag strategy [Smith et al. (2002) Proteomics 2: 513 number of earlier studies have provided increasing levels of 523] for high-throughput analysis (e.g. of individual CSF characterization of the CSF proteome. For the most part, these samples) and accurate quantitation. The general approach for studies have used pooled samples from patient populations AMT tag generation and application as described herein has with diseases or from people with normal CSF clinical labo been successfully implemented for whole microbial [Lipton ratory values (chemistries, cell counts, and microbiology) et al. (2002) Proc Natl AcadSci USA 99: 11049-11054] and who underwent lumbar puncture for investigation of neuro mammalian tissue [Petyuk et al. (2007) Genome Res 17: logical complaints. These CSF samples were used as substi 328-336] and plasma proteomes [Qian et al. (2009) J Pro tutes or surrogates for true normals (healthy volunteers) pos teome Res 8:290–299; Qianetal. (2005) Mol Cell Proteomics sibly due to lack of availability of such normal CSF samples. 4:700-709), but has not been previously applied to CSF from Sickmannet al., [(2000) Electrophoresis 21:2721-2728] used normal subjects. two-dimensional polyacrylamide gel electrophoresis (2D [0033] As described herein, pooled CSF isolated from 11 PAGE) followed by mass spectrometry (MS) to identify close normal healthy volunteers (8 women and 3 men, aged 24 to to 70 CSF proteins. Yuan et al., [(2005) Proteomics 5:541 55, median–28 years) who reported their health as excellent 550] used matrix-assisted laser desorption ionization or good and were taking no medications was examined. Stan (MALDI) MS to identify 22 proteins indesalted CSF. Wenner dard clinical laboratory testing on their CSF was normal et al., [(2004) J Proteome Res 3: 97-103] used 2D liquid (none had more than 3 white blood cells/mm” and protein chromatography (LC) coupled to tandem mass spectrometry levels ranged from 14 to 40 mg/dl with a median of 25 mg/dl). (2D-LC-MS/MS) to identify 249 proteins in pooled CSF. Also examined were pairs of individual serial CSF samples, Maccarrone et al. [(2004) Electrophoresis 25: 2402-2412]: obtained at least 4 weeks apart, from 10 additional normal used immunodepletion techniques and shotgun LC-MS/MS, healthy volunteers to assess the potential variability of par to identify more than 100 proteins in CSF from a patient with ticular CSF protein levels in an individual from one time point normal pressure hydrocephalus. More recently Zougman et to another. US 2013/0237454 A1 Sep. 12, 2013

[0034] To illustrate the utility of such a normal database and 907-11), which are namely: Relapsing-Remitting multiple how one clinical condition might be compared to another the sclerosis (RRMS), Primary Progressive multiple sclerosis present inventors also analyzed and compared one set of CSF (PPMS), Secondary-Progressive multiple sclerosis (SPMS), samples to another set processed in the same mannerto evalu Progressive-Relapsing multiple sclerosis (PRMS). ate, among other issues, if there might be significant differ [0040] According to the present invention, the term “Neu ences among different surrogate-normal groups. rologic Lyme Disease” is used to describe a range of neuro [0035) In summary and as described in greater detail herein logic or psychiatric manifestations that may be associated below, the present inventors applied immunoaffinity separa with Lyme disease. As referred to herein, “Neurologic Lyme tion and high sensitivity and resolution liquid chromatogra Disease” encompasses the range from an acute neurologic phy-mass spectrometry to examine CSF from healthy normal syndrome in an acute case of active Lyme Disease and late individuals. 2630 proteins in CSF from normal subjects were manifestation of Lyme disease (both sometimes referred to as identified, of which 56% were CSF-specific (i.e., as deter neuroborreliosis), to the more poorly defined post-treatment mined using the techniques described herein), not found in Lyme disease syndrome and “chronic Lyme Disease” the much larger set of 3654 proteins identified in plasma. The [0041] According to the present invention, the term above-mentioned 2630 proteins identified in normal subjects “Chronic Fatigue Syndrome” is used to describe a constella were identified with high confidence, meaning that two or tion of symptoms including fatigue that approach those more peptides corresponding to a particular protein were described in the 1994 proposed case definition [Fukuda et al. required as confirmation that the particular protein was, Annals of Internal Medicine, Vol. 121, Dec. 15, 1994, pp. indeed, present in normal CSF. The present inventors also 953-959] that are subject to revision. In practice it is often a examined CSF from groups like those of subjects previously clinical diagnosis of exclusion. examined by others as surrogates for normals, where neuro [0042] As used herein, the terms “patient” or “subject” are logic symptoms warranted a lumbarpuncture but where clini used interchangeably. Such patients may have a neuropsychi cal laboratory were reported as normal. Statistically signifi atric disease or disorder, such as multiple sclerosis, CFS, and cant differences between their CSF proteins and those Neurologic Lyme Disease. With respect to multiple sclerosis, determined for non-neurological normals examined herein for example, the terms “multiple sclerosis patient”, “a subject were noted. The inventors also examined CSF from 10 vol who has multiple sclerosis”, “a patient who has multiple unteer subjects who had lumbar punctures at least 4 weeks sclerosis”, “a multiple sclerosis subject”, and similar phrases, apart and found that there was little variability in CSF pro are intended to refer to subjects who have been diagnosed teins in an individual as compared from subject to subject. with multiple sclerosis. [0036] The present results represent the most comprehen [0043] The terms “healthy subject” or “normal subject”, sive characterization of true normal CSF to date. This normal and similar phrases, are intended to refer to a subject who has CSF proteome establishes a comparative standard and basis not been diagnosed with a neuropsychiatric disease or disor for investigations into a variety of diseases with neurological der. A healthy subject has no other acute systemic disease or, and psychiatric features. With this essential information, the at the least, has no detectable acute systemic disease. With present inventors were able to identify biomarkers diagnostic respect to aspects of the invention directed to, for example, for a number of neuropsychiatric diseases. See Examples multiple sclerosis, the terms “healthy subject”, “non-multiple I-IV. sclerosis subject”,33 “a& 4 subject who does not have multiple [0037] Accordingly, the present invention encompasses sclerosis”, “a patient who does not have multiple sclerosis”, identification of biomarkers diagnostic for a number of neu and similar phrases, are intended to refer to a subject who has ropsychiatric diseases. As indicated in each of Tables 1-10, not been diagnosed with multiple sclerosis. the present inventors have identified biomarkers, whose pres [0044] As used herein, the term “patient” or “subject” may ence or absence as indicated herein is a positive indicator of refer to a mammal, including a human. the presence of a neuropsychiatric disease in a patient. Thus, [0045] As used herein, the term “biological sample” the presence or absence of at least one biomarker for a neu includes a sample of any cell type or from any tissue or body ropsychiatric disease serves as a diagnostic tool for clinicians. fluid, body fluids including, but not limited to: cerebrospinal It is understood that a clinician will evaluate a patient as a fluid (CSF), blood (whole blood, serum, plasma, or cellular whole based on known criteria wellestablished in the field for components), saliva, urine, prostatic fluid, or fluid from any diagnosis of a neuropsychiatric disease and utilize the diag suitable tissue. In a particular embodiment, the biological nostic method of the present invention in conjunction with sample is CSF. In another embodiment, the biological sample such known diagnostic criteria to establish a definitive diag is blood or any component of blood (e.g., serum, plasma, Il QS1S. cells, etc.). [0038] According to the present invention, the term “neu [0046] The term “protein” is used herein to mean protein, ropsychiatric diseases” refers to, without limitation, multiple polypeptide, oligopeptide or peptide. The terms “biologic sclerosis and in particular first attack or early multiple scle marker”, “biomarker” or “disease-associated protein” are rosis, Neurologic Lyme Disease, Chronic Fatigue Syndrome, used herein to refer to proteins associated with specific dis and other diseases with similar features that may place them eases or conditions, including proteins from organs or tissues in the differential diagnosis in evaluating a patient. (“organ-specific” or “tissue-specific” proteins) affected by a [0039] According to the present invention, the term “mul disease or condition. In accordance with the present inven tiple sclerosis” is used to describe the art-recognized disease tion, the presence or absence of a biomarker is positively characterized by inflammation, demyelination, oligodendro correlated with, indicative of of diagnostic for the presence cyte death, membrane damage, other neurologic damage, and of a disease or condition, such as a neuropsychiatric disease, axonal death. Multiple sclerosis can be characterized as one in a patient. Also in accordance with the present invention, a of four main varieties as defined in an international survey of relative increase in levels of a particular biomarker or biom neurologists (Lublin and Reingold, 1996, Neurology 46(4): arkers as compared to a control or normal subject can also be US 2013/0237454 A1 Sep. 12, 2013 positively correlated with, indicative of, or diagnostic for the change or a long term change, in a percent of the biomarkers presence of a disease or condition, such as a neuropsychiatric listed in any one of the Tables described herein. disease, in a patient. [0051] Representative permutations of biomarkers and/or [0047] The present invention, furthermore, encompasses a biomarker signatures are presented herein below for illustra plurality of biomarkers or a “biomarker signature” that is tive purposes. Based on the methods described herein, a bio positively correlated with, indicative of, or diagnostic for the logical sample isolated from a subject may be determined to presence of a disease or condition, such as a neuropsychiatric exhibit any one of the following biomarker signatures, which disease, in a patient. Accordingly, the presence or absence of are set forth in exemplary fashion, and are not to be viewed as a biomarker signature is positively correlated with, indicative limiting. a+; a-; a+, b+, c.4-, or a+, b–, c.4: wherein of, or diagnostic for the presence of a disease or condition, a”-specific protein “a”, “b”=specific protein “b”, such as a neuropsychiatric disease, in a patient. A biomarker “c”=specific protein “c”, etc. and “4” indicates that the pro signature may also encompass a plurality of biomarkers that tein is present or quantitatively increased relative to subjects exhibit a relative increase or decrease in levels as compared to without disease, which could be clinically normal or could a healthy or normal subject (e.g., a control subject) and is have a different disease (e.g., a different disease having over positively correlated with, indicative of, or diagnostic for the lapping clinical symptoms which is, therefore difficult to presence of a disease or condition, such as a neuropsychiatric distinguish) and “-" indicates that the protein is absent or disease, in a patient. quantitatively decreased relative to subjects without disease, [0048] A skilled practitioner would, moreover, appreciate which could be clinically normal or could have a different that the presence or absence of a particular protein in a sample disease (e.g., a different disease having overlapping clinical may be weakly indicative of disease, but not diagnostic, if symptoms which is, therefore difficult to distinguish). noted as a single determinant. If, however, a plurality of such [0052] For example, the easiest identification of a protein single determinants are noted in a biological sample, the biomarker is the presence of a protein associated with a dis combined detection of several weakly indicative determi ease or condition and not with other conditions that might be nants may serve to identify a strong combinatorial diagnostic clinically confused with the disease under consideration. indicator of disease. Furthermore, the single protein/determi Variations to this scenario include the situation wherein a nant need not even approach the threshold of weak diagnostic biomarker is present in an increased quantity or a decreased by itself but in combination with the detection or absence of quantity compared to other conditions or controls. Although detection of another protein or proteins may serve as a strong not a protein biomarker, an example of this is the presence of combinatorial diagnostic indication of a disease state. glucose in the blood in high quantities in diabetics compared Accordingly, also encompassed herein are combinatorial to normal individuals who still have glucose present but not in diagnostic indicators that are associated with a particular elevated quantities. Another variation to the first scenario is disease and not observed in healthy subjects or patients with where the functional biomarker is not just one protein but two other diseases. or more in combination that can be present or absent or [0049] Accordingly, selected sets of one, two, three, and quantitatively different, wherein the ensemble defines its more of the biomarkers of this invention (up to the number biomarker potential. equivalent to all of the biomarkers, including any intervening [0053] In some embodiments, a biomarker of the invention number, in whole number increments, e.g., 1, 2, 3, 4, 5, 6 . . . is a member of a biological pathway. As used herein, the term ) can be indicative of a positive diagnosis or used as diagnos “precursor” or “successor” refers to molecules that precede or tic indicators for methods and/or kits described herein. In one follow the biomarker in the biological pathway. Thus, once a embodiment, larger numbers of the biomarkers identified biomarker is identified as a member of one or more biological herein are used in methods or kits of the invention, since the pathways, the present invention can include additional mem accuracy of the method or kit may improve as the number of bers of the biological pathway that come before (are upstream biomarkers screened increases. With respect to aspects of the of or a precursor of) or follow (are downstream of) the biom invention pertaining to evaluating therapeutic efficacy, the arker. Such identification of biological pathways and their methods and kits of the present invention include evaluating members is within the skill of one in the art. whether administration of a therapeutic composition causes a [0054] Also encompassed herein is the analysis of biomar change, eithera transient change or alongterm change, in one kers identified and listed in the tables presented herein to or more of the biomarkers; in two or more of the biomarkers; identify metabolic pathways implicated in the pathogenesis, in three or more of the biomarkers; in four or more of the maintenance, and/or progression of a disease. Such analyses biomarkers; in five or more of the biomarkers, in six or more may utilize a variety of software programs, including but not of the biomarkers, etc. limited to the commercially available Ingenuity Pathway [0050] Also envisioned are sets of at least 1%, 2%, 5%, Analysis. Multiple hits in a particular metabolic pathway 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, underscore the potential importance of the pathway for the 60%. 65%, 70%, 75%, 80%, 85%, 90%. 95%, 96%, 97%, disease and direct therapeutic intervention toward appropri 98%, 99% or 100% of the biomarkers listed in any one of the ate modulation of same. Accordingly, the present methods tables presented herein, including Tables 1m, 2m, 3, 4H-m, encompass such analyses and the identification of metabolic 4H-1, 4H-c, 5c, 6c, 7L, 8L, and 9, wherein the envisioned sets pathways of potential significance in a particular disease. can be indicative of a positive diagnosis or used as diagnostic Knowing that, for example, activation of a metabolic pathway indicators for methods and/or kits described herein. With appears to be linked or associated with a particular disease respect to aspects of the invention pertaining to evaluating presents the opportunity to test pharmaceutical modulators of therapeutic efficacy, the methods and kits of the present the pathway (i.e., inhibitors) to determine if such modulators invention include evaluating whether administration of a could be used as therapeutics for treatment of patients with therapeutic composition causes a change, either a transient the disease. US 2013/0237454 A1 Sep. 12, 2013

[0055] Metabolic pathways may, for example, be associ capture the target biomarker in the biological sample being ated with several disease conditions based on a quantitative detected. The sample may be CSF or blood, etc. Variations of assessment. Examples of pathways that may be markedly this immuno-based technique may also be used such as, but involved in one condition and not another or others may also not limited to, Western blots wherein a sample comprising a be found. As a specific illustrative example, a comparison of biomarker is transferred to a membrane and then subse Chronic Fatigue Syndrome (CFS) to Neurologic Post Treat quently allowed to interact with specific antibodies that are ment Lyme disease syndrome (nRTLS), when individual coupled to an enzyme (later to be exposed to a substrate that patient samples were analyzed, revealed that four compo permits colorimetric visualization) or fluorescent material ments (CIS, C4B, C10B, C10C) associated with activation of that permit visualization of one or more of the components or the complement cascade were differentially increased in subcomponents (such as antigens) of the target biomarker. abundance consistently across the nPTLS patients compared Alternatively, a non-coupled antibody can be used first and to CFS. In another example, a comparison between CFS and then a second antibody directed to this antibody, which has an nPTLS patiente, looking at the pooled results, revealed that enzyme or fluorescent tag attached thereto, can be used in a the CDK5 signaling pathway was significantly enriched for sandwich-like fashion. Another variation of this protein cap proteins identified only in the pooled CFS proteome. This turing technique could be multiplexing of several target signaling pathway has been linked to Parkinson’s (Smith et biomarkers by using beads coated with multiple antibodies al. 2003. Proc. Natl. Acad. Sci. 100:13650) and Alzheimer’s such as in the Luminex platform. diseases (Lew et al. 1994. Nature 371:423). Another example [0059] In another embodiment, once a disease protein/pep is related to pathways that are involved in two conditions, that tide biomarker is identified subsequent research may demon is, common to both but decreased in abundance in the two strate that the body of disease subjects makes antibodies to the disease conditions of CFS and nPTLS, compared to normal, biomarker or biomarkers and the normal or other disease but at different levels. Quantitative distinguishing differences subject are negative for same. Under such circumstances, the could still be found between the two conditions. A specific presence of antibodies for a disease protein/peptide biomar example relates to networks relevant to neurological function, ker is indicative of disease. Experimentally, the presence of such as axonal guidance, where the proteins in CFS were such disease specific antibodies is determined by using the further decreased relative to nPTLS. disease protein/peptide biomarker as a binding target for the [0056] Also envisioned are panels of biomarkers compris antibodies. This is a common indirect strategy for detection of ing at least 1%, 2%. 5%, 10%, 15%, 20%, 25%, 30%, 35%, infectious disease where the presence of an antibody indi 40%, 45%, 50%, 55%, 60%. 65%. 70%, 75%, 80%, 85%, cates exposure to a foreign agent and in some cases the rise in 90%. 95%, 96%, 97%, 98%, 99% or 100% of the biomarkers titers (quantity of antibodies) over a short period of time listed in any one of the tables presented herein, including indicates a very recent exposure. Tables 1m, 2m, 3, 4H-m, 4H-1, 4H-c, 5c, 6c, 7L, 8L, and 9, [0060] As used herein, a polypeptide is referred to as “iso wherein the envisioned panels can be used to assess a bio lated” when it has been removed from its natural milieu (i.e., logical sample isolated from a patient to evaluate expression that has been subject to human manipulation), and can patterns of the biomarkers of the panel, which expression include purified polypeptides, partially purified polypeptides, patterns are indicative of a positive diagnosis of a neuropsy synthetically produced polypeptides, and recombinantly pro chiatric disease as described herein. Panels of biomarkers duced polypeptides, for example. As such, “isolated” does not comprising at least one, two, three, and more of the biomar reflect the extent to which the polypeptide has been purified. kers listed in any one of Tables 1m, 2m, 3, 4H-m, 4H-1, 4H-c, [0061] According to the present invention, the phrase 5c, 6c, 7L, 8L, and 9 (up to the number equivalent to all of the “selectively binds to" refers to the ability of an antibody or biomarkers in a particular table, including any intervening antigen binding fragment thereof to preferentially bind to number, in whole number increments, e.g., 1, 2, 3, 4, 5, 6 . . . specified proteins. More specifically, the phrase “selectively ) are also envisioned herein. Any of the indicated panels may binds” refers to the specific binding of one protein to another also be used to evaluate efficacy of a therapeutic regimen. (e.g., an antibody or antigen binding fragment thereof to an [0057] Polypeptide biomarkers may be isolated by any suit antigen), wherein the level of binding, as measured by any able method known in the art. Native polypeptide biomarkers standard assay (e.g., an immunoassay), is statistically signifi can be purified from natural sources by standard methods cantly higher than the background control for the assay. For known in the art such as chromatography, centrifugation, example, when performing an immunoassay, controls typi differential solubility or immunoassay. In one embodiment, cally include a reaction well/tube that contain antibody or polypeptide and metabolite markers may be isolated from a antigen binding fragment alone (i.e., in the absence of anti biological sample using standard techniques known in the art, gen), wherein an amount of reactivity (e.g., non-specific bind for example, chromatographic methods or affinity purifica ing to the well) by the antibody or antigen binding fragment tion using substrate-bound antibodies that specifically bind to thereof in the absence of the antigen is considered to be the marker. As described herein, immunoaffinity depletion of background. Binding can be measured using a variety of abundant proteins (with masking potential) enhances cover methods standard in the art including enzyme immunoassays age and detection of low abundance proteins. As indicated (e.g., ELISA), immunoblot assays, etc.). herein above, depletion yields separate fractions that are char [0062] As used herein, the term “specifically binding.’ acterized independently. refers to the interaction between binding pairs such as an [0058] In a positively-associated example, once a protein or antibody and an antigen with an affinity constant of at most peptide is identified (including one lacking name identifica 107° moles/liter, at most 1077 moles/liter, or at most 107° tion, such as a hypothetical protein), a less expensive platform moles/liter. or assay, as compared to mass spectrometry, can be devised or [0063] The present invention includes the use of any of the adapted. The ELISA assay is such an example where an biomarkers as described herein (including genes ortheir RNA antibody to the biomarker protein/peptide can be used to or protein products), as targets for the development or iden US 2013/0237454 A1 Sep. 12, 2013

tification of therapeutic compositions and strategies for the (e.g., mRNA) of a biomarker or biomarkers listed herein is a treatment of neuropsychiatric diseases, such as for example, matter of routine practice with the nucleic acid sequence in multiple sclerosis and/or relapsing multiple sclerosis. hand as provided by publicly available websites such as those [0064] Methods to measure biomarkers of this invention, mentioned above. Such probes and primers are useful for the include, but are not limited to: Western blot, immunoblot, kits described herein. enzyme-linked immunosorbant assay (ELISA), radioimmu [0067] The present invention also includes a method to noassay (MA), immunoprecipitation, surface plasmon reso diagnose a subject as having a neuropsychiatric disease (e.g., nance, chemiluminescence, fluorescent polarization, phos multiple sclerosis, chronic fatigue syndrome, or Neurologic phorescence, immunohistochemical analysis, liquid Lyme Disease, or one that conventionally may be considered chromatography mass spectrometry (LC-MS), matrix-as among the differential diagnoses). In one embodiment, the sisted laser desorption/ionization time-of-flight (MALDI method includes the steps of analyzing a biological sample TOF) mass spectrometry, microcytometry, microarray, isolated from the subject to determine if one or more of the microscopy, fluorescence activated cell sorting (FACS), flow biomarkers listed in Tables 1m, 3m, or 4H-m is present or if cytometry, laser scanning cytometry, hematology analyzer one or more of the biomarkers listed in Table 2m is absent, and and assays based on a property of the protein including but not diagnosing multiple sclerosis, wherein the presence (Tables limited to DNA binding, ligand binding, or interaction with 1m, 3m, or 4H-m) or absence (Table 2m) of one or more of other protein partners. More particularly, high throughput, these biomarkers indicates that the subject has multiple scle high sensitivity, and high resolution nanocapillary liquid rosis. The present invention further encompasses circum chromatography-mass spectrometry (LC-MS), LC-MS/MS, stances wherein there is a change in the level/amount of a pre-fractionation (immunoaffinity depletion chromatogra biomarker of the invention and such a change may also reflect phy) and ultra-high resolution nanocapillary LC separations, the presence of multiple sclerosis or responsiveness to a high efficiency ion transmission technologies (e.g., electro therapeutic regimen. dynamic ion funnel), and the accurate mass and time (AMT) [0068] In another embodiment, the method includes the tag strategy for high-throughput analysis are described herein steps of analyzing a biological sample isolated from the sub and known in the art. ject to determine if one or more of the biomarkers listed in [0065] As described herein, the term “probe” is used to Table 4H-c, or 5c is present or if one or more of the biomar refer to an agent that specifically binds to a biomarker listed in kers listed in Table 6c is absent, and diagnosing chronic one of the tables presented herein. Suitable reagents for bind fatigue syndrome, wherein the presence (Table 4H-c or 5c) or ing with a polypeptide corresponding to a biomarker of the absence (Table 6c) of one or more of these biomarkers indi invention include antibodies, antibody derivatives, labeled cates that the subject has chronic fatigue syndrome. The antibodies, antibody fragments; and the like. The term present invention further encompasses circumstances “probe” may also be used to refer to an agent that specifically wherein there is a change in the level/amount of a biomarker binds to a nucleic acid sequence that encodes a biomarker of the invention and such a change may also reflect the pres listed in one of the tables presented herein. Suitable reagents ence of chronic fatigue syndrome or responsiveness to a forbinding to a nucleic acid (e.g., a genomic DNA, an mRNA, therapeutic regimen. a spliced mRNA, a cDNA, or the like) include complemen [0069. In a further embodiment, the method includes the tary nucleic acids. steps of analyzing a biological sample isolated from the sub [0066] In accordance with the present disclosure, the tables ject to determine if one or more of the biomarkers listed in present information with which an ordinarily skilled practi Table 7L is present or if one or more of the biomarkers listed tioner can access the amino acid sequences of the proteins in Table 8L is absent (within the limits of detection using identified herein as biomarkers, as well as nucleic acid methods and assays described herein), and diagnosing Neu sequences encoding same. A stepwise protocol for identifi rologic Lyme Disease, wherein the presence (Table 7L) or cation of the amino acid sequences listed in the tables pre absence (Table 8L) of one or more of these biomarkers indi sented herein is as follows: access one of the publicly avail cates that the subject has Neurologic Lyme Disease. The able databases such as http://www.ebi.ac.uk/IPI/IPIhelp.html present invention further encompasses circumstances or http://www.uniprot.org/ via the Internet and enter the IPI wherein there is a change in the level/amount of a biomarker number, or the protein name, or the Gene designation. For of the invention and such a change may also reflect the pres example, the first protein listed in Table 1m is designated ence of Neurologic Lyme Disease or responsiveness to a “14-3-3 protein epsilon” and the corresponding Gene desig therapeutic regimen. nation is YWHAE, and IPI designation of IPIO0000816.1. [0070] The invention includes a kit for assessing the Entering the IPI number, protein name, or Gene into one of expression and/or expression levels of at least one of the the above publicly available databases will reveal the 255 biomarkers listed in the tables presented herein, whereby amino acid sequence corresponding to “14-3-3 protein epsi detecting the expression and/or expression levels of at least lon”. The above protocol is a matter of routine practice in one of the biomarkers in a biological sample isolated from a laboratories skilled in the art and can be performed for any of patient is indicative of a positive diagnosis of the relevant the proteins listed therein. Such information may be used to disease to which the table in question pertains (e.g., MS, design probes for detection of any of the proteins listed NLD, or CFS). The kit comprises a plurality of reagents, each therein or to identify commercially available probes for of which is capable of binding specifically with a polypeptide detection of any of the proteins listed therein. Primers for (e.g., an antibody) or nucleic acid encoding same correspond detection nucleic acid sequences encoding any of the proteins ing to a biomarker of the invention, e.g., one of the proteins listed in the tables presented herein are also envisioned. Such listed in any one of the tables presented herein. Suitable primers may be used to detect expression or lack thereof of a reagents for binding with a polypeptide corresponding to a biomarker or biomarker signature of the invention. The biomarker of the invention include antibodies, antibody design of primers for detecting expression levels of RNA derivatives, labeled antibodies, antibody fragments, and the US 2013/0237454 A1 Sep. 12, 2013 like. Suitable reagents for binding to a nucleic acid (e.g., a Spectrom Rev 21: 2-15]. A fourth set, designated as neuro genomic DNA, an mRNA, a spliced mRNA, a cDNA, or the logic surrogate-normals consisted of a pool of CSF from 10 like) include complementary nucleic acids. For example, the people from Sweden with headaches (age 18-35 years; 8 nucleic acid reagents may include oligonucleotides (labeled female and 2 male) who had a lumbar puncture to investigate or non-labeled) fixed to a substrate, labeled oligonucleotides possible CNS infection, and who had normal CSF clinical not bound with a substrate, pairs of PCR primers, molecular laboratory values (hence designation surrogate-normal), was beacon probes, and the like. collected following the same protocol as the third set and [0071] The kit of the invention may optionally comprise analyzed in the same fashion as the second and third sets of additional components useful for performing the methods of normal CSF, CSF from this group was also subjected to the invention. By way of example, the kit may comprise fluids centrifugation to remove cells. CSF from this group was [e.g., phosphate buffered saline (PBS) or SSC buffer] suitable collected following the same protocol as the pool of the 200 for binding an antibody to a protein for which it is immuno non-neurological surrogate-normals. The protein concentra logically specific or for annealing complementary nucleic tions were determined by Coomassie Plus protein assay acids, one or more sample compartments, an instructional (Pierce, Rockford, Ill.) using a bovine serum albumin stan material which describes performance of a method of the dard. invention, a positive control or controls, such as panel of [0076] Immunoaffinity Depletion of 14 High-Abundance proteins corresponding one of the panels set forth in any one CSF Proteins. of the tables presented herein or a biological sample isolated [0077] A total of 18 mL of the pooled CSF sample (from the from a normal subject (a subject who does not manifest clini 11 healthy volunteers) was subjected to the separations of 14 cal symptoms of disease), or a biological sample isolated high-abundance proteins (albumin, IgG, O.1-antitrypsin, IgA, from a patient known to have the disease in questions, and the IgM, transferrin, haptoglobin, Cº-acid glycoprotein, Cº-mac like. roglobulin, apolipoprotein A-I, apolipoprotein A-II, fibrino [0072] The following protocols are provided to facilitate gen, C3 and apolipoprotein B) using a 12.7×79.0 mm Sep the practice of the present invention. proº IgV14 LC10 affinity LC column (Sigma, St Louis, Mo.) [0073] The following examples are put forth so as to pro on an Agilent 1100 series HPLC system (Agilent, Palo Alto, vide those of ordinary skill in the art with a complete disclo Calif.), followed the protocols described previously [Liu et al. sure and description of how to make and use the assay, screen (2006) Mol Cell Proteomics 5: 2167–2174]. ing, and therapeutic methods of the invention, and are not [0078] Protein Digestion. intended to limit the scope of what the inventors regard as [0079] The CSF proteins were incubated in 8 Murea and 10 their invention. Efforts have been made to ensure accuracy mMdithiothreitol at 37°C. for 60 min, followed by alkylation with respect to numbers used (e.g., amounts, temperature, with 40 mM iodoacetamide in the dark for 30 min at room etc.) but some experimental errors and deviations should be temperature. The samples were diluted 10-fold with 50 mM accounted) for. Unless indicated otherwise, parts are parts by ammonium bicarbonate (pH 8) and 1 mM CaCl2, and weight, molecular weight is average molecular weight, tem digested for 3 h at 37°C. using sequencing grade, modified perature is in degrees Centigrade, and pressure is at or near porcine trypsin (Promega, Madison, Wis.) at a trypsin/protein atmospheric. ratio of 1:50. Sample cleanup was achieved using a 1-mL SPE C18 column (Supelco, Bellefonte, Pa.) as described previ Example I ously [Liu et al. (2006) Mol Cell Proteomics 5: 1899-1913]. The final peptide concentration was determined by BCA Materials and Methods assay (Pierce). All tryptic digests were snap frozen in liquid [0074] Cerebrospinal Fluid (CSF) Specimens. nitrogen and stored at —80° C. [0075] All specimens had normal clinical laboratory values [0080] Strong Cation Exchange (SCX) Fractionation. with respect to microbiology, chemistry (including protein [0081] For tryptic digests of the IgV14 bound and flow levels), and cell counts (red blood cell were 0-10/mm” and through fractions (the first set normal CSF pool from BN), white blood cells were 0-5/mm”). Four sets of different types 300 pig of tryptic peptides from CSF samples were resus of normal CSF samples were analyzed. The first set, desig pended in 300 pull 10 mM ammonium formate, 25% acetoni nated as true (healthy) normals was comprised of pooled CSF trile and fractionated by strong cation exchange chromatog from 11 healthy normal individual volunteers from the United raphy as described previously [Liu et al. (2006) Mol Cell States (8 women and 3 men; aged 24 to 55 years with a median Proteomics 5: 1899-1913]. A total of 30 fractions were col age of 28 years) was used for the comprehensive analysis lected for each sample with each fraction being lyophilized using immunoaffinity depletion and 2D-LC-MS/MS. A sec prior to reversed-phase LC-MS/MS analysis. ond set, also true normals included pairs of serial CSF ali [0082] Reversed-Phase Capillary LC-MS/MS and LC-MS quots taken at least 4 weeks apart from 10 healthy volunteers Analysis. from the United States (age 37–44 years; 5 males and 5 [0083] The SCX fractions were analyzed using a custom females). A third set, designated as non-neurologic surrogate built automated four-column high pressure nanocapillary LC normals, was a pool of 200 subjects from Sweden (all without system coupled on-line to either a linear ion trap mass spec a neurologic or psychiatric disease, most who underwent trometer (LTQ: ThermoEisher) or a linear quadrupole ion lumbar puncture for non diagnostic reasons; over 90% were trap-orbitrap mass spectrometer (LTQ-Orbitrap, Ther undergoing spinal anesthesia in preparation for orthopedic moFisher), both modified in-house with an electrodynamic surgery (e.g. limbs-knees and hips)). Ages ranged from 16 to ion funnel [Shaffer et al. (1997) Rapid Commun Mass Spec 65 years with a median of 44 years; 50:50 female:male. They trom 11: 1813-1817|, via an electrospray ionization interface were used in the direct LC-MS analysis using the AMT tag manufactured in-house. The reversed-phase separation was approach. These samples were collected on ice and cells performed as described previously [Liu et al. (2006) Mol Cell removed by centrifugation [Bergquist et al. (2002) Mass Proteomics 5: 1899-1913]. To analyze the SCX fractions of US 2013/0237454 A1 Sep. 12, 2013 the IgV14 bound fraction, the LTQ mass spectrometer was LC-MS features measured by LTQ-Orbitrap. The filtered operated in a data-dependent MS/MS mode (m/z 400-2000) MS/MS peptide identifications obtained from the LTQ and in which a full MS scan was followed by 10 MS/MS scans. LTQ-Orbitrap analyses of CSF samples were included in an The ten most intensive precursor ions were dynamically AMT tag database with their theoretical mass and normalized selected in the order of highest intensity to lowest intensity elution time (NET; from 0 to 1) recorded. LC-MS datasets and subjected to collision-induced dissociation using a nor were then analyzed by in-house software VIPER [Monroe et malized collision energy setting of 35% and a dynamic exclu al. (2007) Bioinformatics 23: 2021-2013] that detects fea sion duration of 1 min. The heated capillary was maintained tures in mass-NET space and assigned them to peptides in the at 200°C., while the ESIvoltage was kept at 2.2 kV. The SCX AMT tag database [Zimmer et al. (2006) Mass Spectrom Rev fractions of the IgV14 flow-through fraction, which are 25: 450-482]. A 11-Da shift strategy analogous to the decoy enriched with lower abundance proteins, were analyzed by database approach used for LC-MS/MS identification of pep the LTQ-Orbitrap instrument operated in a data-dependent tides was applied for estimating the false discovery rate of the MS/MS mode with survey full scan MS spectra (m/z 400 AMT analysis as previously described [Petyuk et al. (2007) 2000) acquired in the orbitrap with resolution of 30,000 at Genome Res 17: 328-336]. A false positive rate of ~4% was m/z 400 (ion accumulation target: 1,000,000), followed by estimated for each of the LC-MS data sets. The resulting lists MS/MS of the 10 most intense ions. In the case of label-free of peptides from 2D-LC-MS/MS or direct LC-MS analysis quantitation using the unfractionated CSF samples (the sec was further analyzed by Proteinprophet software [Nesvizhs ond and third set of normal CSF and the headache CSF), the kiietal. (2003) Anal Chem 75: 4646-4658] to remove redun LTQ-Orbitrap MS was operated in the data dependent mode dancy in protein identification as described previously [Liu et with survey full scan spectra (m/z 400-2000) acquired in the al. (2006) Mol Cell Proteomics 5: 1899-1913]. orbitrap with resolution of 60,000 at m/z 400 (accumulation [0087] Data normalization and quantification of the target: 1,000,000). The six most intense ions were sequen changes in protein abundance between the normal and head tially isolated forfragmentation and detection in the linearion ache CSF samples were performed and visualized using in trap. house software DAnTE [Polpitiya et al. (2008) Bioinformat [0084] Data Analysis. ics 24: 1556-1558]. Briefly, peptide intensities from the [0085] The LTQ LC-MS/MS raw data were converted into LC-MS analyses were log 2 transformed and normalized .dta file by Extract_MSn (version 3.0) in Bioworks Cluster using a mean central tendency procedure. Peptide abun 3.2 (Thermo) and the SEQUEST algorithm (version 27 revi dances were then “rolled up” to the protein level employing sion 12) was used to independently search all the MS/MS the R-rollup method (based on trends observed at peptide spectra against the human International Protein Index (IPI) level) implemented in DAnTE. ANOVA and clustering analy database with a total of 69,731 total protein entries (Version ses were also performed using DAnTE. Gene ontology anno 3.40, released at Feb. 7, 2008). The search parameters used tation was performed using a software tool STRAP [Bhatia et were: 3-Da tolerance for precursor ion masses and 1-Da tol al. (2009) Anal Chem 81: 9819-9823]. The final distribution erance for fragmention masses with no enzyme restraint and charts were generated using Excel. a maximum of 2 missed tryptic cleavages. Static carboxya midomethylation of cysteine and dynamic oxidation of Results methionine were used during the database search. LTQ-Or [0088] A comprehensive analysis of the CSF proteome bitrap MS/MS data were first processed by an in-house soft from healthy normal individuals is described herein and pre ware DeconMSn [Mayampurathet al. (2008) Bioinformatics sents the foundation for future investigation on this biological 24: 1021-1023] to accurately determine the monoisotopic fluid which may be highly reflective of the status of the brain mass and charge state of parentions, followed by SEQUEST and central nervous system. The results described herein search against the IPI database in the same fashion, except make available a comprehensive coverage of CSF proteins that 0.1-Da tolerance for precursor ion masses and 1-Da from normal healthy individuals. From the pool of 11 CSF tolerance for fragmention masses were used. A set of criteria samples from healthy volunteers, the present inventors iden considering the cross correlation score (Xcorr) and delta cor tified with high confidence a total of 19,051 tryptic peptides, relation (ACn) values along with tryptic cleavage and charge covering 2630 non-redundant proteins, with 1506 having at states were developed using the decoy database approach and least two peptide identifications. The immunoaffinity-based applied for filtering the raw data to limit false positive iden partitioning generated a separate bound fraction consisting of tifications to <1% at the peptide level [Peng et al. (2003) J the 14 most abundant proteins and their potential associated Proteome Res 2: 43-50; Elias et al. (2007) Nat Methods 4: proteins, and a flow-through fraction enriched with the less 207-214; Qian et al. (2005).JProteome Res 4:53-62]. For the abundant proteins in CSF. Similar to plasma, the bound frac LTQ-Orbitrap data, the distribution of mass deviation (from tion represents approximately 95% of the total protein mass. the theoretical masses) was first determined as having a stan Both fractions were subjected to 2D-LC-MS/MS analysis. dard deviation (a) of 2.05 part per million (ppm), and peptide [0089] The set of 2630 CSF proteins, and a comprehensive identifications with mass error of greater than 30 were filtered set of 3654 proteins from our previous plasma database [Liu out. In general, slightly lower Xcorr cutoff values were used et al. (2006) Mol Cell Proteomics 5: 1899-1913], showed when combined with ACn and the mass error constraint to very similar distribution of gene ontology terms in biological achieve the same level of false positive rate (<1%). For pep process and molecular function, but different distributions tides identified by both LTQ-Orbitrap (IgV14 flow-through with respect to cellular component: a total of approximately fraction) and LTQ (IgV14 bound fraction) analyses, the data 35% of the CSF proteins are from plasma membrane, cell base matching scores are shown only for the LTQ-Orbitrap surface or extracellular space, while blood plasma has a total analysis, along with their mass errors. of 28% of proteins in those three categories; there are also [0086] The AMT tag strategy [Smith et al. (2002) Proteom fewer CSF proteins derived from the nucleus and cytoplasm ics 2: 513-523] was used for identifying and quantifying (10% versus 15% and 11% versus 16%, respectively. Impor US 2013/0237454 A1 Sep. 12, 2013 tantly, nearly 56% of the proteins are CSF-specific and are not The differences found in the present study suggest that it present in our larger plasma database of 3654 proteins, also would be attractive to extend these studies with immunoaf analyzed by LC-MS/MS. This is notable because the acqui finity depletion applied to different defined categories of sition and analysis conditions likely favored the set of plasma headache subjects. proteins as opposed to the CSF proteins. This is because more proteins were likely available for detection in the plasma of Summary burn patients due to severe tissue leakage, and there was the [0093] The present study provides the most comprehensive additional dimension of sample fractionation via enrichment CSF protein coverage and list reported to date for healthy of cysteinyl and N-linked glycopeptides. It is noteworthy that normal individuals including serial lumbar punctures. this cannot be viewed as a head-to-head comparison in light [Schutzer et al. (2010) Establishing the Proteome of Normal of the differences in sample type and conditions, extensive Human Cerebrospinal Fluid, PLoS One 5(6): e10980]. The ness of fractionation and MS instrumentation. protein set has immediate utility for investigators interested in [0090] Comparison between proteins detected in this study using CSF to study neurological or psychiatric diseases. As and those (which we have termed neurologic surrogate-nor evidenced in Examples II-IV, it serves as a normative base to mals) from the CSF study by Zougman et al., reveals a 92% which disease states may be compared. The present study also overlap (see FIG. 1. suggests that CSF protein variability over a short time may be [0091] In order to assess the CSF protein variability from relatively limited in an individual and thus functionally use serial sample collections, the present inventors examined ful. individual (non-pooled) samples from another group of 10 [0094] The other major previous investigations of CSF healthy volunteers (5 male, 5 female; age range 37–44 years from healthy individuals were published by Zhang et al. old) who had two CSF samples obtained at least 4 weeks apart [(2005) Neurobiol Aging 26: 207-227] and updated by part of using the AMT tag approach. Inter-subject differences were that group, Xu et al. [(2006) Int Rev Neurobiol 73: 29-98]. far greater than intra-subject differences. Statistical tests of What began as detection of approximately 315 proteins was variance of differences (ANOVA) were performed for these expanded to 915 using different mass spectrometry methods. data sets based on different factors (e.g., subject, gender, and Interestingly Xu et al. [(2006) Int Rev Neurobiol 73:29-98) time of sampling), followed by unsupervised hierarchical stated that they believed their coverage of the normal CSF clustering analysis of the statistically significant proteins was insufficient because they were unable to detect two well (p-value-0.01). It is clear that human heterogeneity is the known CSF proteins, cº-synuclein [Yuan et al. (2005) Pro major factor responsible for inter-sample differences; clus teomics 5: 541-550) and gelsolin [Yuan et al. (2002) Electro tering of the “significant” proteins could not distinguish cor phoresis 23: 1185-1196). The present methods and approach responding groups based on the other factors defined in the differed from these references, and included a rigorous sepa ANOVA analysis (i.e., gender and time of sampling), except ration of abundant from less abundant proteins to mitigate the for “subject” (i.e., normal volunteers). masking effect of the most abundant proteins, as well as [0092] As an example of how CSF proteomic databases high-resolution LC coupled to MS/MS analysis for highly may be used to better understand disease states, the present efficient peptide identification. The present inventors did inventors compared the proteomes oftwo similarly processed identified 2630 proteins in total, including O-synuclein and (see Methods) pooled samples of patients using the mass gelsolin. spectrometry strategy [Smith et al. (2002) Proteomics 2: 513 [0095] Due to the challenge in obtaining CSF from healthy 523]. The first set, considered as neurologic surrogate-nor people, most previous studies may have used CSF from “sur mals was a pool of 10 headache patients. CSF had been rogate-normals,” that is CSF collected from people with neu obtained to evaluate the possibility of a CNS infection or rological complaints such as headache but with normal clini bleed but all clinical results were normal. The second set, cal CSF laboratory values. As described herein, the present considered as non-neurologic surrogate-normals, was a pool inventors compared proteomes of two different surrogate of 200 subjects (without a neurologic disease, who underwent normal groups. Significant differences were noted between lumbar puncture for non diagnostic reasons; over 90% were the two groups. Accordingly, this study supports the potential undergoing spinal anesthesia in preparation for orthopedic usefulness of the “true” normal human CSF proteome data surgery (limbs-knees and hips)). Significantly distinct results library as an invaluable tool in investigating pathophysiologi were found between each group. Specifically, 191+7 and cal abnormalities in neurological and psychiatric disorders. 211+8 non-redundant proteins were identified from the 3 [0096] Proteomic databases can be used in several ways. replicates of each data set. Statistical analysis comparing The present inventors’ perspective with regard to using these these CSF data sets showed that the neurologic surrogate proteomic databases for studying diseases involves a step normal CSF pool had distinctive quantitative differences wise strategy. The first step is a comparison of pooled samples compared to the non-neurologic surrogate normal pool (22 representative of the disease to normal subjects or a compara proteins with p-value-0.01 by ANOVA). Unsupervised hier tor disease. The second step involves the selection of specific archical clustering of abundances of all proteins clearly sepa candidate proteins. The selection of candidate proteins is not rates these two groups. One interesting difference was the likely to be predicted in advance and may require bioinfor identification and quantification of certain hemoglobin iso matic strategies and knowledge related to the disease under forms, which were among significantly changed proteins study. A third step would involve analysis of the individual identified by the statistical analysis, in the neurologic surro samples contributing to the pool to ascertain how many of the gate-normal (headache) samples. Although Zougman et al. samples actually contained one or more of the candidate [(2008) J Proteome Res 7: 386-399) previously identified proteins. This step provides a check in the event that a single these same proteins in a qualitative analysis of their neuro individual in the pool disproportionately contributes a protein logic surrogate-normal samples, the present study reveals that compared to other subjects. The results would be subjected to these isoforms were increased by about ten-fold on average. statistical analyses in accordance with standard practice. In

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TABLE 1m-continued Cerebrospinal Fluid (CSF) Proteins present only in Multiple Sclerosis patients compared to Surrogate Non-Neurologic Normals AND Surrogate Neurologic Normals (Headaches): Qualitative List of CSF Proteins Present in the Pooled First Attack Multiple Sclerosis Patients compared to the combined lists of Proteins Found in a Similarly Analyzed Group of Non-neurologic Surrogate Normal Subjects and Proteins Found in Neurologic Surrogate-Normals (Headaches subjects with normal CSF clinical laboratory values). CSF Proteins Present In MS not MinG)f(DRF Normals or Headaches (no IAD) Gene PI:IPIO0384402.1 Myosin-reactive immunoglobulin kappa chain variable region (Fragment) PI:IPIO0385.143.1 Microfibrillar protein 2 (Fragment) PI:IPIO0386131.1 Ig kappa chain V-III region IARC/BL41 precursor PI:IPIO0387096.1 Ig kappa chain V-I region Kue PI:IPIO0387101.1 Ig kappa chain V-I region Scw PI:IPIO0387113.1 Ig kappa chain V-III region B6 PI:IPIOO419442.3 IGLV6-57 protein IGLV6–57 PI:IPIOO455667.5 hypothetical protein LOC402665 LOC402665 PI:IPIOO465255.6 Isoform 1 of Proline-rich acidic protein 1 precursor PRAP1 PI:IPIO0748265.2 Rheumatoid factor RF-ET13 PI:IPIO0816737.1 Rheumatoid factor D5 heavy chain (Fragment) PI:IPIO0829810.1 Uncharacterized protein ENSP00000375027 PI:IPIO0854624.1 Uncharacterized protein ENSP00000375043 PI:IPIO0854745.1 Uncharacterized protein ENSP00000375019 [AD = immunoaffinity depletion

TABLE 2m Qualitative List of CSF Proteins Absent only in the Pooled First Attack Multiple Sclerosis Patients compared to the combined lists of a) Proteins Found in a similarly Analyzed Group of Non-neurologic Surrogate Normal Subjects (both groups analyzed without immunoaffinity depletion (IAD) of most abundant proteins) and b) Proteins Found in an expanded list of True Normals (where immunoaffinity depletion was applied).

CSF Proteins Not Present in MS but Present in Combined MinG)f(DRF Gene Normals and Headaches (no IAD) PI:IPIO0000024.1 PCDH1 soform 1 of Protocadherin-1 precursor PI:IPIO0001477.1 DDR1 soform 1 of Epithelial discoidin domain-containing receptor precursor PI:IPIO0003176.1 HTRA1 Serine protease HTRA1 precursor PI:IPIOOOO3648.2 PVRL1 soform Delta of Poliovirus receptor-related protein 1 jite Cui SOjº PI:IPIO0004946.8 CXCL16 chemokine (C–X—C motif) ligand 16 PI:IPIOOO 10471.5 LCP1 Plastin-2 PI:IPIO0021263.3 YWHAZ 4-3-3 protein zeta/delta PI:IPIO002 1856.3 APOC2 Apolipoprotein C-II precursor PI:IPIO0022333.1 BAI1 Brain-specific angiogenesis inhibitor 1 precursor PI:IPIOOO24570.1 SEMA 3G Semaphorin-3G precursor PI:IPIOOO25155.1 FSTL3 Follistatin-related protein 3 precursor PI:IPIOOO29.193.1 HGFAC Hepatocyte growth factor activator precursor PI:IPIOOO29343.2 CNTNAP2 soform 1 of Contactin-associated protein-like 2 precursor PI:IPIOO169383.3 PGK1 Phosphoglycerate kinase 1 PI:IPIOO2.16171.3 ENO2 Gamma-enolase PI:IPIOO2.18570.6 PGAM2 Phosphoglycerate mutase 2 PI:IPIOO2 18834.9 FCGR3A Low affinity immunoglobulin gamma Fc region receptor III A precursor PI:IPIOO2 19425.3 PVR soform Beta of Poliovirus receptor precursor PI:IPIOO297.040.2 SPINK6 Serine protease inhibitor Kazal-type 6 precursor PI:IPIO03067.10.2 CHRD soform 1 of Chordin precursor PI:IPIOO3287.03.1 OAF Out at first protein homolog precursor PI:IPIO0329775.7 CPB2 soform 1 of Carboxypeptidase B2 precursor PI:IPIOO385.980.8 ROBO2 ROBO2 isoform a PI:IPIO0387119.1 g kappa chain V-III region POM PI:IPIOO41 1680.8 PCMT1 soform 1 of Protein-L-isoaspartate(D-aspartate) O methyltransferase PI:IPIOO4446.05.1 CDNA FLJ45296 fis, clone BRHIP3003340, moderately similar to Actin, alpha skeletal muscle 2 PI:IPIOO456736.4 RGMB soform 1 of RGM domain family member B precursor PI:IPIOO4791 16.1 CPN2 Carboxypeptidase N subunit 2 precursor PI:IPIO0554474.3 LOC284297 Hypothetical LOC284297 MinGföRF = Non redundant IPI designation

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TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

CSF Proteins 738 Gene 00382492 g heavy chain V-III region LAY 00334492 soform 3 of Coiled-coil domain-containing protein 144A LOC731479; CCDC144A; LOC652491; CCDC144E. 00018880 Tumor necrosis factor receptor superfamily member 1A precursor TNFRSF1A 007843.85 Adenylate cyclase type 1 ADCY1 004651.68 soform 1 of Serine/threonine-protein kinase TAO2 TAOK2 00028213 Semaphorin-3D precursor SEMA 3D 00296.421 EH domain-binding protein 1-like protein 1 0078.7587 similar to Temporarily Assigned Gene name family member LOC729549 00028980 Uncharacterized protein KIAA0133 00430792 soform 1 of Protein ERGIC-53-like precursor LMAN1 L. 00018335 soform Flt1 of Vascular endothelial growth factor receptor 1 precursor FLT1 00795736 Fer-1-like 4 00000656 soform 1 of Uncharacterized protein KIAA0892 precursor |Zinc finger FYVE domain-containing protein 9 ZFYVE9 00419675 hypothetical protein LOC150763 LOC150763 00003893 soform 1 of Protocadherin gamma B3 precursor PCDHGB3 0041 0127 Transforming, acidic coiled-coil containing protein 2 TACC2 0000571 1 Histone deacetylase 6 HDAC6 00883997 Coiled-coil domain-containing protein 19 CCDC19 00419180 CDNA FLJ41429 fis, clone BRHIP2005354 CC2D2B 00335711 Ciliary dynein heavy chain 11 DNAH11 0041 1291 Peroxisome biogenesis factor 1 PEX1 00397622 soform 1 of Transmembrane and immunoglobulin domain-containing protein 1 TMIGD1 jite Cui SOjº 00003564 Lymphocyte antigen 86 precursor 00.100247 Thioredoxin domain-containing protein 13 precursor 00059711 LRP11 protein (Fragment) 00.141933 Mitotic checkpoint serine/threonine-protein kinase BUB1 beta 00387098 g kappa chain V-I region OU 002995.54 Kinesin-like protein KIF14 005.15034 87 kDa protein 000446.08 soform 1 of Protein KIAA1881 004441.38 CDNA FLJ46074 fis, clone TESTI2001915, highly similar to Homo sapiens actin filament associated protein 00807406 hypothetical protein isoform 1 OC285346 006.45729 62 kDa protein QTNF8 00789856 tubulin tyrosine ligase-like family, member 3 ; TLL3 00032680 Apolipoprotein-L5 POL5 00298.214 soform 1 of ATP-binding cassette sub-family G member 2 BCG2 00030945 Urocortin-2 precursor .CN2 00333503 Uncharacterized protein ENSP00000315571 (Fragment) 00005567 soform 3A of Voltage-dependent L-type calcium channel subunit beta-3 CACNB3 00.185038 soform 1 of Dual oxidase 1 precursor DUOX1 00005537 39S ribosomal protein L12, mitochondrial precursor MRPL12 007.955.75 39 kDa protein 002.21240 soform 2 of Leucyl-cystinyl aminopeptidase LNPEP 00655.865 soform 2 of Protein diaphanous homolog 3 DIAPH3 00019270 Tankyrase-2 NKS2 00302614 V-set domain containing T cell activation inhibitor 1 VTCN1 00.176976 Novel protein similar to mitochondrial ribosome recycling factor isoform 1 RP1-57A13.2 00786931 similar to fatty acid amide hydrolase LOC729037 00063878 soform 1 of Multidrug resistance-associated protein 9 ABCC12 000294.73 Protein Njmu-R1 C17orf75 008:84076 ENV polyprotein (coat polyprotein) family protein 00449923 soform 1 of Retinoic acid-induced protein 1 RAI1 002941.87 Protein-arginine deiminase type-2 PADI2 00045473 Similar to C. Elegans protein F17C8.5 LOC339.123 00.167433 CDNA FLJ39703 fis, clone SMINT2012.195 FDX1L 00183572 soform 2 of Dedicator of cytokinesis protein 7 DOCK7 00001835 Zinc finger and BTB domain-containing protein 4 ZBTB4 00.148768 TRIO and F-actin binding protein isoform 1 TRIOBP 00.170548 soform 1 of ATPase family AAA domain-containing protein 2 ATAD2 002.20257 soform 3 of Probable tubulin polyglutamylase TTLL1 00298058 soform 1 of Transcription elongation factor SPT5 SUPTSH 00.102281 Retroviral-like aspartic protease 1 precursor SASP 00030355 Protein phosphatase 1 regulatory subunit 11 PPP1R11 0021791.5 soform 1 of Transmembrane protein 136 TMEM136 002.20986 soform 3 of ADAMTS-9 precursor ADAMTS9 00.175169 soform 1 of ADP-ribosylation factor GTPase-activating protein 1 ARFGAP1 00550862 hypothetical protein LOC387911 LOC3879.11 US 2013/0237454 A1 Sep. 12, 2013 18

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene

PIOO746459 CDNA FLJ34517 fis, clone HLUNG2006781 - PIOO444234 CDNA FLJ45743 fis, clone KIDNE2016464 FLJ45743 PIO0002534 Isoform 1 of Purine-rich element-binding protein gamma PURG PIO0556.253 Isoform 1 of Coiled-coil domain-containing protein C60rfl.99 C6Orfl 99 PIO0017592 Leucine zipper-EF-hand-containing transmembrane protein 1, mitochondrial LETM1 jite Cui SOjº PIO001.6007 Myosin-Vc MYOSC PIO0744927 gastrotropin isoform 1 FABP6 PIO0024319 Forkhead box protein J1 FOXJ1 PIO0339297 Polypeptide N-acetylgalactosaminyltransferase 4 GALNT4 PIO0254408 bromodomain PHD finger transcription factor isoform 1 BPTF PIO0304324 Histone deacetylase 11 HDAC11 PIOO477693 fatty acid binding protein LOC646486 PIO0025310 Zinc finger protein 217 ZNF217 PIOO427808 Isoform 1 of Uncharacterized protein C10orf71 C10orf71 PIO0735313 similar to Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 - PIO0384013 Polypeptide N-acetylgalactosaminyltransferase-like protein 2 GALNTL2 PIO0382495 Ig heavy chain V-III region ZAP - PIOO477820 Isoform 1 of FRAS1-related extracellular matrix protein 1 precursor FREM1 PIO0024776 Calmegin precursor CLGN PIO0023110 Potassium channel subfamily K member 3 KCNK2 PIO0182833 Coiled-coil alpha-helical rod protein 1 CCHCR1 PIO0394994 Isoform 1 of Nesprin-3 C14Orf249 PIOO419992 Isoform 1 of Acyl-CoA synthetase family member 4 AASDH PIO0004445 Gamma-2-syntrophin SNTG2 PIO0878015 12 kDa protein - PIO0328094 Isoform 1 of Forkhead box protein P3 FOXP3 PIO0873348 63 kDa protein A1CF PIOO640240 59 kDa protein SPTLC3 PIO0002824 Cysteine and glycine-rich protein 2 CSRP2 PIO0398.272 Isoform 1 of Collagen alpha-1(XVII) chain COL17A1 PIO0061009 Isoform 1 of WD repeat-containing protein 67 WDR67 PIO0299301 Isoform 1 of Desmuslin DMN PIO0152011 PTPL1-associated RhoGAP 1 ARHGAP29 PIO0847790 Protein of unknown function DUF1725 domain containing protein - PIO0065121 Isoform 2 of Coiled-coil domain-containing protein 36 CCDC36 PIO0373867 glycolipid transfer protein domain containing 2 GLTPD2 PIO0872354 armadillo repeat containing 2 ARMC2 PIO0152975 Isoform 1 of Coiled-coil domain-containing protein 90A, mitochondrial precursor CCDC90A PIO0374804 Isoform 1 of Diacylglycerol kinase delta DGKD PIO0292894 Pre-rRNA-processing protein TSR1 homolog TSR PIO0028232 Putative uncharacterized protein FGF4 PIO00272.69 E3 ubiquitin-protein ligase CBL CBL PIO0797567 9 kDa protein GNAI2 PIO0032958 Isoform 2 of Actin-binding protein anillin ANLN PIO0057815 intestinal facilitative glucose transporter 7 SLC2A7 PIO0014367 Isoform 1 of Non-SMC element 4 homolog A NSMCE4A PIO0884022 Similar to Immunglobulin heavy chain variable region - PIOO465319 Chondroitin sulfate synthase 2 CHPF PIO0549844 Isoform 1 of Protein FAM134B FAM134B PIOO457114 Isoform 1 of IQ motif and Sec7 domain-containing protein 1 IQSEC1 PIO0002773 Isoform 2 of Tyrosine-protein kinase JAK3 JAK3 PIO0005667 NEDD4-binding protein 1 N4BP1 PIOO300594 CDNA FLJ35435 fis, clone SMINT2002620 SPATA13 PIO0103142 Nudo domain-containing protein 2 NUDCD2 PIO0290785 Isoform 1 of SET domain-containing protein 6 SETD6 PIO0297763 Retinal-specific ATP-binding cassette transporter ABCA4 PIO0000861 Isoform 1 of LIM and SH3 domain protein 1 LASP1 PIOO168255 hypothetical protein LOC400451 LOC4004:51 PIO0015990 Isoform 1 of Eyes absent homolog 3 EYA3 PIO0171500 Uncharacterized protein C14orf.45 C14Orf245 PIO0170765 Isoform 3 of Alanine--glyoxylate aminotransferase 2-like 2 AGXT2L2 PIO0099977 platelet-derived growth factor C precursor PDGFC PIO0292953 Isoform 2 of Ankycorbin RAI14 PIOO159072 57 kDa protein ROD1 PIOO305692 Thioredoxin-like protein 1 TXNL1 PIO003.1630 Melanocyte protein Pmel 17 precursor SILV PIOO167446 Isoform 2 of Uncharacterized protein C17orf78 C17orf78 PIOO479625 Isoform 1 of ELAV-like protein 4 ELAVL4 PIO0745395 Conserved hypothetical protein KIAA0508 PIO0043069 Ankyrin repeat domain-containing protein 30A ANKRD30A PIO0014316 Cyclin-dependent kinase 5 activator 1 precursor CDK5R1 US 2013/0237454 A1 Sep. 12, 2013 19

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0301726 Isoform 1 of Uncharacterized protein C3orf20 C3orf20 PIOO185361 ATP-dependent RNA helicase DDX55 DDX55 PIO0293867 D-dopachrome decarboxylase DDT PIOO794779 DNA polymerase theta POLQ PIOO478354 Putative uncharacterized protein CXorf31 CXOrfºl PIO0166414 Coiled-coil domain-containing protein 96 CCDC96 PIO0300053 Keratin type II cuticular Hb2 KRT82 PIO0749062 Conserved hypothetical protein - PIOO452161 Isoform 1 of Mucolipin-1 MCOLN1 PIOO384546 CDNA FLJ25883 fis, clone CBR02735 - PIOO412272 SH3 domain-binding glutamic acid-rich-like protein 2 SH3BGRL2 PIO0006298 Isoform 1 of Peptidyl-prolyl cis-trans isomerase G PPIG PIO0031497 Conserved hypothetical protein C7orf.49 PIO0022061 Sodium/hydrogen exchanger 6 SLC9A6 PIO0217418 Isoform 2 of Rho GTPase-activating protein 12 ARHGAP12 PIO0743545 Conserved hypothetical protein - PIO0328156 Amine oxidase [flavin-containing] B MAOB PIOO644785 Protein PLXNB3 PIOO654693 Protein FAM44C FAM44C PIO0880011 116 kDa protein - PIO0018583 Isoform 1 of Intracellular hyaluronan-binding protein 4 HABP4 PIO0030986 Isoform Long of Kelch repeat and BTB domain-containing protein 10 KBTBD10 PIO0045503 Isoform 2 of Protein phosphatase 1 regulatory subunit 14A PPP1R14A PIO0793408 6 kDa protein ADAMTS9 PIO0024255 G patch domain and KOW motifs-containing protein GPKOW PIO0028262 67 kDa protein |glutamate receptor 3 precursor GRM3 PIO0296535 2-hydroxyacyl-CoA lyase 1 HACL1 PIO0062882 ATP-binding domain-containing protein 3 ATPBD3 PIOO445167 CDNA FLJ44499 fis, clone UTERU3000665, highly similar to Homo sapiens SRCAP Snf2-related CBP activator protein PIOO442582 CDNA FLJ26893 fis, clone RCT00305 - PIO001 1274 Isoform 1 of Heterogeneous nuclear ribonucleoprotein D-like HNRPDL PIO0002791 Isoform Wnt-16b of Protein Wnt-16 precursor WNT16 PIO0290432 Natural resistance-associated macrophage protein 1 SLC11A1 PIO001.2540 Prominin-1 precursor PROM1 PIOO477396 Uncharacterized protein ZNF324B (Fragment) ZNF584; ZNF324B PIO0853149 RW1 protein TMEM131 PIO0168977 Olfactory receptor 6J1 OR6J1 PIO0165955 Isoform 1 of Mitogen-activated protein kinase 15 MAPK15 PIO0377211 Isoform 3 of Cadherin-like protein 26 precursor CDH26 PIO0736.558 THAP domain containing 4 THAP4 PIOO470518 Mitotic spindle assembly checkpoint protein MAD1 MAD1 L1 PIO0005087 Tropomodulin-3 TMOD3 PIO0029.227 LOC93622 protein LOC93622 PIO0218839 Cytochrome P450 1A1 CYP1A1 PIO0006356 Isoform 1 of Patatin-like phospholipase domain-containing protein 5 PNPLA5 PIO0005616 Isoform 1 of Trace amine-associated receptor 2 TAAR2 PIO07894.94 8 kDa protein TUSC4 PIO0745346 Isoform 11 of Peroxisomal N(1)-acetyl-spermine?spermidine oxidase PAOX PIO0027596 Secreted frizzled-related protein 2 precursor SFRP2 PIO0008455 Isoform 2 of Myosin-VI MYO6 PIO0217850 Isoform 1 of GRAM domain-containing protein 1C GRAMD1C PIO0020771 Isoform 3 of Ensconsin MAP7 PIO0170800 Isoform 1 of Otoancorin precursor OTOA PIO0063181 CDKN2A interacting protein N-terminal like CDKN2AIPNL PIO0328225 Isoform 1 of T-box transcription factor TBX20 TBX20 PIO0166331 Ankyrin repeat domain-containing protein 35 ANKRD35 PIO0294386. Myosin-Ia MYOIA US 2013/0237454 A1 Sep. 12, 2013 20

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0061680 SAGA-associated factor 29 homolog CCDC101 PIOO220901 TBC1D4 protein TBC1D4 PIO0059139 Vacuolar proton pump subunit E 2 ATP6V1 E2 PIO0010893 Left-right determination factor 2 precursor LEFTY2 PIO0746222 ATP-binding cassette, sub-family B (MDR/TAP), member 5 ABCB5 PIO0010843 Isoform 1 of Amyloid beta A4 precursor protein-binding family B member 1 APBB1 PIO001.2353 Mitochondrial 39S ribosomal protein L3 MRPL3 PIO0385065 Isoform 1 of Coiled-coil domain-containing protein 46 CCDC46 PIOO413930 Elongation of very long chain fatty acids protein 2 ELOVL2 PIO00067.15 Double-strand-break repair protein rad21 homolog RAD21 PIO0787189 similar to thioredoxin domain containing 4 LOC727931 PIO0215965 Isoform A1-B of Heterogeneous nuclear ribonucleoprotein A1 HNRNPA1 PIO0030237 Isoform 1 of Uncharacterized protein Clorf.49 C1orf249 PIO0088953 Phosphoinositide 3-kinase regulatory subunit 6 C17orf28 PIO0031490 Isoform 1 of Collectin-11 precursor COLEC11 PIOO430079 Isoform 2 of PHD finger protein 8 PHF8 PIO0296942 Cadherin-12 precursor CDH12 PIO0852688 Isoform 1 of Low density lipoprotein receptor-related protein 5-like protein LRP5L PIO0060440 Zinc finger protein GLI4 GLI4; ZFP41 PIO0845299 Putative uncharacterized protein LOC285733 LOC285733 PIO0003897 Isoform 1 of Protocadherin gamma B6 precursor PCDHGB6 PIOO1522.57 Enkurim C10orf63 PIO0043526 Uncharacterized protein C14orf.44 C14Orf244 PIO001.3373 Orexin precursor HCRT PIO0829925 Uncharacterized protein ENSP00000365090 ELA2A PIO0009333 Transmembrane protein 9 precursor TMEM9 PIOO470917 Isoform 2 of Uncharacterized protein KIAA1529 |cardiac muscle, beta MYHTB PIO0876962 Isoform 2 of Inverted formin-2 INF2 PIO0026512 Isoform HERA-A of GTP-binding protein era homolog ERAL1 PIO0180375 Isoform I of Beta-arrestin-2 ARRB2 PIO0297407 Solute carrier family 45 member 4 SLC45A4 PIOO152879 Monocarboxylate transporter 10 SLC16A10 PIO02901.55 66 kDa protein ZNF148 PIO0747017 Putative uncharacterized protein DKFZp686D06121 NEK1 PIO0793836 11 kDa protein ARHGDIB PIO0382422 Ig lambda chain V-I region NEWM - PIO0328842 ARHGAP4 protein ARHGAP4 PIO0008632 Isoform 1 of Putative homeodomain transcription factor 1 PHTF1 PIO0065253 Uncharacterized protein C3orf50 C3orf.30 PIO0883751 RNA-directed DNA polymerase (Reverse transcriptase), related domain - containing protein PIO0216137 Synaptonemal complex protein 1 SYCP1 PIO0005621 7.h3 protein (Fragment) SYDE1 PIO0001933 Coiled-coil domain-containing protein 113 CCDC113 PIO0383294 Putative uncharacterized protein pp.7518 MNT PIO0016861 102 kDa protein GTF3C2 PIO0020903 Isoform 1 of AF4/FMR2 family member 2 AFF2 PIOO465247 Isoform 1 of Stimulated by retinoic acid gene 6 protein homolog STRA6 PIO0382394 Isoform 5 of Cytosolic phospholipase A2 beta PLA2G4B PIO0167913 Isoform 1 of Spermatid-associated protein SPERT US 2013/0237454 A1 Sep. 12, 2013 21

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0874276 Putative uncharacterized protein DKFZp761N1814 EPB41 L4B PIOO446767 Isoform 3 of Transducin-like enhancer protein 4 TLE4 PIOOO2O754 PRO1751 - PIO0300060 WD repeat-containing protein 70 WDR70 PIO0021979 Peroxisomal membrane protein 11A PEX1 1A PIO0031768 Hook homolog 3 HOOK3 PIO0216986 Isoform C of Complement receptor type 2 precursor CR2 PIOO470771 SAMD4B protein SAMD4B PIO0021143 Class B basic helix-loop-helix protein 2 BHLHB2 PIO0297931 Isoform 1 of AP1 subunit gamma-binding protein 1 AP1GBP1 PIO0018691 28S ribosomal protein S18a, mitochondrial precursor MRPS18A PIO0010604 Isoform 1 of 1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase epsilon-1 PLCE1 PIO0022438 Isoform Long of Transcription factor Maf MAF PIO0396527 Isoform 1 of Coiled-coil domain-containing protein 128 CCDC128 PIO0291840 Isoform 1 of Zinc finger protein 90 homolog ZFP90 PIO0646410 Isoform 2 of Flavin-containing amine oxidase domain-containing protein 1 AOF1 PIOO451413 Intersectin 1 isoform 7 TSN1 PIO0787410 similar to Polypeptide N-acetylgalactosaminyltransferase 9 GALNT9 PIO0552601 Putative uncharacterized protein DKFZp686M12165 (Fragment) - PIO0166833 LAG1 longevity assurance homolog 5 LASS5 PIO0183425 CDKN1A interacting zinc finger protein 1 CIZ1 PIO0027228 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, mitochondrial PET112N. jite Cui SOjº PIO0007917 Collectin-10 precursor COLEC10 PIO0552787 similar to Matrin-3 RBM20 PIO0065484 CDNA FLJ32471 fis, clone SKNMC2000322, weakly similar to MAJOR PTRH2 CENTROMERE AUTOANTIGEN B PIO0384447 Sarcoma antigen NY-SAR-22 (Fragment) NEXN PIO0830073 Isoform 1 of RING finger protein 207 RNF207 PIO001.2411 Zinc finger protein 32 ZNF32 PIO0760993 IQ motif and Sec7 domain 2 isoform 2 QSEC2 PIO0004527 Uncharacterized protein KIAA0355 |Plakophilin-3 PKP3 PIO0014852 Isoform 1 of Phosphoglucomutase-like protein 5 PGM5 PIO0332628 Otopetrin-3 OTOP3 PIO0296830 Isoform 1 of Leucine zipper protein 1 LUZP1 PIO0306127 THUMP domain-containing protein 3 THUMPD3 PIO0022881 Isoform 1 of Clathrin heavy chain 2 CLTCLI PIO0397015 A.T hook DNA-binding motif-containing protein 1 AHDC1 PIO0029184 Hyaluronan and proteoglycan link protein 2 precursor HAPLN2 PIO0795917 126 kDa protein CXOrf245 PIO0815976 Transmembrane protein 120B TMEM120B PIO0382671 Isoform 6 of C-type lectin domain family 4 member M CLEC4M PIO0018303 Isoform 2 of Protocadherin-11 X-linked precursor PCDH.11x PIO0176210 hypothetical protein LOC133558 FLJ40243 PIO01661.53 Protein KIAA0082 |

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIOO401002 Zinc finger protein 740 ZNF140 PIOO607829 Isoform 1 of Retfmger protein-like 2 RFPL2 PIOO402280 Isoform 1 of Small leucine-rich proteoglycan family member LOC150356 CHADL precursor PIO0006800 Isoform Long of Autophagy protein 5 ATG5 PIO0218559 Gamma-sarcoglycan SGCG PIOO479897 Chromosome 9 open reading frame 75 C901 f/5 PIO0216003 Cullin-5 CUL5 PIOO445796 CDNA FLJ43383 fis, clone OCBBF2006058, highly similar to Homo sapiens ACAD8 acyl-Coenzyme A dehydrogenase-8 mRNA PIO0742114 similar to tripartite motif protein 11 LOC653978 PIO0023164 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 HCN4 PIOOO12480 FKSG42 RACGAP1 P PIO0004538 similar to nascent polypeptide-associated complex alpha polypeptide isoform 1 NACAD PIO0297462 Uncharacterized protein C10rf65 C1 Orf65 PIO0793454 7 kDa protein USP19 PIO0028392 specifically androgen-regulated protein isoform 1 C1orf116 PIO0385495 Transmembrane protein 153 LMF2 PIO0017726 Isoform 1 of 3-hydroxyacyl-CoA dehydrogenase type-2 HSD17B10 PIO0791509 Neural precursor cell expressed, developmentally down-regulated 1 NEDD1 PIO0289931 Isoform 1 of Mucosal addressin cell adhesion molecule 1 precursor MADCAM1 PIOO442601 CDNA FLJ26817 fis, clone PRS06446 - PIO0012891 Phosphorylase b kinase gamma catalytic chain, testis/liver isoform PHKG2 PIO0021338 Dihydrolipoyllysine-residue acetyltransferase component of pyruvate DLAT dehydrogenase complex, mitochondrial precursor PIOO455083 Uncharacterized protein ENSP00000371558 - PIOO168877 helicase (DNA) B HELE PIO0641214 177 kDa protein ADCY10 PI00290837 Isoform 2 of F-box/WD repeat-containing protein 10 FBXW10 PIO00092.13 Isoform 1 of B-cell lymphoma/leukemia 11B BCL11B PIO0003421 T-brain-1 protein TBR1 PIO0396314 Isoform 3 of CCR4-NOT transcription complex subunit 10 CNOT 10 PIO0000106 Signal transducer and activator of transcription 4 STAT4 PIO0339217 Ovochymase-1 precursor OVCH1 PIO0395631 Isoform 1 of E3 ubiquitin-protein ligase TRAF7 TRAF7 PIOO455397 DMWD protein DMWD PIO0744557 kazrin isoform E RPI-21 O18.1 PIOO152692 D-tyrosyl-tRNA(Tyr) deacylase 1 DTD1 PIO0397526 Isoform 1 of Myosin-10 MYH10 PIO0640654 RAP1 GTPase activating protein RAP1GAP PIO0791831 10 kDa protein ADRBK I PIOO479904 Uncharacterized protein COL27A1 COL27A1 PIO001.3256 Isoform 1 of Cleavage stimulation factor 64 kDa subunit CSTF2 PIO00592.79 Exocyst complex component 4 EXOC4 PIO0299402 Pyruvate carboxylase, mitochondrial precursor PC PIO0167639 Vacuolar proton pump subunit d 2 ATP6VOD2 PIO0170855 tetratricopeptide repeat domain 19 TTC19 PIOO445563 Putative uncharacterized protein MGC21675/FLJ43787 C4Orf242 PIO0884334 Conserved hypothetical protein LOC72996.8 PIO0007910 Isoform 1 of Sodium-dependent phosphate transport protein 2B SLC34A2 PIO0083708 BAT2-iso BAT2D1 PIOO3287.15 Protein LYRIC MTDH PIO0290035 Isoform 1 of Protocadherin-15 precursor PCDH15 PIO0385511 Uncharacterized protein TNRC6B TNRC6B PIO0006561 Isoform 1 of Protein KIAA0317 |

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO010.1267 Isoform 1 of Uncharacterized protein C190rf60 C190rf60 PIO0739927 similar to vasoactive intestinal peptide receptor 2 LOC6454.64 PIO0782965 huntingtin interacting protein 1 HIP1 PIOO444375 Rh blood group, CcEe antigens RHCE PIO0794880 Isoform 1 of Chromodomain-helicase-DNA-binding protein 7 CHD7 PIOO419791 Isoform 1 of Arginine/serine-rich coiled-coil protein 2 RSRC2 PIO0100106 resistance to inhibitors of cholinesterase 8 homolog A RIC8A PIO0216593 Isoform NOH-1LV of NADPH oxidase homolog 1 NOX1 PIO0395667 Interferon-related IFRD2 (PC4-B) protein NAT6: IFRD2 PIO0008708 Ribosomal L1 domain-containing protein 1 RSL1D1 PIO0748649 25 kDa protein - PIO0100362 erythrocyte membrane protein band 4.1 like 4B isoform 1 EPB41 L4B PIO0219898 Isoform 2 of Nephrin precursor NPHS1; PRODH2 PIO0872098 Zinc finger protein Pegasus KZF5 PIO0043294 Isoform 1 of Uncharacterized protein C7orf26 C7orf26 PIO0152535 Chromodomain-helicase-DNA-binding protein 5 CHD5 PIO0217507 Neurofilament medium polypeptide NEFM PIO0216356 Isoform 2 of RasGAP-activating-like protein 1 RASAL1 PIO0290562 Nuclear factor interleukin-3-regulated protein NFIL3 PIO0006003 CD83 antigen precursor CD83 PIO0166528 Isoform 3 of Rapamycin-insensitive companion of mTOR RICTOR PIO0221325 E3 SUMO-protein ligase Ranbp2 RANBP2 PIO0084684 similar to Zinc finger protein 469 ZNF469 PIOO643.809 Protein CNTNAP3B PIOO164776 Similar to RIKEN cDNAA230078105 gene TMEM198 PIO0023410 Integrin alpha-8 precursor TGA8 PIOO787593 Similar to CG33300-PA LOC730407 PIO0180781 Isoform 1 of Mixed lineage kinase domain-like protein MLKL PIO0339309 Isoform 1 of Proto-oncogene DBL MCF2 PIO0843923 Phosphodiesterase PDE7B2 PDE7B PIO0640865 Integrin beta-like protein 1 precursor TGBLI PIO0029144 Isoform PR130 of Serine/threonine-protein phosphatase 2A regulatory subunit B" PPP2R3A subunit alpha PIO0175439 F-box only protein 43 FBXO43 PIO0646485 Protein EFCAB2 PIO0023105 Peptidylglycine alpha-amidating monooxygenase COOH-terminal interactor PAMCI PIO0301144 Isoform 1 of Sulfatase-modifying factor 1 precursor SUMF1 PIOO439935 UDP-glucuronosyltransferase 1-4 precursor UGT1A4; UGT1A6 PIO0001753 Myosin-4 MYH4 PIOO401829 Putative uncharacterized protein ENST00000281581 - PIO0056324 Isoform 1 of Hermansky-Pudlak syndrome 3 protein HPS3 PIO0220493 U6 snRNA-associated Sm-like protein LSms LSMS PIO0386390 Olfactory receptor 6N2 OR6N2 PIO0044761 Pseudouridylate synthase 7 homolog PUS7 PIO0032342 TRIP12 protein TRIP12 PIO0307536 Isoform 1 of Testis-expressed sequence 11 protein TEX11 PIO0244812 Tetratricopeptide repeat protein 6 TTC6 PIO0030487 CDNA FLJ30993 fis, clone HLUNG1000064, weakly similar to KARYOGAMY |Tropomyosin alpha-4 chain - PIO0737735 similar to cell division cycle 10 isoform 1 LOC646913 PIO0065415 Isoform 1 of Coiled-coil domain-containing protein 138 CCDC138 PIO0376206 Isoform 2 of 17-beta hydroxysteroid dehydrogenase 13 precursor HSD17B13 PIO0011589 Isoform A of Septin-4 SEPT4 PIO0032158 Isoform 2 of NMDA receptor-regulated protein 1 NARG1 PIO0013468 Mitotic checkpoint protein BUB3 BUB3 PIO0745955 EBNA1 binding protein 2 EBNA1BP2 PIOO157237 Isoform 1 of MAGUK p55 subfamily member 4 MPP4 PIO0009040 Ornithine decarboxylase antizyme 3 OAZ3 PIO0383774 Mihl/Tx protein CASP4 PIOO182774 SH3 yL1 protein SH3NZL.1 PIO0217691 Isoform 1 of EF-hand domain-containing protein C17orf57 C17orf57 PIO0514843 KIAA0082 KIAA0082 PIO0216346 Isoform 2 of Nucleolar protein 3 NOL3 PIO0644968 Similar to Heterogeneous nuclear ribonucleoprotein A1 - PIOO414122 coiled-coil domain containing 141 CCDC141 US 2013/0237454 A1 Sep. 12, 2013 24

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0884216 RNA-directed DNA polymerase (Reverse transcriptase), related domain - containing protein PIO0397759 similar to ribosomal protein L21 LOC3886.21 PIO0156871 Isoform 2 of Ubiquitin carboxyl-terminal hydrolase 49 |USP49 PIO0168692 Isoform 2 of Zinc finger protein 318 ZNF318 PIO0187082 Isoform 3 of Multiple C2 and transmembrane domain-containing protein 1 MCTP1 PIO0018805 Uncharacterized protein C14orf105 C14Orf105 PIOO446685 CDNA FLJ41345 fis, clone BRAWH2002761 - PIOO470515 Isoform 1 of Uncharacterized protein Clorf173 C1 Orfl 73 PIO0001317 Rho-related BTB domain-containing protein 1 RHOBTB1 PIO0024523 Isoform A of DnaJ homolog subfamily B member 6 DNAJB6 PIO0030814 Fibroblast growth factor 22 precursor FGF22 PIOO441064 Isoform 1 of Uncharacterized protein C15orf26 C15 Orf26 PIO0867744 Isoform 3 of Pleckstrin homology domain-containing family H member 2 PLEKHH2 PIO0784027 Rod cº?P-specific 3',5'-cyclic phosphodiesterase subunit beta precursor PDE6B PIO0879277 436 kDa protein TRRAP PIO0011631 Centromere/kinetochore protein zwl.0 homolog ZW 10 PIO0014186 Isoform A of Zinc forger homeobox protein 3 ZFHX3 PIO0852699 4 kDa protein - PIO0.400834 Mediator of RNA polymerase II transcription subunit 13-like MED1.3L PIO0018203 Isoform SRP55-2 of Splicing factor, arginine/serine-rich 6 SFRS6 PIO0335259 deleted in liver cancer 1 isoform 1 DLC1 PIO023.9405 Isoform 1 of Nesprin-2 SYNE2 PIO0788010 similar to 60S ribosomal protein L21 RPL21; LOC728501 PIO0027487 Creatine kinase M-type CKM PIO0029662 Isoform 1 of Potassium voltage-gated channel subfamily H member 2 KCNH2 PIO0651669 Putative uncharacterized protein - PIO0029446 Isoform 1 of Myotubularin-related protein 5 SBF1 PI00883929 Conserved hypothetical protein - PIO0641155 20 kDa protein HIRIP3 PIO0030307 Solute carrier family 41 member 2 SLC41A2 PIO0398162 Isoform 2 of Nebulin-related-anchoring protein NRAP PIOO158506 Isoform 3 of Zinc finger protein 688 ZNF688 PIO0003768 Isoform 1 of Pescadillo homolog 1 PES1 PIO0100910 Isoform 2 of Armadillo repeat-containing protein 5 ARMC5 PIOO445894 CDNA FLJ42978 fis, clone BRTHA2004821 - PIO0022325 Isoform 4 of Pro-neuregulin-2, membrane-bound isoform precursor NRG2 PIO0747271 zinc finger protein SBZF3 ZNF695 PIO0006178 Yé encoding protein NPY6R PIO0796745 22 kDa protein PPP1R14D PIO0299880 Isoform 2 of Calcium-activated potassium channel subunit beta-3 KCNMB3 PIO0328885 eEF1A2 binding protein DKFZp-434B1231 PIO0009305 Glucosamine-6-phosphate isomerase GNPDA1 PIOO465054 Putative uncharacterized protein DKFZp686C1054 THUMPD1 PIOO456676 Isoform 1 of F-box only protein 38 FBXO38 PIO0328089 Kappa B and V(D)J recombination signal sequences binding protein HIVEP3 PIO0002506 Dolichyl-phosphate beta-glucosyltransferase ALG5 PIO0.410325 Low-density lipoprotein receptor class A domain-containing protein 3 precursor LDLRAD3 PIOO450358 Putative uncharacterized protein TOP PIO0004472 Isoform 1 of Serine/threonine-protein kinase WNK1 WNK1 PIO0.428677 Putative olfactory receptor (Fragment) - PIO0788014 similar to Opioid growth factor receptor LOC7290.15 PIOO442208 CDNA FLJ16344 fis, clone TESTI2032643, moderately similar to ADCY4 ADENYLATECYCLASE, TYPE IV PIO0019932 ubiquitin-conjugating enzyme E2D 2 isoform 2 UBE2D2 PIO0869224 Pseudogene candidate - PIO0000102 Progonadoliberin-1 precursor GNRH1 PIOO470896 Isoform 2 of Zinc finger FYVE domain-containing protein 26 ZFYVE26 PIO03294.88 Isoform IB of Tyrosine-protein kinase ABL2 ABL2 PIO0219604. Dual specificity mitogen-activated protein kinase kinase 1 MAP2K1 PIO0000030 Isoform Delta-1 of Serine/threonine-protein phosphatase 2A 56 kDa regulatory PPP2R5D subunit delta isoform PIO0017538 Isoform 2 of Separin ESPL1 PIO0787099 similar to SR protein related family member LOC728676 PIOO297235 cDNA FLJ17204 CCPG1 PIO0002405 2'-5'-oligoadenylate synthetase 3 OAS3 PIO001.3205 Isoform 1 of JmjC domain-containing histone demethylation protein 3B JMJD2B PIO0218715 Isoform 2 of ADAM 33 precursor ADAM33 PIOO410666 Isoform 3 of Protein LAP4 SCRIB PIO0827815 Light chain Fab (Fragment) - PIO0013651 Isoform 3 of RNA-binding protein 33 RBM33 PIO0002344 steroid 5 alpha-reductase 3 SRD5A3 US 2013/0237454 A1 Sep. 12, 2013 25

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene

PIOO444408 CDNA FLJ45600 fis, clone BRTHA3020369 - PIO0005013 poly(rC) binding protein 4 isoform b PCBP4 PIO0294728 Dmix-like protein 1 DMXL1 PIO0004288 Isoform 1 of Sialic acid-binding Ig-like lectin 7 precursor SIGLEC7 PIO0855960 Integral membrane protein GPR137C GPR137C PIO0003571 Isoform S-CaRP1 of Calcium-binding protein 1 CABP1 PIO0021751 Neurofilament heavy polypeptide NEFH PIO0174347 Inactive dual specificity phosphatase 27 DUSP27 PIO0787774 similar to collagen, type I, alpha 1 LOC730756 PIOO419903 Putative L-aspartate dehydrogenase LOC554235 PIO0165357 Isoform 1 of Metastasis-associated protein MTA3 MTA3 PIO0299406 Pituitary adenylate cyclase-activating polypeptide type I receptor precursor ADCYAP1R1 PIOO401789 Isoform 2 of Highly divergent homeobox HDX PIO0303732 Uncharacterized protein C20orf106 precursor C20orf106 PIO0016425 Isoform 2 of Synaptopodin 2-like protein SYNPO2L PIO0017640 Isoform 1 of Slithomolog 3 protein precursor SLIT2 PIO001.4577 Ras-related protein Rab-18 RAB18 PIO0023856 Peregrin BRPF1 PIO0294241 Transcription factor IIIA GTF3A PIO0025717 Metaxin-2 MTX2 PIO0023095 Myeloid leukemia factor 2 MLF2 PIO0009645 Ran-binding protein 17 RANBP17 PIO0022629 Isoform 1 of Protein regulator of cytokinesis 1 PRC1 PIO0031082 Putative uncharacterized protein DKFZp761O17121 LDOC1L PIO0788120 similar to CG1418.2-PA LOC7300.94 PIO0396063 C-myc promoter-binding protein DENND4A PIO001.3296 40S ribosomal protein S18 RPS18 PIO00043.62 MORC family CW-type zinc finger protein 1 MORC1 PIO0787625 similar to 60S ribosomal protein L23a LOC389101 PIO0385020 Putative uncharacterized protein DKFZp686D159 (Fragment) CAPRIN2 PIO0374223 hypothetical protein LOC389119 C3orf S4 PIO00396.26 Isoform D of UPF0318 protein FAM120A FAM120A PIO02952.53 Isoform 1 of Cell surface glycoprotein OX2 receptor precursor CD200R1 PIO0299040 Polycystin-2 PKD2 PIO0307165 Tripartite motif-containing protein 47 TRIM47 PIOO152685 Tetratricopeptide repeat protein 15 TTC15 PIO0013789 SET and MYND domain-containing protein 5 SMYD5 PIO0396025 hypothetical protein LOC254122 FLJ30934 PIO0014232 ADP-ribosylation factor-like protein 6-interacting protein 1 ARL6IP1 PIO0021715 Isoform 1 of Collagen alpha-5(IV) chain precursor COL4A5 PIO0026305 Hook homolog 1 HOOK1 PIOO184160 Isoform 2 of RING finger protein 180 RNF180 PIO0216308 Voltage-dependent anion-selective channel protein 1 VDAC1 PIO0651633 CASKIN1 protein (Fragment) CASKIN1 PIOO247063 Neprilysin MME PIO0398779 Isoform 4 of Plectin-1 PLEC1 PIO0168418 Putative uncharacterized protein C11orf64 C11orf64 PIOO167764 Transmembrane protein 102 TMEM102 PIOO171716 OTTHUMP00000028696 TTC28 PIO0394818 Isoform 1 of Ankyrin repeat domain-containing protein 47 |

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0028066 class IV alcohol dehydrogenase 7 mu or sigma subunit ADHZ PIO0152960 RNA polymerase I-specific transcription initiation factor RRN3 RRN3 PIOO792370 6 kDa protein GNAT1 PIOO167762 Isoform 1 of Uncharacterized protein C190rf.47 C1901.f47 PIO0385321 Isoform 2 of Protein kinase C-binding protein 1 ZMYND8 PIOO385153 HUMEEP ATXN10 PIO0337348 Growth differentiation factor 7 GDF7 PIO0060627 Coiled-coil domain-containing protein 124 CCDC124 PIOO401190 LOC155006 protein LOC155006 PIO002503.9 rRNA 2'-O-methyltransferase fibrillarin FBL PIOO479578 similar to Nonhistone chromosomal protein HMG-14 hCG 1659.830 PIO0018245 Isoform 3 of DNA-directed RNA polymerase III subunit RPC5 POLR3E PIOOO20565 PRO1598 - PIOO446711 CDNA FLJ41261 fis, clone BRAMY2034920 - PIO0787990 similar to ribosomal protein S14 LOC6441.19 PIO0218743 Isoform 2 of Bestrophin-1 BEST1 PIO0736826 similar to Temporarily Assigned Gene name family member LOC402217 PIOO412024 Zinc finger protein 485 ZNF485 PIO0297559 Isoform 1 of USH1C-binding protein 1 USHBP1 PIO0396147 Protocadherin-20 precursor PCDH2O PIOO478572 Collagen alpha-4(IV) chain precursor COL4A4 PIO0032785 Isoform II of Amyloid beta A4 precursor protein-binding family B member 3 APBB3 PIO0009982 Isoform 1 of Tudor and KH domain-containing protein TDRKH PIO0216164 Peroxisomal bifunctional enzyme EHEIADH PIOO419912 YY2 transcription factor YY2 PIO0735531 proline-rich synapse-associated protein 2 isoform 4 SHANK3 PIO0005104 Inhibitor of nuclear factor kappa-B kinase subunit alpha CHUK PIO0008837 Tyrosine-protein phosphatase non-receptor type 5 PTPN5 PI00017800 ATP-binding cassette sub-family A member 3 ABCA3 PIO0737972 Transcription factor 24 (Fragment) TCF24 PIO0374074 similar to CG40449-PA.3 LOC388795 PIO0220533 Isoform D of Transmembrane protease, serine 3 TMPRSS3 PIO0302458 Exportin-7 XPO7 PIO0646826 Putative uncharacterized protein FLJ32658 FLJ32658 PIO0016859 Isoform 1 of Transcription factor IIIB 90 kDa subunit BRF1 PIO0031386 Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha isoform PIK3CA PIOOO65547 OTTHUMP00000031495 RP11–93B14.6 PIO0043370 WD repeat-containing protein 52 WDR52 PIO0064767 Isoform 1 of Rho GTPase-activating protein 17 ARHGAP1 7 PIO021.9689 Isoform Beta of Protein vav-3 VAV3 PIO0328.291 Cytoskeleton-associated protein 2-like CKAP2L PIO0647897 RING finger protein 113B RNF113B PIO0024285 similar to testicular serine protease 2 LOC1386.52 PIO0783200 38 kDa protein RAPGEF3 PIO0014877 Isoform 2 of Glutaminyl-peptide cyclotransferase-like protein QPCTL PIOO186554 Uncharacterized protein KIAA1853 KIAA1853 PIOO418336 Isoform 2 of Integrator complex subunit 3 INTS3 PIO0872730 Macrophin 1 isoform MACF1 PIO0303207 ATP-binding cassette sub-family E member 1 ABCE1 PIO0301609 Serine/threonine-protein kinase Nek9 NEK9 PIO07445.27 Conserved hypothetical protein - PIO0302351 Isoform 1 of Serine/threonine-protein kinase 33 STK33 PIO0878483 30 kDa protein - PIO0744179 Uncharacterized protein ENSP00000370856 (Fragment) - PIO0396.279 Isoform 1 of CLIP-associating protein 1 CLASP1 PIO001.3378 Isoform Long of DNA topoisomerase 3-alpha TOP3A PIOO429.190 Ras-related protein Rab-11A RAB1 1A PIOO464994 Isoform 1 of tRNA modification GTPase GTPBP3, mitochondrial precursor GTPBP3 PIO0008449 Isoform 3 of Pre-mRNA 3’-end-processing factor FIP1 FIP1L1 PIOO414402 Olfactory receptor 2T27 OR2T27 PIO0168913 Isoform 2 of Limbin EVC2 PIO0009315 Golgi resident protein GCP60 ACBD3 PIO0871625 cDNA FLJ77072, highly similar to Homo sapiens prostaglandin E receptor 3 PTGER3 (subtype EP3) (PTGER3), transcript variant 9, mRNA PIOO479296 Isoform 1 of ATP-binding cassette sub-family A member 8 ABCA8 PIO0300221 Putative uncharacterized protein DKFZp-43411916 ELL PIO0026036 Isoform 5 of Dipeptidyl peptidase 8 DPP8 PIO0647205 Uncharacterized protein C60rf174 precursor C6Orfl 74 PIO000.6932 Isoform 1 of Putative RNA-binding protein Luc'7-like 2 LUC7L2 PIO0017819 Bile acid-CoA:amino acid N-acyltransferase BAAT PIO0145121 GPI mannosyltransferase 3 PIGB PIO0744357 Conserved hypothetical protein - US 2013/0237454 A1 Sep. 12, 2013 27

TABLE 5c-continued CSF Proteins Present in Chronic Fatigue and not in Normals or Neurologic Lyme subjects all had immunoaffinity depletion

Cº CSF Proteins 738 Gene PIO0.410320 Sodium-dependent glucose transporter SLC5A11 PIOOO65085 CDNA FLJ25371 fis, clone TSTO1885 FLJ25371 PIO0289914 MutS protein homolog 4 MSH4 PIO0012438 Isoform Long of 52 kDa repressor of the inhibitor of the protein kinase PRKRIR PIO0217895 rai-like protein SHC4 PIO0294618 Proline-rich protein PRCC PRCC PIO0000784 Isoform MEF2DAB of Myocyte-specific enhancer factor 2D MEF2D PIO0848.180 Conserved hypothetical protein - PIO0045208 Zinc finger protein 300-B ZNF300 PIO087.1452 Isoform 1 of PWWP domain-containing protein 2A PWWP2A PIO0102820 Isoform 3 of Mitochondrial tumor suppressor 1 MTUS1 PIO0215786 3',5'-cyclic nucleotide phosphodiesterase 10A2 PDE10A PIO0845401 Isoform 6 of Neuron navigator 1 NAV1 PIO0217979 Myeloid/lymphoid or mixed-lineage leukemia 5 MLL5 PIOO440764 Isoform 1 of Gamma-glutamyltransferase 6 precursor GGT6 PIO0374068 Isoform 1 of ADAMTS-like protein 4 precursor ADAMTSL4 PIO0186439 Zinc finger protein 643 ZNF643 PIO0062467 Isoform 1 of Zinc finger protein 274 ZNF274 PIO0000890 Isoform 1 of Growth hormone variant precursor GH2 PIO0065351 Zinc finger protein 354B ZNF354B PIO0552455 12 kDa protein INPP5A PIO0395.473 Zinc finger protein 135 ZNF135 PIO0003842 Isoform 1 of Microtubule-associated protein 2 MAP2 PIO06557.60 Envelope polyprotein - PIO0384767 FLJO0332 protein (Fragment) TBC1D10C PIO0028050 Selenocysteine-specific elongation factor EEFSEC PIO0152033 Isoform 1 of Transient receptor potential cation channel subfamily M member 8 TRPM8 PIO07895.64 Isoform 3 of Metallophosphoesterase 1 MPPE1 PIO001 1253 40S ribosomal protein S3 RPS3 PIOO454620 HERV-K 11q22.1 provirus ancestral Pol protein - PIO0337335 Isoform 1 of Myosin-14 MYH14 PIO0103426 Isoform 1 of Solute carrier family 13 member 3 SLC13 A3 PIO0291839 Isoform 2 of Rap guanine nucleotide exchange factor 6 RAPGEF6

TABLE 6c CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals

CleanTPI Protein Gene 00:160369 PRKCA-binding protein PICK1 002898.62 Secernin-1 SCRN1 00002478 SOIC) rm B of Endothelin-converting enzyme 1 ECE1 00027438 Flotillin-1 FLOT1 008:52669 Zinc finger protein 516 ZNF516 00017297 Matrin-3 MATR3 0064.2645 Methylenetetrahydrofolate reductase MTHFR 00470812 Puta ive uncharacterized protein DKFZp781E21107 LOC339977 00556.381 Puta ive uncharacterized protein (Fragment) TRIM16 00004569 SOIC) rm MZF1A of Myeloid zinc finger 1 MZF1 00240059 Transmembrane and coiled-coil domains protein 3 TMCC3 00022.361 Ban 3 anion transport protein SLC4A1 00017964 Sma I nuclear ribonucleoprotein Sm D3 SNRPD3 004.78640 SOIC) rm 1 of Transmembrane protein C17orf&7 C17orf&7 00013290 oma-derived growth factor-related protein 2 isoform 1 HDGF2 00011051 leukemia homeobox protein 1 TLX1 00004838 SOIC) rm Crk-II of Proto-oncogene C-crk CRK 00.154858 Plate et endothelial aggregation receptor 1 precursor PEAR1 007487.33 Simi ar to Slithomolog 3 protein precursor 00023919 26S protease regulatory subunit 8 PSMC5 00830051 Simi ar to Immunolgoobulin heavy chain LOC909.25 00007423 SOIC) rm 1 of Acidic leucine-rich nuclear phosphoprotein 32 ANP32B ami y member B 00553215 V1-5 protein IGLV2–18 00020005 Arylsulfatase E precursor ARSE 00550720 SOIC) rm 1 of Uncharacterized protein C190rf57 C 1901.f57 00.103510 Relaxin receptor 2 RXFP2 00373872 polycystin 1-like 2 isoform a PKD1 L2 US 2013/0237454 A1 Sep. 12, 2013 28

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0015181 Integrin alpha-9 precursor ITGA9 PIO0013945 Isoform 1 of Uromodulin precursor |UMOD PIO0295172 Ninjurin-1 NINJ1 PIO0328522 KTEL motif-containing protein 1 KTELC1 PIO0000811 Proteasome subunit beta type-6 precursor PSMB6 PIO0847415 Isoform 4 of Dual specificity protein kinase CLK3 CLK3 PIO0251596 Isoform 1 of Collagen alpha-1(XXIII) chain COL23A1 PIO0550906 Cleavage stimulation factor 64 kDa subunit, tau variant CSTF2T PIO0550263 Isoform 5 of Serine/threonine-protein kinase MRCK alpha CDC42BPA PIO0045219 Sorting nexin-18 SNAG1 PIO0063245 Uncharacterized protein FUBP3 FUBP3 PIO0221235 nucleoporin 160 kDa NUP 160 PIO0167560 PAP-associated domain-containing protein 4 PAPD4 PIO0005719 Isoform 1 of Ras-related protein Rab-1A RAB1A PIO0013933 Isoform DPI of Desmoplakin DSP PIO0098902 2-oxoglutarate dehydrogenase E1 component, OGDH mitochondrial precursor PIO0012079 Eukaryotic translation initiation factor 4B EIF4H PIO0005793 AP-3 complex subunit beta-2 AP3B2 PIO0289271 Liprin-alpha-2 PPFIA2 PIO0216470 Isoform 1 of Phosphatidylinositol-5-phosphate 4-kinase PIP4K2B type-2 beta PIO0.410391 Isoform 1 of Major facilitator superfamily domain- MFSD2 containing protein 2 PIOO441952 Isoform 1 of Ninein NIN PIO0744825 Conserved hypothetical protein - PIO0016940 Phospholipid scramblase 2 PLSCR2 PIO0217264. Isoform 3 of MAP7 domain-containing protein 3 MAP7D3 PI00005675 NF-kappa-B-repressing factor NKRF PIO0218628 Isoform 2 of Integrin alpha-IIb precursor ITGA2B PIO0217989 Isoform 1 of Protein-associating with the carboxyl-terminal SCYL3 domain of ezrin PIO0217405 Isoform 1 of E3 ubiquitin-protein ligase UBR1 |UBR1 PIO0829915 similar to PR domain zinc finger protein 16 LOC6478.68 PIOO455731 Protein FAM26F FAM26F PIOO411656 Isoform 1 of Protein piccolo PCLO PIO0217258 CCDC100 protein CCDC100 PIO0604430 Isoform 2 of Receptor expression-enhancing protein 2 REEP2 PIOO456670 Isoform 13 of Peroxisomal N(1)-acetyl- PAOX spermine?spermidine oxidase PIOO414927 Transmembrane and immunoglobulin domain-containing C1 Orf}2 protein C10tfº PIO087.1458 39 kDa protein C10orf.4 PIO010.1299 C1GALT1-specific chaperone 1 C1GALT1 C1 PIO0186621 Orofacial clefting chromosomal breakpoint region 1 OFCC1 PIO0295098 Signal recognition particle receptor subunit beta SRPRB PIO0071824 Isoform 1 of Cytoskeleton-associated protein 2 CKAP2 PIO0747494 Glutamate receptor delta-2 subunit precursor GRID2 PIO0879409 28 kDa protein - PIO0760941 Uncharacterized protein ENSP00000371687 DKFZp-434J1015 PIOO169259 Small VCP/p07-interacting protein SVIP PIO0514966 Recombining binding protein suppressor of hairless RBPJL PIO0106506 Isoform 1 of Evolutionarily conserved signaling ECSIT intermediate in Toll pathway, mitochondrial precursor PIO0006900 Something about silencing protein 10 UTP3 PIO0021772 S-adenosylmethionine synthetase isoform type-1 MAT1A PIOO472332 similar to polyhomeotic 1-like isoform 4 LOC653441 PIO0240909 similar to eukaryotic translation initiation factor 3, subunit 5 hCG 15200 PIO0004671 Golgin subfamily B member 1 GOLGB1 PIO0789245 Isoform 2 of Probable organic cation transporter protein SLC22A23 C6Orf&5 PIO0291922 Proteasome subunit alpha type-5 PSMA5 PIO0217899 RING finger protein 168 RNF168 PIO0242905 Uncharacterized protein ENSP00000344689 (Fragment) - PIO0152145 Protein odd-skipped-related 1 OSR1 PIO0152462 Ciliary dynein heavy chain 3 DNAH3 PIO0021770 Isoform 1 of 3-hydroxy-3-methylglutaryl-coenzyme A HMGCR reductase PIOO465045 DIP2 disco-interacting protein 2 homolog B DIP2B PIO0004509 Leukotriene N synthase LTC4S PIO0018803 homeobox D12 HOXD12 PIO0884371 Uncharacterized protein ENSP00000383215 - US 2013/0237454 A1 Sep. 12, 2013 29

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0002881 Bcl-2-related protein A1 BCL2A1 PIO0021594 Isoform 1 of Glycosylphosphatidylinositol anchor GPAA1 attachment 1 protein PIO0010360 Isoform 1 of Collagen alpha-3(IV) chain precursor COL4A3 PIO0022890 Ig lambda chain V region 4A precursor GLV7–43 PIO0219468 Isoform IIa of Profilin-2 PFN2 PIO0065352 Isoform 1 of Uncharacterized serine/threonine-protein FLJ25006 kinase Sgk294 PIO0000388 Zinc finger protein 175 ZNF175 PIO0017163 Isoform 1 of E3 ubiquitin-protein ligase HECW2 HECW2 PIOO465044 Protein RCC2 RCC2 PIO0013847 Cytochrome b-c1 complex subunit 1, mitochondrial UQCRC1 jite Cui SOjº PIO0394807 Regenerating islet-derived protein 3 gamma precursor REG3G PIO0024248 Sodium/iodide cotransporter SLC5A5 PIO0022830 Isoform 2 of NSFL1 cofactor p37 NSFL1C PIO0026665 Glutaminyl-tRNA synthetase QARS PIO0180386 Isoform GN-1L of Glycogenin-1 GYG1 PIOO465345 Isoform 3 of Pre-mRNA-processing factor 40 homolog B PRPF40B PIO0065388 Isoform 1 of Coiled-coil domain-containing protein 17 CCDC17 PIO0289540 Isoform 2 of Usherin precursor |USH2A PIOO748.216 CDNA FLJ20187 fis, clone COLFO433 GTF3C5 PIO0167638 Isoform 1 of GTP-binding protein 10 GTPBP10 PIO0294.713 Isoform 1 of Mannan-binding lectin serine protease 2 MASP2 jite Cui SOjº PIO0022143 Isoform 1 of Extended-synaptotagmin-1 FAM62A PIO0023663 Putative transcription factor Ovo-like 1 OVOL1 PIO0003406 Isoform 1 of Drebrin DBN1 PI00015602 Mitochondrial precursor proteins import receptor TOMMZOA PIOOO72377 ISOform 1 Of Protein SET SET PIO0554752 caNMP-dependent protein kinase type II-beta regulatory PRKAR2B subunit PIO0011604 Glycine cleavage system H protein, mitochondrial GCSH; LOC730.107 jite Cui SOjº PIOO401586 Chromosome 18 open reading frame 62 C18Orf62 PIO0026492 2-amino-3-ketobutyrate coenzyme A ligase, mitochondrial GCAT jite Cui SOjº PIO0384861 Isoform 1 of ARF GTPase-activating protein GIT1 GIT1 PIO0644529 Isoform 2 of Zinc finger protein 615 ZNF615 PIO0028880 Putative DNA polymerase POLN PIO0020008 NEDD8 precursor NEDD3 PIO0180707 Isoform 1 of FMS1-related extracellular matrix protein 2 FREM2 jite Cui SOjº PIO0014878 Uncharacterized protein PRKD1 PRKD1 PIO0794791 Isoform 2 of IQ domain-containing protein D IQCD PIO0009853 Vomeronasal type-1 receptor 1 VN1 R1 PIO0022250 Lymphocyte antigen 96 precursor LY96 PIO0332371 Isoform 1 of 6-phosphofructokinase, liver type PFKL PIO0004337 Zinc finger and BTB domain-Containing protein 11 ZBTB11 PIOO478860 Glycoprotein endo-alpha-1,2-mannosidase MANEA PIO0005708 Heparan sulfate glucosamine 3-O-sulfotransferase 3B1 HS3ST3B1 PIO0169430 Isoform 1 of Spermatid perinuclear RNA-binding protein STRBP PIO0007057 Rabenosyn-5 ZFYVE20 PIO0386822 Putative uncharacterized protein (Fragment) TGFBI PIOO477539 Uncharacterized protein C14orf102 C14Orf102 PIO02962.19 Glutaminase liver isoform, mitochondrial precursor GLS2 PIO0005564 Stanniocalcin-1 precursor STC PIO0376087 putative binding protein 7as 7A5 PIOO413344 Cofilin-2 CFL2 PIO000.6648 IDN4-GGTR14 protein RABGAP1L PIO0302176 Isoform 1 of H/ACA ribonucleoprotein complex subunit 1 NOLA1 PIO0014850 Astrocytic phosphoprotein PEA-15 PEA15 PIO0794679 Major histocompatibility complex, class I, B MICA; HLA-B; HLA A: LOC730410; HLA C; HLA-A29.1 PIO0008282 Isoform 1 of Calcium/calmodulin-dependent 3',5'-cyclic PDE1A nucleotide phosphodiesterase 1A PIO0007277 Isoform 1 of Leucine-rich repeat flightless-interacting LRRFIP2 protein 2 PIO0294519 Isoform 1 of Telomerase protein component 1 TEP1 PIOO478586 Isoform 2 of Vacuolar protein sorting-associated protein VPS13A 13A US 2013/0237454 A1 Sep. 12, 2013 30

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0060439 KIAA0226 protein KIAA0226 PIO0303343 Splicing factor, arginine/serine-rich 19 SCAF1 PIO0179589 Myotrophin MTPN PIO0744811 Low-density lipoprotein receptor-related protein 5 LRP5 jite Cui SOjº PIO0031485 Mitochondrial ribosomal protein 63 MRP63 PIO0784044 Isoform 1 of Methylcrotonoyl-CoA carboxylase beta chain, MCCC2 mitochondrial precursor PIO0869070 Ankyrin repeat containing protein - PIO0783186 Isoform 2 of Ankyrin repeat domain-containing protein 17 ANKRD17 PIO0303152 collagen, type XXII, alpha I COL22A1 PIOO429191 Eukaryotic peptide chain release factor subunit 1 ETF1 PIO0514594 Isoform 1 of Protein FAM5B precursor FAMSB PIO0853376 additional sex combs like 3 ASXL3 PIO0216914 Vitelline membrane outer layer protein 1 homolog VMO1 jite Cui SOjº PIOO423379 Putative uncharacterized protein DKFZp686G24.192 C20Orfø6 PIO0025308 Homeobox protein prophet of Pit-1 PROP1 PIO0219358 Isoform 1 of Mannose-6-phosphate isomerase MPI PIOO400967 KIAA1843 protein (Fragment) ÇIAA1843 PIO0166010 Isoform 1 of CCR4-NOT transcription complex subunit 1 CNOT1 PIO0793576 7 kDa protein PRH2; PRB4; PRH1 PIO0307757 Isoform 1 of Membrane-associated phosphatidylinositol PITPNM3 transfer protein 3 PIO0166738 Zinc-binding alcohol dehydrogenase domain-containing ZADH2 protein 2 PIO0399252 Isoform 1 of Protein Jade-1 PHF17 PIOO412977 Prothymosin alpha - PI00396077 Isoform 1 of E3 ubiquitin-protein ligase Topors TOPORS PIO0144243 Human immunodeficiency virus type I enhancer-binding HIVEP2 protein 2 PIOO446355 CDNA FLJ41803 fis, clone NHNPC2002749 ERSL PIOO167861 Protein SMG5 SMG5 PIO0005530 FMRFamide-related peptides precursor NPVF PIOO186004 hypothetical protein LOC57730 &IAA1641 PIOO465178 Isoform 1 of Vacuolar proton translocating ATPase 116 kDa ATP6V0A1 subunita isoform 1 PIO0291463 Radical S-adenosyl methionine domain-containing protein 2 RSAD2 PIOO472171 RPL7 protein RPL7 PIO0187091 Isoform 2 of MAP kinase-interacting serine/threonine- MKNK1 protein kinase 1 PIO0398421 Isoform 1 of Potassium channel subfamily T member 2 KCNT2 PIO0007040 Zinc finger protein 222 ZNF222 PIO0220578 Guanine nucleotide-binding protein G GNAI3 PIO0740191 similar to Forkhead box protein L1 LOC651986 PIO0044607 Protein phosphatase inhibitor 2-like protein 1 PPP1R2P1 PIO0301923 Isoform 1 of Cell division protein kinase 9 CDK9 PIO0255145 hypothetical protein LOC342346 PIO0022228 Vigilin HDLBP PIO0010737 Thrombomodulin precursor THED PIO0059395 Kinesin-like protein KIFC2 KIFC2 PIO0030319 Forkhead box protein F2 FOXF PIO0168806 Isoform 1 of Myeloid/lymphoid or mixed-lineage leukemia MLL3 protein 3 homolog PIO0018275 Prion-like protein doppel precursor PRND PIO0216704 Isoform 2 of Spectrin beta chain, erythrocyte SPTB PIO0034277 Isoform A of Probable cation-transporting ATPase 13A1 ATP13A1 PIO0015285 Ethanolamine-phosphate cytidylyltransferase PCYT2 PIO0152853 Isoform 1 of Phostensin ÇIAA 1949 PIO0302850 Small nuclear ribonucleoprotein Sm DI SNRPDI PIOO478.124 61 kDa protein UCKL1 PIO0013681 N-terminally extended type 3 canonical transient receptor TRPC3 potential channel PIOO446785 CDNA FLJ41116 fis, clone BRACE1000572 - PIO0784272 Putative uncharacterized protein - PIO0293460 ATP-binding cassette sub-family A member 1 ABCA1 PIO0019208 Similar to 60S ribosomal protein L29 - PIO0304596 Non-POU domain-containing octamer-binding protein NONO PIOO411452 Uncharacterized protein DOCK11 DOCK11 PIOO444395 CDNA FLJ45615 fis, clone BRTHA3026180 - PIO0019278 Thiamine transporter 2 SLC19A3 PIO0012895 Isoform 1 of Carbonic anhydrase 12 precursor CA12 US 2013/0237454 A1 Sep. 12, 2013 31

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0299627 Dual oxidase 2 precursor DUOX2 PIO0216132 Isoform Alpha 1 of Ribosomal protein S6 kinase beta-1 RPS6KB1 PIO0023513 Isoform 1 of E3 ubiquitin-protein ligase CHFR CHFR PIO0063827 Isoform 1 of Abhydrolase domain-containing protein 14B ABHD14E PIO0025019 Proteasome subunit beta type-1 precursor PSMB1 PIO0328115 Isoform 3 of 5'-3' exoribonuclease 1 XRN1 PIO0022048 Prostaglandin F2 receptor negative regulator precursor PTGFRN PIO0103055 Isoform 1 of Solute carrier family 35 member F5 SLC35F5 PIOO1671.94 CDNA FLJ25694 fis, clone TSTO4471 FLJ25694 PIO0002966 Heat shock 70 kDa protein 4 HSPA4 PIO0152536 Isoform 1 of Transmembrane channel-like protein 2 TMC2 PIO0783271 Leucine-rich PPR motif-containing protein, mitochondrial LRPPRC jite Cui SOjº PIO0298476 Isoform 1 of Gremlin-1 precursor GREM1 PIOO1500.57 Isoform 2 of SWI/SNF-related matrix-associated actin- SMARCC2 dependent regulator of chromatin subfamily C member 2 PIOO456996 Conserved hypothetical protein PVT1 PIO0232891 Isoform 3 of Fibronectin type III domain-containing protein 1 FNDC1 PIO0018402 Tubulin-specific chaperone E TBCE PIOO166817 Zinc finger protein 561 ZNF561 PIO0375174 Ankyrin repeat and sterile alpha motif domain-containing ANKS 1B protein 1B PIO0030404 Transcriptional repressor NF-X1 NFX1 PIO0296866 interphotoreceptor matrix proteoglycan 2 IMPG2 PIO0219661 Isoform 1 of Myelin proteolipid protein PLPI PIO0040730 protocadherin 21 precursor PCDH21 PIO0013508 Alpha-actinin-1 ACTN1 PIO0186853 pecanex-like 2 PCNXL2 PIO0001120 CDNA F1131810 fis, clone NT2RI2009289, weakly LINGO2 Similar to CARBOXYPEPTIDASE N 83 KD CHAIN PIO0395376 Isoform 1 of Semaphorin-5B SEMASB PIO0555621 p21-activated kinase 2 variant (Fragment) - PIO0746232 coiled-coil domain containing 112 isoform 2 CCDC112 PIO002.2020 Type II inositol-3,4-bisphosphate 4-phosphatase NPP4B PIO0644231 Isoform 1 of Cytoplasmic FMR1-interacting protein 1 CYFIP1 PIO0007193 Isoform 2 of Ankyrin repeat domain-containing protein 26 ANKRD26 PIOO418236 Factor in the germline alpha FIGLA PIO0328762 Isoform 1 of ATP-binding cassette sub-family A member ABCA13 3 PIO0748342 Beclin-1 BECN1 PIO0739423 similar to c11.1 CG12132-PA isoform 11 LOC377711 PIO0026970 FACT complex subunit SPT16 SUPT16H PIO0013466 Arsenical pump-driving ATPase ASNA1 PIO0016605 Uncharacterized protein C10rf123 C1orf123 PIO0872861 PTDO16 protein LOC51 136 PIO00101.30 Glutamine synthetase GLUL PIOO166619 Isoform 2 of Putative transporter SVOPL SVOPL PIO0549.384 Isoform 1 of Bromodomain-containing protein 9 BRD9 PIOO4.79893 Isoform 2 of Uncharacterized protein C10orf18 C10orf18 PIOO410585 Isoform 1 of Crumbs homolog 2 precursor CRB2 PIO0876910 Isoform 1 of Ankyrin repeat and SOCS box-containing ASB18 protein 18 PIO0008202 Headcase protein homolog HECA PIOO477766 Isoform 3 of Protein PTHE1 BBS9 PIO0029722 Kinesin heavy chain isoform 5A KIF5A PIO030.1503 Isoform 1 of Splicing factor, arginine/serine-rich 10 SFRS10 PIO0031696 FAST kinase domain-containing protein 3 FASTKD3 PIOO425688 Isoform I of RUN and SH3 domain-containing protein 1 RUSC1 PIO0787427 ankyrin repeat domain 36 ANKRD36 PIO0796647 HIG1 domain family, member 1C HIGD1 C PIO0852758 Similar to Ankyrin repeat domain-containing protein 26. ANKRD18B Soform 2 PIO0023087 Ubiquitin-conjugating enzyme E2 T UBE2T PIO0167241 Zinc finger protein 283 ZNF283 PIO0220325 Isoform Short of Insulin receptor precursor NSR PIOO465322 Uncharacterized protein BOC BOC PIO0161119 Isoform 1 of NF-kappa-B inhibitor beta NFKBIB PIO0016577 CDNA: FLJ22814 fis, clone KAIA3004 CD22 PIO0032541 Keratin type II cuticular Hbs KRT85 PIO0852633 16 kDa protein RABL2B US 2013/0237454 A1 Sep. 12, 2013 32

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIOO163391 Isoform 1 of Putative methyltransferase METT10D METT10D PIO0299679 Isoform B of Ral guanine nucleotide dissociation stimulator R GL1 ike 1 PIO0797699 20 kDa protein - PIO0384874 Isoform 1 of ATP-binding cassette sub-family A member ABCA10 O PIO0019690 death-inducing-protein DIP PIOO794119 13 kDa protein ABCC8 PIO0027723 Elastase-2B precursor ELA2B PIO0816274 Chemokine-like factor superfamily 1 transcript variant 26 CMTM1 PIO0015737 15 kDa protein DCAKD PIO0641954 22 kDa protein TMED5 PIO0739676 Isoform 2 of Protein DDX26B DDX26B PIO0038378 Isoform 1 of Enolase-phosphatase E1 ENOPH1 PIO0171737 Isoform 2 of Leucine-rich repeat and death domain- LRDD containing protein PIO0385003 Putative transposase TIGD1 PIOO477763 Serine/threonine-protein kinase MRCK beta CDC42BPB PIO0029123 Isoform A of Endothelin B receptor precursor EDNRB PIO0158992 snRNA-activating protein complex subunit 4 SNAPC4 PIOO402006 Similar to DNA-binding protein - PIO0306576 Arylsulfatase B precursor ARSB PIO0184997 cDNA FLJ78771, highly similar to Homo sapiens discs, DLG7 large homolog 7 (Drosophila), mRNA PIOO477949 Isoform 1 of Zinc finger MYM-type protein 4 ZMYM4 PIO0001869 Pappalysin-1 precursor PAPPA PIO0027834 heterogeneous nuclear ribonucleoprotein L isoform a HNRNPL PIO0062730 Uncharacterized protein C16orf245 C16orf245 PI00737448 similar to heat shock 70 kD protein binding protein LOC338805 PIO0298258 UNC13B protein UNC13 B PIO0383261 Peroxin Pexop PEX6 PIO0022735 Synaptotagmin-4 SYT4 PIO0003391 Teneurin-1 ODZ.1 PIO0744366 Conserved hypothetical protein - PIO0000792 Quinone oxidoreductase CRYZ PIO0008905 UDP-glucuronosyltransferase 2B15 precursor |UGT2B15 PIO0031411 Cadherin-related tumor suppressor homolog precursor FAT PIO0026058 Isoform 1 of Leucine zipper putative tumor suppressor 1 LZTS1 PIO0377077 Isoform 3 of Astrotactin-2 precursor ASTN2 PIOO479789 Isoform 1 of Uncharacterized protein Clorf103 C1 Orfl03 PIO0186581 amplified in osteosarcoma isoform 2 precursor OS 9 PIOO445364 CDNA FLJ44171 fis, clone THYMU2036058 - PIO0.41 1637 Galactose-3-O-sulfotransferase 4 GAL3ST4 PIOO154834 Isoform 1 of Neighbor of punce11 precursor NOPE PIO0216697 Isoform Er1 of Ankyrin-1 ANK1 PIO0021985 transmembrane 9 superfamily protein member 4 TM9SF4 PIO0166071 B-cell CLL/lymphoma 6 member B protein BCL6B PIO0007360 Zinc finger protein 238 ZNF238 PIO0217023 MMAA protein MMAA PIO0218130 Glycogen phosphorylase, muscle form PYGM PIO0384280 Prenylcysteine oxidase 1 precursor PCYOX1 PIOO152733 FLJO0237 protein (Fragment) OLFML2A PIO0034006 Tyrosine-protein phosphatase non-receptor type 23 PTPN23 PIO0793585 57 kDa protein OC90 PIOO419253 Isoform 1 of Nck-associated protein 5 NAP5 PIO0029133 ATP synthase subunit b, mitochondrial precursor ATP5F1 PIOO178727 Novel protein C10orf79 PIO0218271 Isoform 3 of MAGUK p55 subfamily member 2 MPP2 PIO0003949 Ubiquitin-conjugating enzyme E2 N |UBE2IN PIO0292393 Sodium channel protein type 4 subunit alpha SCN4A PIO0304992 Isoform 1 of Zinc finger protein 503 ZNF503 PIO0029012 Eukaryotic translation initiation factor 3 subunit A EIF3A. PIO0043.201 Centromere protein J CENPJ PIO0022891 ADP/ATP translocase 1 SLC25A4 PIO0006612 Isoform 1 of Clathrin coat assembly protein AP180 SNAP91 PIO0385042 Nucleolar GTP-binding protein 1 GTPBP4 PIO0642305 MCM8 protein MCM8 PIO0.402144 Isoform 1 of Zinc finger protein 555 ZNF555 PIOO478986 Similar to 40S ribosomal protein S4 LOC126235 PIO0029623 Proteasome subunit alpha type-6 PSMA6 PIO0026320 E3 ubiquitin-protein ligase UBR5 |UBR5 PIO0010142 Ubiquitin-conjugating enzyme E2 G2 |UBE2G2 US 2013/0237454 A1 Sep. 12, 2013 33

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIOO478521 Isoform 1 of UPF0475 protein RILPL.1 PIO0029769 Isoform p59-HCK of Tyrosine-protein kinase HCK HCK PIOO446138 CDNA FLJ42768 fis, clone BRAWH3003522 - PIO0046057 Isoform 2 of Syntaxin-binding protein 1 STXBP1 PIOO449071 Isoform 5a of Paired box protein Pax-6 PAX6 PIO0328268 EIF4G3 protein EIF4G3 PIOO305477 Cystatin-SN precursor CST1 PIOO432893 INPP5E protein (Fragment) NPP5E PIO0220039 Isoform 1 of Transmembrane protein 16K TMEM16K PIO0021347 Ubiquitin-conjugating enzyme E2 L3 UBE2I.3 PIO0025700 Isoform CD6A of T-cell differentiation antigen CD6 CD6 jite Cui SOjº PIO0061507 Isoform 3 of Ester hydrolase C11orf54 C11orf54 PIO0000270 Ribonuclease 7 precursor RNASE7 PIOO479430 Isoform 2 of Complement C1q tumor necrosis factor- CIQTNF9 related protein 9 precursor PIO0386754 Isoform 2 of Cysteine-rich with EGF-like domain protein 2 CRELD2 jite Cui SOjº PIO0016949 Isoform 4 of Electrogenic sodium bicarbonate cotransporter 1 SLC4A4 PIO0031547. Desmoglein-3 precursor DSG3 PIO0382756 Isoform 2 of Pleiotropic regulator 1 PLRG1 PIO0604599 Transmembrane emp24 domain-containing protein 3 TMED3 jite Cui SOjº PIO0296798 Isoform 1 of Fibrinogen C domain-containing protein 1 FIBCD1 PIO0743284 Methionine synthase MTR PIO0021363 Histone demethylase JARID1A JARID1A PIO0749440 Uncharacterized protein ENSP00000368180 - PIO0216683 M-phase inducer phosphatase 3 CDC25C PI00737969 microtubule associated monoxygenase, calponin and LIM MICAL3 domain containing 3 PIO0015522 Growth/differentiation factor 5 precursor GDF5 PIO0877084 Isoform 1 of Coiled-coil domain-containing protein 144C CCDC144C PIO0060265 Zinc finger protein 775 ZNF175 PIO0171199 Isoform 2 of Proteasome subunit alpha type-3 PSMA3 PIO0003483 Isoform 1 of Neuralized-like protein 1 NEURL PIO0024802 TATA-binding protein-associated factor 172 BTAF1 PIO0374039 Conserved hypothetical protein C1 Orfl 89 PIOO419575 Protein of unknown function DUF410 family protein C7orf20 PIO0019090 Collagen alpha-1 COL19A1 PIO0011756 Homeobox protein Meis1 MEIS1 PIO0021834 Isoform Alpha of Tissue factor pathway inhibitor precursor TFPI PIO0167254 Isoform 4 of Inactive phospholipase D5 PLD5 PIOO44.2121 delta-aminolevulinic acid dehydratase isoform a ALAD PIO0013455 CLIP1 protein CLIP1 PIO0026299 Isoform Glycophorin C of Glycophorin-C GYPC PIO0012687 27 kDa protein C1 Orfè3 PIO0845508 BAH domain and coiled-coil containing 1 BAHCC1 PIO0332106 Isoform 1 of Pre-B-cell leukemia transcription factor- PBXIP1 interacting protein 1 PIOO418426 Metal transporter CNNM4 CNNM4 PIO0002524 ATP-sensitive inward rectifier potassium channel 14 KCNJ14 PIO0745300 31 kDa protein NAT11 PIO0000110 Zinc finger protein 337 ZNF337 PIO0009148 Diphosphoinositol polyphosphate phosphohydrolase 1 NUDT3 PIO0297767 Casein kinase I isoform gamma-2 CSNK1 G2 PIOO186826 Ephrin receptor EPHB4 PIO0787932 similar to zinc finger protein 10 hCG 1646157 PIO0007207 Isoform 1 of Lysosomal acid lipase/cholesteryl ester LIPA hydrolase precursor PIO0023868 Canalicular multispecific organic anion transporter 1 ABCC2 PIOO1661 61 Protein SIX6C)S1 C14Orf$9 PIO0180426 Isoform 3 of G protein-coupled receptor kinase 4 GRK4 PIO0031522 Trifunctional enzyme subunit alpha, mitochondrial HADHA jite Cui SOjº PIO001.3219 Integrin-linked protein kinase ILK PIO0070070 Novel protein FLJ32784 PIO0329142 Glutamate-rich protein 1 ERICH1 PIOO169253 Olfactory receptor OR1-45 ORSAT1 PIO0045801 Flt3-interacting zinc finger protein 1 FIZ1 PIO0017802 Isoform 1 of Methylglutaconyl-CoA hydratase, AUH mitochondrial precursor PIO0796906 8 kDa protein ABCF3 US 2013/0237454 A1 Sep. 12, 2013 34

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0384549 TTC31 protein (Fragment) TTC31 PIO0028932 Microtubule-associated serine/threonine-protein kinase 3 MAST3 PIO001.2756 Interferon-induced protein with tetratricopeptide repeats 5 FITS PIO0297985 Uncharacterized protein C60rf103 Côorf103 PIO0514394 Family with sequence similarity 120A opposite strand FAM120AOS PIO0034088 Interleukin-27 beta chain precursor EBIG PIOO305856 Homeobox protein Hox-D11 HOXD11 PIO0387159 Isoform 1 of Inhibitor of growth protein 3 NG3 PIO0737429 Teneurin-4 ODZ4 PIO0645089 Kv channel interacting protein 1 isoform 3 KCNIP1 PIO0797859 10 kDa protein LOC6437.11 PIO0385737 similar to Nonhistone chromosomal protein HMG-17 LOC646853 PIO0015195 Cleavage stimulation factor 77 kDa subunit CSTF3 PIO0006158 Lymphoid-restricted membrane protein LRMP PIO0008554 Angiogenin precursor ANG PIOO412216 vacuolar protein sorting 13C protein isoform 2B VPS13C PIO00281.58 Neurotensin/neuromedin N precursor NTS PIO0020884 Plexin-A3 precursor PLXNA3 PIO0374862 Isoform 1 of Kelch-like protein 5 KLHL5 PIO0384393 Myosin-reactive immunoglobulin heavy chain variable - region (Fragment) PIOOOO!9377 HSPC212 C3orf19 PIO0005969 F-actin-capping protein subunit alpha-1 CAPZA1 PIO0021129 Isoform 1 of AP-3 complex subunit beta-1 AP3B1 PIO001.3871 Ribonucleoside-diphosphate reductase large subunit RRM1 PIO0020039 Cylicin-1 CYLC1 PIO0300244 zinc finger, CW type with PWWP domain 1 ZCWPW1 PIO0060308 Isoform 6 of PDZ and LIM domain protein 7 PDLIM7 PI00333410 Isoform 1 of Ubiquitin-conjugating enzyme E2 Q1 UBE2O1 PIO0737712 CCDC125 protein CCDC125 PIO0219036 dicer1 DICER1 PIO0168862 Conserved hypothetical protein PXT1 PIO0025647 Isoform 1 of F-box only protein 21 FBXO21 PIOO218075 Protein FAM9B FAM9B PIO0738499 Ferritin light chain FTL PIOO297212 Paladim ÇIAA1274 PIO0252845 SYT9 protein SYT9 PIOO477361 10 kDa protein SDHALP1 PIOO418185 Putative uncharacterized protein FLJ20097 CCDC132 PIOO423562 Isoform 1 of Ubiquitin carboxyl-terminal hydrolase 6 USP6 PIO0397578 135 kDa protein PPFIA4 PIO0004101 Betaine--homocysteine S-methyltransferase 1 BHMT PIO0017659 Protein kinase substrate CapzIP RCSD1 PIO0025094 CDNA: FLJ22037 fis, clone HEP08868 (Fragment) MYH16 PIO0008475 Hydroxymethylglutaryl-CoA synthase, cytoplasmic HMGCS1 PIO0023315 Bone morphogenetic protein 3b precursor GDF10 PIOO412107 FLJ43980 protein FLJ43980 PIO0328793 Sterol regulatory element-binding protein 2 SREBF2 PIO0216963 Isoform 9 of CASP8 and FADD-like apoptosis regulator CFLAR jite Cui SOjº PIO0010895 Tubby-related protein 2 TULP2 PIO0739106 similar to ribosomal protein L5 isoform 1 LOC647436 PIO0022606 Isoform 1 of Proline-serine-threonine phosphatase- PSTPIP1 interacting protein 1 PIO0004563 Protein FAM105. A FAM105A PIO0550232 cardiomyopathy associated 3 isoform 1 XIRP2 PIO0299147 Small ubiquitin-related modifier 3 precursor SUMO3 PIO0295.502 Isoform 1 of Protein Wiz WIZ PIOO43.5925 PP14214 GFBP3 PIO0216106 Isoform 3 of Obg-like ATPase 1 OLA1 PIO001.3257 Single-stranded DNA-binding protein 4 SSBP4. PIO0002707 Isoform 1 of Spastin SPAST PIO0010118 Isoform 1 of Prostate tumor overexpressed gene 1 protein PTOV1 PIO0158804 basic, immunoglobulin-like variable motif containing BIVM PIOO166606 KIAA0913 protein (Fragment) ÇIAA0913 PIO0329014 Isoform 1 of Ankyrin repeat domain-containing protein 46 ANKRD46 PIO0300990 Isoform 1 of Uncharacterized protein Clorf77 C1Orf77 PIO0741.780 similar to CG4845–PA LOC65.2559 PIO0395603 Isoform 3 of Uncharacterized protein C18Orf34 C18Orf$4 PIOO454858 similar to alpha 3 type VI collagen isoform 1 precursor LOC344875

US 2013/0237454 A1 Sep. 12, 2013 36

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0000203 Low-density lipoprotein receptor-related protein 6 LRP6 jite Cui SOjº PIO0749338 Hypothetical gene supported by BC063892 hCG 1651889 PIO0221009 Isoform 7 of Transcription factor 7-like 2 TCF7L2 PIO0101927 Leucine zipper putative tumor suppressor 2 LZTS2 PIO0010346 Neurolysin, mitochondrial precursor NLN PIO0398725 Isoform 1 of Zinc finger protein 644 ZNF644 PIO0745832 IQ calmodulin-binding region domain containing protein - PIOO167228 CDNA FLJ40966 fis, clone UTERU2012.407 CHCHD7 PIO0216572 Barh-like homeobox 2 BARX2 PIO0007067 Golgi-associated plant pathogenesis-related protein 1 C90 rifl 9 PIO0.410616 Isoform 1 of Endonuclease VIII-like 2 NEIL2 PIO0644025 Isoform 1 of Synaptic vesicle glycoprotein 2A SV2A PIO0005978 Splicing factor, arginine/serine-rich 2 SFRS2 PIO0171647 Isoform 1 of Sialic acid-binding Ig-like lectin 8 precursor SIGLEC8 PIO0020058 Isoform I of Copper-transporting ATPase 2 ATP7B PIO0844512 RHOV protein (Fragment) RHOV PIO0026570 Cytochrome c oxidase polypeptide VIIa-liver/heart, COX7A2 mitochondrial precursor PIO0021997 Protein CREG1 precursor CREG1 PIO08793.89 20 kDa protein ZMYND11 PIO0329251 Isoform 1 of Transmembrane protein 146 precursor TMEM146 PIO0027726 Isoform 1 of Krueppel-like factor 3 ÇLF PIO0064.241 Isoform 1 of Zinc finger protein Eos KZF4 PIO0295503 Isoform 2 of Probable ATP-dependent RNA helicase DDX58 DDX58 PIOO465087 Ubiquitin carboxyl-terminal hydrolase BAP1 BAP1 PIO0290292 Rhomboid 5 homolog 1 RHBDF1 PIO0251507 Isoform IB of Synapsin-1 SYN1 PIO0103812 PWWP domain-containing protein 2B PWWP2B PIO0008580 Antileukoproteinase precursor SLPI PIO0010953 CDNA FLJ11251 fis, clone PLACE1008813 EXOC6 PIO0639924 97 kDa protein LOC374920 PIO0003348 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit GNB2 beta-2 PIO0029533 Integrin beta-8 precursor TGB3 PIO0815786 Hexokinase 1 (Fragment) HK1 PIO0292579 Stabilin-2 precursor STAB2 PIO0067920 FXYD domain-containing ion transport regulator 7 FXYD7 PIO08791.62 Uncharacterized protein ENSP00000374866 - PIO0008998 Protein tyrosine phosphatase-like protein PTPLAD1 PTPLAD1 PIO0658112 32 kDa protein SPEG PIO0009804 DNA-binding protein SATB1 SATB1 PIOO479361 Isoform 1 of UDP-GlcNAc:betaGal beta-1,3-N- B3GNT4 acetylglucosaminyltransferase 4 PIOO448465 Isoform 1 of Ankyrin repeat domain-containing protein 12 ANKRD12 PIO0215925 Glycine N-methyltransferase GNMT PIO000.6675 Multidrug resistance-associated protein 4 ABCC4 PIO0745122 Conserved hypothetical protein MGC33894 PIOO442551 CDNA FLJ26989 fis, clone SLV03395 ATP9B PIO0027436 Tumor necrosis factor receptor superfamily member 16 NGFR jite Cui SOjº PIO0005531 Isoform 1 of Probable DNA dC->dU-editing enzyme APOBEC3H APOBEC-3B PIO0023542 transmembrane emp24 protein transport domain containing 9 TMED9 PIO0783313 Glycogen phosphorylase, liver form PYGL PIOO166190 Isoform 1 of Uncharacterized protein C190rf19 C 1901.fl.9 PIO0383832 Protein kinase C-binding protein RACK8 DVL3 PIO0024976 Mitochondrial import receptor subunit TOM22 homolog TOMM22 PIOO154567 Isoform 2 of Spermatogenesis-associated protein 20 SPATA20 jite Cui SOjº PIO0027685 C-C chemokine receptor type 1 CCR1 PIO0009335 Brain protein 16 C8orf}0A PIO0008495 NADH-ubiquinone oxidoreductase chain 4 MT-ND4 PIO0179172 Isoform 2 of Liprin-beta-1 PPFIBP1 PIO001.2315 Nucleoside diphosphate kinase 3 NME3 PIOO432755 PPRR6495 FAM124A PIO0550949 Bone morphogenetic protein 7 precursor BMP7 PIO0796777 17 kDa protein CRYAA PIO0872928 Several ankyrin repeat protein transcript variant 2 ANKRD42 (Fragment) PIOO412647 CDNA: FLJ21792 fis, clone HEP00441 THADA US 2013/0237454 A1 Sep. 12, 2013 37

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0032929 Isoform 1 of Thrombospondin type-1 domain-containing THSD1 protein 1 precursor PIO0008894 Carboxypeptidase A4 precursor CPA4 PIO0154451 MMS19 nucleotide excision repair homolog MMS 19 PIO0186145 Isoform 1 of Protein phosphatase 1.L PPM1L PIO0847759 DENN domain-containing protein 4B DENND4B PIO0008315 Isoform 1 of Ephrin type-B receptor 1 precursor EPHB1 PIO0386.364 Olfactory receptor 2L2 OR2L2 PIO0031005 Protein kinase-like protein Sgkl96 FLJ23356 PIO0787414 Uncharacterized protein ENSP00000381388 MGC34829 PIO0003527 Ezrin-radixin-moesin-binding phosphoprotein 50 SLC9A3R1 PIO0218823 Isoform 1 of WW domain-binding protein 7 MLL4 PIO0019988 N-sulphoglucosamine sulphohydrolase precursor SGSH PIO0059164 Galactose-3-O-sulfotransferase 3 GAL3ST3 PIO0873740 Uncharacterized protein ENSP00000383832 (Fragment) - PIO0060379 Integrator complex subunit 12 INTS12 PIO0032416 Isoform Long of Protein jagged-2 precursor JAG2 PIOO444706 CDNA FLJ45007 fis, clone BRAWH301.2005 KALRN PIO0216710 Isoform 1 of Nuclear receptor ROR-gamma RORC PIO0335589 RNA methyltransferase-like protein 1 RNMTL1 PIOO411690 Isoform 3 of La-related protein 1 LARP1 PIO0295519 Isoform 1 of Uncharacterized protein C3orf17 C3orf1 7 PIO0514153 transmembrahe and tetratricopeptide repeat containing 4 TMTC4 isoform 1 PIO0398728 Isoform 1 of Retinitis pigmentosa 1-like 1 protein RIP1L1 PIO0843819. Similar to Dual specificity protein kinase CLK2 - PIO0065276 Isoform 2 of Tether containing UBX domain for GLUT4 ASPSCR1 PIO0021473 59 kDa protein CBFA2T3 PI00745775 Similar to PR domain containing 4 - PIO0016703 24-dehydrocholesterol reductase precursor DHCR24 PIO0013880 Semaphorin-5A precursor SEMA 5A PIO0010157 S-adenosylmethionine synthetase isoform type-2 MAT2A PIOO794307 hypothetical protein LOC729505 PIOOO15782 UPF0171 protein C16orf25 C16orf25 PIO0011652 Isoform Efs] of Embryonal Fyn-associated substrate EFS PIO0644522 PNKP protein PNKP PIO0045511 Isoform 1 of Chloride channel CLIC-like protein 1 CLCC1 precursor PIO0028881 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex NDUFA3 subunit 3 PIO0604763 Transmembrane protein 66 precursor TMEM66 PIO0235647 similar to fibrillarin LOC3456.30 PIO0879950 15 kDa protein - PIOO413385 Inter-alpha-trypsin inhibitor heavy chain H5-like protein ITIHSL precursor PIO02949.10 Protein PARM-1 precursor DKFZP564O0823 PIO0022334 Ornithine aminotransferase, mitochondrial precursor OAT PIO0023617 Zinc finger protein 197 ZNF197 PIO00084.33 40S ribosomal protein S5 RPS5 PIO0642798 Nucleolar autoantigen No.55 SC65 PIOO470805 Isoform 2 of Mediator of DNA damage checkpoint protein 1 MDC1 PIO0167089 Isoform 2 of Activated CDC42 kinase 1 TNK2 PIO0102575 ATPase family, AAA domain containing 5 ATAD5 PIO0783753 UPF0235 protein C15orf10 C15 Orf240 PIOO383895 CDNA FLJ40559 fis, clone THYMU2002910 PRDM11 PIOO152157 Isoform 1 of Zinc finger protein 509 ZNF509 PIO0296803 30 kDa protein TCP.1.1L2 PIO0020501 Myosin-11 MYH11 PIO0168056 Zinc finger and BTB domain-containing protein 38 ZBTB38 PIO0030919 Mitogen-activated protein kinase kinase 1-interacting MAP2K1 IP1 protein 1 PIO0827745 Isoform 1 of RNA-binding protein 24 RBM24 PIO0005776 Nucleotide-binding oligomerization domain-containing NOD1 protein 1 PIO0026105 Isoform SCPx of Non-specific lipid-transfer protein SCP2 PIO0385255 Ig lambda chain V-II region NIG-84 - PIO0328178 Isoform 3 of TOM1-like protein 2 TOM1L2 PIO0394879 Leucine-rich repeat-containing protein 9 LRRC9 PIOO401852 Conserved hypothetical protein DKFZP434L187 PIOO442865 CDNA FLJ26488 fis, clone KDNO5770, highly similar to SLC12A1 Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2 US 2013/0237454 A1 Sep. 12, 2013 38

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0748891 hypothetical protein LOC283635 isoform 1 C14Orf24 PIOO414320 Annexin A11 ANXA11 PIO08740.23 Uncharacterized protein ENSP00000379699 - PIO0027144 Cytochrome b561 CYB561 PIO0827584 similar to kinesin family member 27 KIF27 PIO0217688 Uncharacterized protein C12Orf60 C12Orf60 PIO0020199 Alpha-2,8-sialyltransferase 8B ST8SIA2 PIO0003799 Isoform 2 of Heme-binding protein 2 HEBP2 PIO0220126 Isoform EP2B of Sperm-associated antigen 11B precursor SPAG11B PIO0007757 Isoform 1 of Zinc finger protein Helios IKZF2 PIOO791513 CDNA FLJ16614 fis, clone TESTIA013365 CTA-21 6E10.6 PIO0008756 Isoform 1 of Bullous pemphigoid antigen 1, isoforms DST /2/3/4/5/8 (Fragment) PIO03284.00 Zygote arrest protein 1 ZAR1 PIO0020201 CMP-N-acetylneuraminate-poly-alpha-2,8-sialyltransferase ST8SIA4 PIOO465147 Isoform 1 of Uncharacterized protein C90rfø7 C90 r?97 PIO0002884 CDNA: FLJ22222 fis, clone HRCO1658 FLJ22222 PIO0217465 Histone H1.2 HIST1H1C PIO002.5092 Myosin-binding protein C, slow-type MYBPC1 PIO0003363 Isoform 1 of Protein phosphatase 1 regulatory subunit 1B PPP1R1B PIO0333016 Isoform 3 of DnaJ homolog subfamily C member 11 DNAJC11 PIO0005705 Isoform Gamma-1 of Serine/threonine-protein phosphatase PPP1CC PP1-gamma catalytic subunit PIO0014897 Isoform 2 of 1-phosphatidylinositol-4,5-bisphosphate PLCB4 phosphodiesterase beta-4 PIOO181279 hypothetical protein LRRC37A4; LOC728863 PIOOO22078 Protein NDRG1 NDR G1 PIO0011894 MRNA clone with similarity to L-glycerol-3- - phosphate:NAD oxidoreductase and albumin gene sequences PIOO794248 47 kDa protein - PIO0002511 Cyclic AMP-dependent transcription factor ATF-6 alpha ATF6 PIO0164949 Isoform NELF-C of Negative elongation factor C/D TH1 L PIO0029647 Zymogen granule membrane protein 16 precursor ZG16 PIOO414481 GTF3C1 protein GTF3C1 PIOO472754 Polycystic kidney disease 1-related protein KIAA0319L PIO0640818 Isoform 3 of Neuropathy targetesterase PNPLA6 PIO0514774 Isoform 1 of PAB-dependent poly(A)-specific ribonuclease PAN3 subunit 3 PIO0307733 Isoform 1 of Histone-lysine N-methyltransferase SETD2 SETD2 PIO0154528 Isoform 1 of Structural maintenance of chromosomes SMC6 protein 6 PIO0164861 Isoform 3 of Kinesin-like protein KIF13A ÇIF13A PIO0218896 Alcohol dehydrogenase 1A ADH1A PIOO411674 Isoform 1 of Zinc finger protein 254 ZNF254 PIOO414973 FAST kinase domain-containing protein 5 FASTKDS PIO0002441 Syndecan-1 precursor SDC PIOO413272 Isoform 3 of Mediator of RNA polymerase II transcription MED23 subunit 23 PIO0249982 Isoform 1 of Death-inducer obliterator 1 DIDO1 PIO0299853 Protocadherin beta 16 precursor PCDHB16 PIO0328270 Neuronal PAS domain-containing protein 2 NPAS2 PIOO442544 CDNA FLJ27034 fis, clone SLV07984 - PIO0175019 similar to Temporarily Assigned Gene name family LOC643677 member PIO0027898 Isoform A of Uncharacterized protein C21 orf70 C21 Orf70 PIO0023340 Histone acetyltransferase MYST3 MYST3 PIO0735857 similar to ATP-binding cassette sub-family D member 1 LOC651.123 PIO0300052 Keratin type II cuticular Hb4 ÇRT84 PIOO454695 Histone H2B type 2-C HIST2H2BC PIO0647254 7 kDa protein - PIO0217467 Histone H1.4 HIST1H1E PIO0328118 Sperm-associated antigen 5 SPAG5 PIO0094740 Isoform 1 of RING finger protein 31 RNF31 PIO0019158 ADAM metallopeptidase domain 8 precursor ADAM8 PIOO3833 18 PRO2272 - PIO0045928 Sodium/hydrogen exchanger 7 SLC9A7 PIO0292470 dapper, antagonist of beta-catenin, homolog 2 DACT2 PIO000.9532 4-aminobutyrate aminotransferase, mitochondrial precursor ABAT PIO0215884 Isoform ASF-1 of Splicing factor, arginine/serine-rich 1 SFRS1 PIO0306332 60S ribosomal protein L24 RPL24 PIO0013488 Isoform Alpha-2 of N-chimaerin CHN1

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TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0297.277 Isoform 1 of RING finger protein 150 precursor RNF150 PIO0304885 Centromere protein C 1 CENPC1 PIO0784013 ianus kinase 1 AK1 PIO0216139 Isoform I of Septin-6 SEPT6 PIO0289954 Heparan sulfate glucosamine 3-O-sulfotransferase 6 HS3ST6 PIO0018134 Isoform 4 of Protein SOLO FLJ10357 PIO0855742 sterile alpha motif domain containing 12 isoform a SAMD12 PIOO415037 Isoform 12L of ADAM 12 precursor ADAM12 PIOO411298 Connector enhancer of kinase suppressor of ras 3 CNKSR3 PIO0016685 Enamelin precursor ENAM PIO0002191 Putative uncharacterized protein FLJ12684 - PIO0007928 Pre-mRNA-processing-splicing factor 8 PRPF8 PIO0031288 Claudin-14 CLDN14 PIO0028053 Gap junction alpha-9 protein GJA9 PIO0867582 Similar to SCAN domain-containing protein 2. Isoform 2 ZNF496 PIOO418885 Epididymal-specific lipocalin-10 precursor LCN10 PIO0166465 hypothetical protein LOC221416 Côorf223 PIO0795.992 Hypothetical short protein - PIO0847373 hypothetical protein LOC54627 ÇIAA1383 PIO0030070 Gap junction beta-5 protein GJB5 PIO0293095 Isoform 1 of Coiled-coil domain-containing protein 83 CCDC83 PIOO418238 Isoform 1 of HIV-1 Rev-binding protein-like protein HRBL PIO0008504 Carbonic anhydrase 14 precursor CA14 PIO0293409 Zinc finger protein 81 ZNF81 PIO0003927 40 kDa peptidyl-prolyl cis-trans isomerase PPID PIO0747142 Centaurin-gamma-like family member 6 CTGLF6 PIO0024801 E3 ubiquitin-protein ligase NRDP1 RNF41 PIO0040900 Isoform 2 of Heparan sulfate 2-O-sulfotransferase 1 HS2ST1 PIO0103356 Uncharacterized protein ITGB2 TGB2 PIO0604798 Bitter taste receptor T2R2 (Fragment) - PIO0011515 Protein kinase C and casein kinase substrate in neurons PACSIN1 protein 1 PIO0164066 Isoform 4 of Coiled-coil domain-containing protein 136 CCDC136 PIO0307702 H53 GS1 (Fragment) - PIO001.3887 Beta-galactoside alpha-2,6-sialyltransferase 1 ST6CAL1 PIO0025084 Calpain small subunit 1 CAPNS1 PIO0014899 CDNA FLJ20744 fis, clone HEP06585 BRPF3 PIO0307611 Isoform 1 of Microtubule-associated serine/threonine- MAST4 protein kinase 4 PIO001.4444 Isoform 1 of Protein SERAC1 SERAC1 PIOO479217 Isoform Short of Heterogeneous nuclear ribonucleoprotein U HNRNPU PIO0384971 hypothetical protein LOC643155 DKFZP686E2158 PIO0025721 COP9 signalosome complex subunit 3 COPS3 PIOOO17334 Prohibitin PHB PIO0183206 Isoform 1 of RIM-binding protein 2 RIMBP2 PIO0220070 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 PFKFB4 PIO0023322 Zinc finger protein ubi-d4 DPF2 PIO0216699 Isoform 2 of Unc-112-related protein 2 FERMT3 PIO0855747 hypothetical protein LOC57481 RP13–347D8.3 PIOO445054 CDNA FLJ44715 fis, clone BRACE3021430 FLJ44715 PIOO303318 Protein FAM49B FAM49B PIO0030360 RUN domain-containing protein 2A RUNDC2A PIOO220503 dynactin 2 DCTN2 PIO0784739 Uncharacterized protein C14orf.43 C14Orf243 PIO0328159 Isoform 1 of Uncharacterized protein Clorf&8 C1orf&8 PIO0003881 Heterogeneous nuclear ribonucleoprotein F HNRPF PIO0003990 Isoform 2 of Valacyclovir hydrolase precursor BPHL PIO0847485 Similar to PFIV protein - PIO0738920 similar to CG3104-PA, isoform A LOC642574 PIO0056314 Pre-rRNA-processing protein TSR2 homolog TSR2 PIO0007300 BTB/POZ domain-containing protein 3 BTBD3 PIO0019517 Wilms tumor 1 isoform D WT1 PIO0797694 3 kDa protein - PIO0294210 DNA-binding protein inhibitor ID-2 D2 PIO0217490 Isoform 1 of Fibronectin type III domain-containing protein FNDC3B 3B PIO0848330 Conserved hypothetical protein LOC285.144 PIO0000787 Isoform LMP2.L of Proteasome subunit beta type-9 PSMB9 jite Cui SOjº PIO0004379 Homeobox protein HMX1 HMX1 PIO0004373 Mannose-binding protein C precursor MBL2 PIO0787020 similar to Dynamin-1 LOC6441.53 US 2013/0237454 A1 Sep. 12, 2013 41

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0375820 Interferon-induced transmembrane protein 5 IFITM5 PIOO411635 180 kDa protein - PIO0795566 6 kDa protein - PIO0217117 Isoform 1 of Glycerate kinase GLYCTK PIO0167941 Midasin MDN1 PIO0300086 Nicotinate-nucleotide pyrophosphorylase QPRT PIO0016701 P2Y purinoceptor 14 P2RY14 PIO0007010 Lysozyme-like protein 6 precursor LYZL6 PIOO2351 67 Profilin-3 PFN3 PIO0026126 Mammaglobin-B precursor SCGB2A1 PIO00098.99 Uncharacterized protein C5orf5 C5orfs PIOO220167 Isoform 1 of Putative methyltransferase NSUN7 NSUN7 PIOO155168 Leukocyte common antigen precursor (EC 3.1.3.48) (L- PTPRC CA) (T200) (CD45 antigen). Isoform 2 PIO0217948 FRMD4B protein FRMD4B PIO0384268 XRCC6BP1 protein XRCC6BP1 PIO0027457 C1q-related factor precursor C1GL1 PIO0002993 Transcription initiation factor TFIID subunit 9 TAF9 PIO0216348 Isoform 2Cof Cytoplasmic dynein 1 intermediate chain 2 DYNC1L2 PIO0299507 Condensin complex subunit 2 NCAPH PIO0555600 Solute carrier family 26, member 1 isoform a variant IDUA (Fragment) PIOO419221 Membrane-bound O-acyltransferase domain-containing MBOAT2 protein 2 PIOO445643 CDNA FLJ43684 fis, clone TBAES2001492 - PIO0165591 Isoform 4 of Transmembrane channel-like protein 6 TMC6 PIO0010334 Isoform 3 of Inactive phospholipase C-like protein 2 PLCL2 PIO0021634 Kinesin light chain 2 ÇLC2 PIOO451429 NIF3L1 isoform gamma NIF3L1 PIO0375803 Isoform 1 of GON-4-like protein GON4L PIO0023184 Isoform 1 of Poly [ADP-ribose] polymerase 3 PARP3 PIO0872739 Uncharacterized protein C18Orf2 C18orf2 PIO0241409 hypothetical protein LOC55747 FAM21B PIO0152149 CENP-B, N-terminal DNA-binding domain containing - protein PIO0090764 Toll-like receptor 1 precursor TLR1 PIO0024253 Isoform 1 of Fibroblast growth factor 14 FGF14 PIO0029643 Isoform 2 of Mitogen-activated protein kinase kinase ZAK kinase MLT PIO0218637 Major histocompatibility complex, class II, DQ beta 2 HLA-DQB2 PIO0000875 Elongation factor 1-gamma EEF1G PIO0215948 Isoform 1 of Catenin alpha-1 CTNNA1 PIO0022918 Isoform 2 of Protein FAM125B FAM125B PIO0787765 similar to solute carrier family 35, member F4 SLC35F4 PIO0216921 Isoform 2 of Stathmin-4 STMN4 PIO0011416 Delta(3,5)-Delta(2,4)-dienoyl-CoA isomerase, ECH1 mitochondrial precursor PIO0007208 Probable ATP-dependent RNA helicase DDX41 DDX41 PIO0260755 similar to Rho GTPase activating protein 18 C20Orfø5 PIO0337385 Isoform 1 of Pre-mRNA-processing factor 40 homolog A PRPF40A PIO0304527 Protein FAM83H FAM83H PIO0000459 Transmembrane gamma-carboxyglutamic acid protein 1 PRRG1 jite Cui SOjº PIO0030741 Uncharacterized protein C21orf13 LCASL PIO0012007 Adenosylhomocysteinase AHCY PIO0855922 Isoform 4 of DENN domain-containing protein 3 DENND3 PIO0399.296 hypothetical protein LOC3901.10 LOC3901 10 PIO0233358 islet cell autoantigen 1, 69 kDa-like isoform 2 CA1 L PIO0879842 6 kDa protein - PIO0328826 Uncharacterized protein CADPS2 CADPS2 PIO0021476 Eukaryotic translation initiation factor 4E-binding protein 3 EIF4FBP3 PIO0028383 Uncharacterized protein C16orf24 C16orf24 PIO0007074 Tyrosyl-tRNA synthetase, cytoplasmic YARS PIO0031056 Zinc finger MYND domain-containing protein 15 ZMYND15 PIO0641614 47 kDa protein AKAP8L PIO0002134 26S proteasome non-ATPase regulatory subunit 5 PSMD5 PIO0056040 Neuritin 1-like NRN1.L PIO0012948 Proheparin-binding EGF-like growth factor precursor HBEGF PIO0856045 AHNAK nucleoprotein 2 AHNAK2 PIO0009329 Utrophin UTRN PIOO298.337 cDNA FLJ17671 SLC14A1 PIO0218235 dehydrogenase/reductase member 2 isoform 2 DHRS2 US 2013/0237454 A1 Sep. 12, 2013 42

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0297315 Alpha-2B adrenergic receptor ADRA2B PIO0219005 FK506-binding protein 4 FKBP4. PIO0044842 Isoform 2 of RAB3A-interacting protein RAB3 IP PIO0107855 Hephaestin precursor HEPH PIO0217662 Uncharacterized protein C11orf35 C11orf25 PIO0386119 Isoform 5 of Splicing factor 1 SF1 PIO0025489 Serine/threonine-protein kinase MAK MAK PIO001.3004 Isoform 1 of Pyridoxal kinase PDXK PIO002.2055 Histone acetyltransferase PCAF PCAF PIOO328260 Protein FAN NSMAF PIO0807418 Isoform 9 of Lymphoid-specific helicase HELLS PIO0027774 THAP domain-containing protein 2 THAP2 PIO0183002 Isoform 1 of Protein phosphatase 1 regulatory subunit 12A PPPIRIXA PIO0027415 Isoform 1 of Probable ATP-dependent RNA helicase DHX36 DHX36 PIOO163601 Putative uncharacterized protein FLJ10213 FLJ102.13 PIOO4287.41 LP2477 FLJ35348 PIO0006252 Multisynthetase complex auxiliary component p43 SCYE1 PIO0021907 Isoform 1 of Myelin basic protein MBP PIO0176125 Collagen XXIX alpha 1 COL29A1 PIO0007321 Isoform I of Acyl-protein thioesterase 1 LYPLA1 PIO0217617 palmitoylated membrane protein 7 MPP7 PIO0008303 Isoform 1 of N-acetylglucosamine-1-phosphodiester alpha- NAGPA N-acetylglucosaminidase precursor PIOO418614 67 kDa protein - PIO0016046 Protein MGR2 homolog C20Orf52 PIO0024662 Chromobox protein homolog 5 CBX5 PIO0550364 Phosphoglucomutase-2 PGM2 PI00169331 Phosphatidylcholine:ceramide cholinephosphotransferase 2 SGMS2 PIO0028450 Isoform 1 of Sodium/calcium exchanger 1 precursor SLC8A1 PIO0783464 dynein heavy chain domain 3 DNAH2 PIO0002841 Sodium/hydrogen exchanger 2 SLC9A2 PIOO472712 Coiled-coil domain containing 7 CCDC7 PIOOO61355 Isoform 3 of Protein ZNF673 ZNF673 PIOO445804 Uncharacterized protein ENSP00000374264 DKFZp761B107 PIO0790813 8 kDa protein RAD51AP1 PIO0010405 Isoform Long of Tyrosine-protein kinase transmembrane ROR1 receptor ROR1 precursor PIO0061780 Isoform 1 of E3 ubiquitin-protein ligase Itchy homolog ITCH PIO0873774 Uncharacterized protein ENSP00000383488 (Fragment) - PIO0847335 FLJ45422 protein - PIO0030099 Adenylate cyclase type 9 ADCY9 PIO0217740 C20orf12 protein C20orf12 PIO0396961 Leucine-rich repeat and fibronectin type-III domain- LRFN5 containing protein 5 precursor PIO051.4533 Uncharacterized protein SYCP2L SYCP2L PIO0016095 Transcription termination factor, mitochondrial precursor MTERF PIO0024689 Aquaporin-1 AQP1 PIO0877800 32 kDa protein - PIO0008497 Ornithine decarboxylase ODC1 PIO0741608 similar to eukaryotic translation initiation factor 5A EIF5AL3 PIO0010808 Interferon-gamma receptor alpha chain precursor IFNGR1 PIO0872550 Uncharacterized protein PRDM2 PRDM2 PIO0004521 Ewing's tumor-associated antigen 1 ETAA1 PIO0171525 Sentrin-specific protease 3 SENP3 PIO0514622 Ran-binding protein 6 RANBP6 PIO0373824 Testis serine protease 1 precursor TESSP1 PIO0017231 Neurensin-2 NRSN2 PIO0009203 Sorting nexin-7 SNX7 PIO0790021 Zinc finger protein 652 ZNF652 PIO0299729 Transcobalamin-1 precursor TCN1 PIO0018860 NKG2D ligand 2 precursor |ULBP2 PIO0022290 Beta-defensin 1 precursor DEFB1 PIO0007444 Epiphycan precursor EPYC PIO0855918 mucin 5, subtype B, tracheobronchial MUCSB PIO0167014 EID2 protein (Fragment) EID2 PIO0180384 dynein, axonemal, heavy chain 7 DNAH7 PIO0007327 Isoform 1 of Tapasin precursor TAPBP PIO0244346 Troponin 1, cardiac muscle TNNI3 PIO0009066 similar to protein tyrosine phosphatase, receptor type, Q PTPRQ isoform 1 precursor US 2013/0237454 A1 Sep. 12, 2013 43

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0303.195 Syncoilin-1 SYNC1 PIO0008.404 Isoform Long of Segment polarity protein dishevelled DVL1L1 homolog DVL-1-like PIO0658025 Putative novel transcript - PIO0022958 PROO 149 C16orf72 PIO0032313 Protein S100-A4 S100A4 PIO0024094 Rhesus blood group-associated glycoprotein RHAG PIO0027626 T-complex protein 1 subunit zeta CCT6A PIO0031812 Nuclease sensitive element-binding protein 1 YBX1 PIO0018854 Coiled-coil domain-containing protein 68 CCDC68 PIO0027009 Isoform 1 of Protein kinase C and casein kinase substrate in PACSIN2 neurons protein 2 PIO0084582 Isoform 7 of Collagen alpha-1(XIII) chain COL13A1 PIO0023162 UDP-N-acetylglucosamine 2-epimerase/N- GNE acetylmannosamine kinase PIO0216815 Isoform 2 of DNA topoisomerase 3-beta-1 TOP3B PIO0062599 71 kDa protein - PIO0789181 115 kDa protein PLCL1 PIO0060549 G-protein coupled receptor-associated sorting protein 1 GPRASP1 PIO0795943 7 kDa protein - PIO0005132 Guanine nucleotide-binding protein-like 3-like protein GNL3L PIO0642204. Thioredoxin domain-containing protein 16 precursor TXNDC16 PIO0646199 Zinc finger, MYM-type 2 ZMYM2 PIO0742725 Conserved hypothetical protein LOC388564 PIO0791447 Pseudogene candidate LOC3399.29 PIO0878755 43 kDa protein - PIO0152050 ataxin 2-binding protein 1 isoform 3 A2BP1 PIO0385480 Caskin-1 CASKIN1 PI00745433 eukaryotic translation initiation factor 2C, 2 EIF2C2 PIOO465123 KIAA0415 gene product ÇIAA0415 PIO0398992 Isoform 1 of Chromodomain-helicase-DNA-binding CHD8 protein 8 PIO0026031 Uncharacterized protein C60rf72 precursor C6Orf72 PIO0103090 Isoform 1 of RNA polymerase-associated protein LEO1 LEO1 PIO001.2441 Isoform 1 of Synaptojanin-1 SYNJ1 PIO0006054 Syntaphilin SNPH PIO0215746 Fatty acid-binding protein, adipocyte FABP4 PIO0216780 Cartilage intermediate layer protein 2 precursor CILP2 PIO0101186 Isoform 1 of RRP12-like protein RRP12 PIO0013404 Mothers against decapentaplegic homolog 4 SMAD4 PIO0385918 CDNA FLJ90582 fis, clone PLACE1000442, moderately ZNF627 Similar to ZINC FINGER PROTEIN ZFP-36 PIO0219067 Glutathione S-transferase Mu 2 GSTM2 PIO0008438 40S ribosomal protein S10 RPS10 PIO0152849 Isoform 1 of G2/mitotic-specific cyclin-B3 CCNB3 PIO0220038 Isoform B of Arsenite-resistance protein 2 ARS2 PIO0029556 Uncharacterized protein C10rf105 C1 Orfl05 PIO0385683 Ig heavy chain V-III region GAR - PIOO441344 Beta-galactosidase precursor GLB1 PIO0217012 pleckstrin and Sec7 domain containing PSD PIO0006030 Dynein intermediate chain 1, axonemal DNAI1 PIO0215914 ADP-ribosylation factor 1 ARF1 PIO0024714 Isoform 1 of Regulator of G-protein signaling 12 RGS12 PIO0015980 Isoform 2 of Multiple PDZ domain protein MPDZ PIO010.3853 Isoform 1 of Putative ribosome-binding factor A, C18orf22 mitochondrial precursor PIO0102678 Isoform 1 of Pecanex-like protein 1 PCNX PIO0020356 331 kDa protein MAP1A PIO0259671 Taste receptor type 2 member 44 TAS2R44 PIO0008226 73 kDa protein THSD3 PIO0551062 Isoform 1 of Protein canopy homolog 3 precursor CNPY3 PIO0219622 Proteasome subunit alpha type-2 PSMA2 PIO0010903 Dopey family member 1 DOPEY1 PIO0220741 spectrin, alpha, erythrocytic 1 SPTA1 PIO0735934 similar to capicua homolog LOC646070 PIO0335581 Isoform 1 of E3 ubiquitin-protein ligase UBR3 |UBR3 PIO0031086 Insulin-like growth factor-binding protein 1 precursor IGFBP1 PIO0004416 Charged multivesicular body protein 2a CHMP2A PIOO465234 Cytokine receptor common beta chain precursor CSF2RB PIO0010.303 Serpin B4 SERPINB4 PIO0028828 Isoform Beta of Zinc finger protein 202 ZNF202 PIO0514795 Isoform 1 of Tubulin--tyrosine ligase-like protein 7 TTLL7 US 2013/0237454 A1 Sep. 12, 2013 44

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0008091 Putative DNA helicase INO80 complex homolog 1 NOC1 PIO0016112 peroxidasin homolog PXDN PIO0010193 Isoform 1 of Interferon-alpha/beta receptor beta chain FNAR2 precursor PIO0101987 Uncharacterized protein C190rf62 C190rf62 PIO0853224 START domain containing 7 STARD7 PIO0329791 cDNA FLJ78679, highly similar to Homo sapiens DEAD DDX46 (Asp-Glu-Ala-Asp) box polypeptide 46 (DDX46), mRNA PIO0001141 Mitochondrial import inner membrane translocase subunit TIMM22 Tim22 PIOO152344 Pyridoxal phosphate phosphatase PHOSPHO2 PHOSPHO2 PIOO465363 Histone H2B type 1-A HIST1H2BA PIO0028601 Putative metallothionein C20orf127 MT1P3 PIO0514975 Chromosome 1 open reading frame 133 C1 Orfl 33 PIO0744029 Similar to Zinc finger, FYVE domain containing 21 - PIO0399320 Transmembrane protein 59 precursor TMEM59 PIOO4791.25 SLIT-ROBO Rho GTPase-activating protein 2 SRGAP2 PIOO455852 Isoform 1 of Rho guanine nucleotide exchange factor 15 ARHGEF15 PIO001.9812 Serine/threonine-protein phosphatase 5 PPP5C PIO0550876 Protein maestro MRO PIO0217687 Isoform 1 of Coiled-coil domain-containing protein 135 CCDC135 PIO0829745 Cellular titin isoform PEVK variant 2 (Fragment) - PIO0216544 Isoform 2 of Protein hairless HR PIOOO64296 PROO633 - PIO0216651 Isoform 1 of Interleukin-28 receptor alpha chain precursor IL28RA PIOO792945 38 kDa protein CHFR PIO0646323 Isoform 1 of Uncharacterized protein C10orf76 C10orf76 PIO014.9375 Isoform 2 of Uncharacterized protein C11orf56 C11orf56 PI00386797 Isoform 1 of Folliculin-interacting protein 1 FNIP1 PIO0304589 Isoform 1 of 182 kDa tankyrase 1-binding protein TNKS1 BP1 PIO0015913 5,6-dihydroxyindole-2-carboxylic acid oxidase precursor TYRP1 PIO0002857 Isoform CSBP2 of Mitogen-activated protein kinase 14 MAPK14 PIO0399.180 Serine/threonine-protein kinase SBK1 SBK1 PIO0007512 Glutathione transferase omega-2 GSTO2 PIO0016576 Isoform 1 of Grainyhead-like protein 2 homolog GRHL2 PIO0290308 Tribbles homolog 1 TRIB PIO0017567 Isoform Long of Endoglin precursor ENG PIO0005859 Keratin, type II cytoskeletal 75 KRT75 PIO001.7630 Nuclear fragile x mental retardation-interacting protein 1 NUFIP1 PIO0019992 Myb-related protein A MYBL1 PIO0025622 AN1-type zinc finger protein 5 ZFANDS PIO0168848 UDP-GlcNAc:betaGal beta-1,3-N- B3GNT7 acetylglucosaminyltransferase 7 PIO0019901 Isoform 1 of Alpha-adducin ADD PIO0006510 Tubulin beta-1 chain TUBB1 PIO0102808 Isoform 1 of Dual specificity protein phosphatase 19 DUSP19 PIO0023942 Isoform 2 of Syndecan-3 SDC3 PIO0031506 Potassium/sodium hyperpolarization-activated cyclic HCN nucleotide-gated channel 1 PIO0018208 Tetratricopeptide repeat protein 33 TTC33 PIO0166865 CDGSH iron sulfur domain-containing protein 2 CISD2 PIO0305833 Smu-1 suppressor of mec-8 and unc-52 protein homolog SMU PIO0219129 Ribosyldihydronicotinamide dehydrogenase NQO2 PIO0004533 Kinesin-like protein KIF3B KIF3B PIO0028614 erythrocyte membrane protein band 4.2 isoform 2 EPB42 PIO0216917 Isoform 1 of Uncharacterized protein C22Orfø C22Orfø PIO0043499 Probable urocanate hydratase UROC1 PIOO477468 RNA polymerase-associated protein CTR9 homolog CTR9 PIO0005668 Aldo-keto reductase family 1 member C2 AKR1C2 PIO0018098 Isoform 1 of Pre-mRNA-splicing factor 38B PRPF38B PIO0026241 Bone marrow stromal antigen 2 precursor BST2 PIO0056507 Isoform 1 of F-box/WD repeat-containing protein 5 FBXW5 PIO0017451 Splicing factor 3 subunit 1 SF3A1 PIO0243338 24 kDa protein KRT23 PIO0786937 similar to deleted in malignant brain tumors 1 isoform b LOC73 1940 precursor PIOO465273 UHRF1-binding protein 1 UHRF1 BP1 PIO0550746 Nuclear migration protein nudo NUDC PIO0738999 similar to ubiquitin-conjugating enzyme E2 variant 1 LOC643227 PIO0218918 Annex in A1 ANXA1 PIO0031047 CDNA: FLJ23571 fis, clone LNG12303 QCG PIO0295577 Receptor-type tyrosine-protein phosphatase beta precursor PTPRB US 2013/0237454 A1 Sep. 12, 2013 45

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0718806 arylhydrocarbon receptor repressor AHRR; PDCD6 PIO0029372 Uncharacterized protein C4Orfis C4Orfl 5 PIO0022256 AP-2 complex subunit mu-1 AP2M1 PIO0744226 Conserved hypothetical protein - PIO02991.16 Podocalyxin-like protein 1 precursor PODXL PIO0792229 20 kDa protein TATDN1 PIOO151141 Isoform 1 of Serine/threonine-protein kinase WNK4 WNK4 PIO0.220271 Alcohol dehydrogenase AKR1A1 PIOO786893 Similar to LYRIC/3D3 LOC730296; LOC728998 PIO00272.32 Insulin-like growth factor 1 receptor precursor IGF1R PIO0028387 Isoform 1 of Uncharacterized protein C20orf116 precursor C20orf116 PIO0015954 GTP-binding protein SAR1a SAR1A PIO0397949 G protein-coupled receptor 56 isoform b GPR56 PIO0328.748 Protein ARMET precursor AIRMET PIO0027547 Dermcidin precursor DCD PIO00093.96 Isoform 1 of Cannabinoid receptor 1 CNR1 PIO0306853 Carbohydrate sulfotransferase 3 CHST3 PIOO418735 hypothetical protein LOC400566 LOC400566 PIO0553006 Probable prolyl-tRNA synthetase, mitochondrial precursor PARS2 PIO0102803 Ankyrin repeat domain-containing protein 22 ANKRD22 PIO0306413 Tubulin polymerization-promoting protein family member 3 TPPP3 PIO0018755 High mobility group protein 1-like 10 HMG1 L10 PIO0030153 Tudor domain-containing protein 6 TDRD6 PIO0010212 U6 snRNA-specific terminal uridylyltransferase 1 TUT1 PIO0844501 MG44 protein SUV39H1 PIO0385543 Isoform 3 of UPF0469 protein KIAA0907 ÇIAA0907 PIOO456060 Protein - PIO0299076 Receptor-binding cancer antigen expressed on SiSo cells EBAG9 (Fragment) PIO0386393 CDNA FLJ13729 fis, clone PLACE3000121, weakly EXOC6B Similar to VESICULAR TRAFFIC CONTROL PROTEIN SEC15 PIO0016480 Isoform 1 of NACHT, LRR and PYD domains-containing NLRP2 protein 2 PIO0166043 Isoform 2 of Progestin and adipoC) receptor family member 6 PAQR6 PIO08785.11 45 kDa protein - PIOO411545 Isoform 3 of Thrombopoietin precursor THPO PIOO442564 CDNA FLJ26948 fis, clone RCT08241 - PIO0257508 Dihydropyrimidinase-related protein 2 DPYSL2 PIO0398918 Putative uncharacterized protein DKFZp686I21167 DKFZp686O24166 PIOO412408 Breast cancer type 2 susceptibility protein BRCA2 PIO0005614 Isoform Long of Spectrin beta chain, brain 1 SPTBN1 PIOO168239 Zinc finger protein GLIS1 GLIS1 PIOO165990 Isoform 4 of Transcription factor RFX4 RFX4 PIO0021831 cAMP-dependent protein kinase type I-alpha regulatory PRKAR1A subunit PIO0749489 fibrocystin L PKHD1 L1 PIO0552578 Serum amyloid A protein precursor SAA1; SAA2 PIO00084.22 Isoform 2 of SWI/SNF-related matrix-associated actin- SMARCAD1 dependent regulator of chromatin subfamily. A containing DEAD/H box 1 PIO0018953 Dipeptidyl peptidase 4 DPP4 PIOO413778 Peptidyl-prolyl cis-trans isomerase FKBP1A PIO0007682 Vacuolar ATP synthase catalytic subunit A ATP6V1A PIO0024502 Ubiquilin-4 UBQLN4 PIO0059144 Protein FAM46B FAM4.6B PIO0550792 Isoform 1 of Bridging integrator 2 BIN2 PIO0029175 Strumpellin ÇIAA0196 PIO0045360 Capicua-like protein/double homeodomain 4 fusion protein CIC PIO0787697 similar to Oligophrenin 1 isoform 4 FLJ32810 PIO0749171 Conserved hypothetical protein LOC340184 PIO0033419 Protein Fem-1 homolog b FEM1B PIO0043237 CDNA FLJ32095 fis, clone OCBBF2000998 LOC730193; STX6 PIO0298738 DNA-directed RNA polymerase, mitochondrial precursor POLRMT PIO0028641 Isoform 4 of Protein phosphatase 1 regulatory subunit 12B PPP1R12B PIO0554711 Junction plakoglobin UP PIO0879159 9 kDa protein - PIOO445278 CDNA FLJ44033 fis, clone TESTIA028062 - PIO0335541 Isoform 1 of Protein timeless homolog TIMELESS PIO0644840 Hypothetical protein LOC255783 PIO000.9771 Lamin-B2 LMNB2 00444842 CDNA FLJ45125 fis, clone BRAWH3036561 US 2013/0237454 A1 Sep. 12, 2013 46

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0007800 Angiopoietin-related protein 2 precursor ANGPTL2 PIO0181743 Isoform 1 of BAI1-associated protein 3 BALAP3 PIO0018099 E3 ubiquitin-protein ligase FANCL FANCL PIOO455076 Double C2-like domain-containing protein alpha DOC2A PIO0023152 Isoform 1 of N-acetylated-alpha-linked acidic dipeptidase- NAALADL1 ike protein PIO0296727 Kinesin-like protein KIF2B KIF2B PIO0005347 Zinc finger Ran-binding domain-containing protein 1 ZRANB1 PIO0295940 Protein unc-84 homolog B UNC84B PIOO470913 RANBP2-like and GRIP domain containing 1 RGPD1; RGPD2 PIOO444331 Isoform 4 of Histone-lysine N-methyltransferase NSD3 WHSC1L1 PIO0023407 Nck-associated protein 1-like NCKAP1L PIO0306046 Isoform 1 of EGF-like repeat and discoidin I-like domain-Ö) EDIL3 PIOO426727 Isoform 1 of Methyl-CpG-binding domain protein 4 MBD4 PIO0002970 Beta-sarcoglycan SGCB PIO0878142 68 kDa protein - PIO0554488 caNMP-dependent protein kinase type I-beta regulatory PRKAR1B subunit PIO030.1288 polydom SVEP1 PIO0030279 Isoform 1 of Zinc finger Ran-binding domain-containing ZRANB3 protein 3 PIO007.4656 Isoform 1 of Coiled-coil domain-containing protein C6Orf65 C6Orf65 PIO0031907 Isoform 1 of Transmembrane protein 108 precursor TMEM108 PIOO456635 Isoform 1 of Protein unc-13 homolog D |UNC13D PIOO4453.15 Protein FAM47C FAM47C PIO0065931 Isoform 2 of A-kinase anchor protein 13 AKAP13 PIO0020230 Frizzled-9 precursor FZD9 PI00149044 Isoform 2 of Suppressor of hairy wing homolog 4 ZNF280D PIO0014903 Isoform 1 of FGFR1 oncogene partner 2 FGFR1OP2 PIO0019502 Myosin-9 MYH9 PIO0007834 Isoform 1 of Ankyrin-2 ANK2 PIO001 1961 Isoform 1 of Sialoadhesin precursor SIGLEC1 PIO0746681 Similar to Bcl-2-related ovarian killer protein - PIO0000977 Mitogen-activated protein kinase kinase kinase 11 MAP3K11 PIO0007047 Protein S100-A8 S100A8 PIO0884399 RNA-directed DNA polymerase (Reverse transcriptase), red) – PIO0871556 107 kDa protein ZFYVE28 PIO0746666 hypothetical protein LOC7282.62 PIO0018879 Alpha-L-iduronidase precursor IDUA PIO0170770 Isoform 1 of PHD finger protein 3 PHF3 PIO0000057 Conserved oligomeric Golgi complex component 2 COG2 PIO0003814 Isoform 1 of Dual specificity mitogen-activated protein MAP2K6 kinase kinase 6 PIO0290854 A-kinase anchor protein 3 AKAP3 PIO0301058 Vasodilator-stimulated phosphoprotein WASP PIO0245940 immunoglobulin superfamily 5 like IGSF5 PIOO657699 Protein MUC19 PIOO435928 PP13187 RASGRF1 PIO0290094 Splicing factor, arginine/serine-rich 8 SFRS8 PIO0030706 Activator of 90 kDa heat shock protein ATPase homolog 1 AHSA1 PIO0013721 Serine/threonine-protein kinase PRP4 homolog PRPF4B PIO0853516 dynein, axonemal, heavy chain 17 DNAH17 PIOO4100.93 coiled-coil domain containing 69 CCDC69 PIO0748607 Conserved hypothetical protein - PIO0168404 Zinc finger and BTB domain containing 34 ZBTB34 PIO0021266 60S ribosomal protein L23a RPL23A; hoG 16001 PIO0644766 cDNA FLJ78048, highly similar to Homo sapiens torsin A (2) TOR1AIP1 PIO0167154 Uncharacterized protein MAPKBP1 MAPKBP1 PIO0031228 Isoform 2 of Pleckstrin homology domain-containing PLEKHB2 family B member 2 PIO0871533 Uncharacterized protein C3orf.48 (Fragment) C3orf.48 PIO0007812 Vacuolar ATP synthase subunit B, brain isoform ATP6V1B2 PIO0877615 15 kDa protein - PIO0030352 Isoform 2 of Growth inhibition and differentiation-related C10orf28 protein 88 PIO0384051 Uncharacterized protein PSME2 PSME2 PIO0337415 Guanine nucleotide-binding protein G(i), alpha-1 subunit GNAI1 PIO0003377 Isoform 1 of Splicing factor, arginine/serine-rich 7 SFRS7 PIO0006146 serum amyloid A2 SAA1; SAA2 PIO0017551 Isoform 1 of Regucalcin RGN PIO0032.338 kelch-like 20 KLHL20 US 2013/0237454 A1 Sep. 12, 2013 47

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0293679 Isoform 1 of Potassium voltage-gated channel subfamily KCNQ4 KQT member 4 PIO0745396 Stromal RNA regulating factor HNRPLL PIO0604752 Isoform 3 of Sterile alpha motif domain-containing protein SAMD13 13 PIO0382534 Ig heavy chain V-II region OU - PIO0748682 Pheromone shutdown-related, TraB family protein - PIO0008444 Isoform 1 of Cytidine and dcMP deaminase domain- CDADC1 containing protein 1 PIOO792933 zinc finger protein 462 ZNF462 PIO0019888 Succinate-semialdehyde dehydrogenase, mitochondrial ALDH5A1 precursor PIO0032597 RNA-binding motif protein, X-linked 2 RBMX2 PIOO402005 Similar to DNA-binding protein ZNF528 PIO0020036 Neuronal acetylcholine receptor subunit alpha-4 precursor CHRNA4 PIO0783855 neighbor of BRCA1 gene 1 NBR PIO0329054 Osteopetrosis-associated transmembrane protein 1 OSTM1 jite Cui SOjº PIO0028864 Neurexophilin-3 precursor NXPH3 PIO0023757 Isoform 1 of X-linked retinitis pigmentosa GTPase RPGR. regulator PIO0746987 Ribosomal protein S1 family protein - PIO0295469 Copine-6 CPNE PIO0000663 Isoform Mitochondrial of Malonyl-CoA decarboxylase, MLYCD mitochondrial precursor PIO0788258 similar to lysyl oxidase-like 1 preproprotein LOXL1 PIO0739387 hypothetical protein LOC401478 FLJ45872 PIOO456599 hypothetical protein LOC84792 MGC12966 PIOO607831 PRAME family member 3 PRAMEF3 PIO0399254 Isoform 1 of OTU domain-containing protein 4 OTUD4 PIOO164352 zinc finger protein 292 ZNF292 PIO0719505 RABL2A protein RABL2A PIO0008913 Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 ST6CALNACS PIO0020454 Deoxycytidine kinase DCK PIO0784880 Cancer/testis antigen 75 LOC440934 PIO0514028 21 kDa protein RNF207 PIO0884353 Ets-1 transcript variantets-1 delta - PIO0852725 Isoform 7 of Prolactin receptor precursor PRLR PIO0024292 Low-density lipoprotein receptor-related protein 2 LRP2 jite Cui SOjº PIO0005600 Isoform 1 of Bifunctional heparan sulfate N-deacetylase/N- NDST2 sulfotransferase 2 PIO0028357 Exportin-4 XPO)4 PIOO438355 Fibrillin-3 precursor FBN3 PIO0009043 Apoptotic-related protein PCAR (Fragment) - PIO0791593 8 kDa protein GLYCAM1 PIO0024346 snRNA-activating protein complex subunit 3 SNAPC3 PIO0293396 adaptor-related protein complex 1, gamma 1 subunit AP1G1 isoform a PIO0010859 cortistatin preproprotein CORT; APITD1 PIO0220412 S100 calcium binding protein A1 S100A1 PIO0018914 Tyrosine-protein phosphatase non-receptor type 14 PTPN14 PIO0027442 Alanyl-tRNA synthetase, cytoplasmic AARS PIO0553138 Vesicle-associated membrane protein 2 VAMP2 PIO0296913 ADP-sugar pyrophosphatase NUDT5 PIO0014845 Isoform 1 of Ciliary dynein heavy chain 8 DNAH8 PIO0185.146 Importin-9 IPO9 PIO0385687 similar to Ubiquinol-cytochrome c reductase complex 14 kDa – protein PIO0143753 Isoform 1 of U2-associated protein SR140 SR 140 PIO0219682 Erythrocyte band 7 integral membrane protein STOM PIO0377214 Isoform 2 of NLR family member X1 NLRX1 PIO0054521 Frizzled-1 precursor FZD1 PIO0217791 Coiled-coil domain-containing protein 105 CCDC105 PIO0329.538 Prostasin precursor PRSS8 PIOO794829 16 kDa protein ACADS PIO0167006 Uncharacterized protein C130rf26 C13orf26 PIO00284.81 Ras-related protein Rab-8A RAB8A PIO0294215 Uncharacterized protein KIAA0232 KIAA0232 PIO0027806 Cysteine-rich secretory protein LCCL domain-containing 1 CRISPLD1 jite Cui SOjº PIO0216423 Isoform 4 of Intersectin-2 ITSN2 US 2013/0237454 A1 Sep. 12, 2013 48

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0303870 Seven transmembrane helix receptor - PIO007.1185 Isoform SV1 of PITSLRE serine/threonine-protein kinase CDC2L.1 CDC2L.1 PIO0848229 EGF, latrophilin and seven transmembrane domain- ELTD1 containing protein 1 precursor PIOO166776 Protein CREG2 precursor CREG2 PIOO456969 Dynein heavy chain, cytosolic DYNC1LI1 PIO0293.857 Isoform 1A of Beta-arrestin-1 ARRB1 PIO0001796 Tumor necrosis factor receptor superfamily, member 18 TNFRSF18 (Fragment) PIO0549972 LIM domain-containing protein 2 LIMD2 PIO0604551 Isoform 1 of Cell division cycle-associated protein 7 CDCAT PIO0293565 fims-related tyrosine kinase 4 isoform 1 FLT4 PIO0022471 minor histocompatibility antigen HA-1 HMHA1 PIO0029050 Isoform 1 of Glycosyltransferase-like protein LARGE1 LARGE PIO0848.252 hypothetical protein LOC285501 LOC285501 PIO0288939 Isoform 3 of Coiled-coil domain-containing protein 40 CCDC40 PIO0029107 Werner syndrome ATP-dependent helicase WRN PIO0065057 Putative uncharacterized protein CXorf58 CXorf58 PIO0073769 48 kDa protein PALM2 PIO0065520 Isoform 1 of Protein phosphatase 1M PPM1M PIOO470468 Isoform 3 of Protein EFR3 homolog A EFR3A PIO0436518 Benzodiazepine receptor ligand - PIO0382515 CDNA FLJ30384 fis, clone BRACE2008114 - PIO0749514 attractin-like 1 ATRNL1 PIO0853312 Uncharacterized protein ENSP00000324580 - PIO0217871 Delta-1-pyrroline-5-carboxylate dehydrogenase, ALDH4A1 mitochondrial precursor PI00015345 Cadherin EGF LAG seven-pass G-type receptor 3 CELSR3; SLC26A6 jite Cui SOjº PIO0644191 70 kDa protein ZNF90 PIO0847391 Isoform 1 of Zinc finger protein 276 ZNF276 PIO0001654 Isoform 3 of Pericentriolar material 1 protein PCM1 PIOO470490 Isoform 1 of Nuclear receptor coactivator 1 NCOA1 PIOO410488 Isoform 1 of CD276 antigen precursor CD276 PIO0001433 Protocadherin beta 15 precursor PCDHB15 PIO0220156 Isoform B of Transforming growth factor beta-2 precursor TGFB2 PIO0024818 Isoform 1 of Ubiquitin-specific peptidase-like protein 1 USPL1 PIO0335437 Ankyrin repeat and zinc finger domain-containing protein 1 ANKZF1 PIO0000076 Beta-nerve growth factor precursor NGFB PIO0100980 EH domain-containing protein 2 EHD2 PIO0215610 55 kDa erythrocyte membrane protein MPP1 PIO0015148 Ras-related protein Rap-1b precursor RAP1 B PIO0028493 Isoform 1 of Tuberin TSC2 PIOO410657 Isoform 2 of mRNA cap guanine-N7 methyltransferase RNMT PIO0328361 Seryl-tRNA synthetase, mitochondrial precursor SARS2 PIO0029700 Isoform Long of Down syndrome cell adhesion molecule DSCAM jite Cui SOjº PIO0332583 chorionic somatomammotropin hormone 1 isoform 2 CSH1; CSH2; GH1 PIO0552591 V1-20 protein GLV10–54 PIO0022277 Coiled-coil domain-containing protein 56 CCDC56 PIO0301844 Zinc fingers and homeoboxes protein 3 ZHX3 PIO0013788 HIV Tat-specific factor 1 HTATSF1 PIO0216.288 Isoform 3 of Lethal L3MBTL PIO0025499 Isoform Tau-F of Microtubule-associated protein tau MAPT PIO0001151 Isoform 2 of Uncharacterized MFS-type transporter C20Orf59 C20orf59 PIO0787083 similar to peptidylprolyl isomerase A isoform 1 LOC256374 PIO085.6012 collagen type VI alpha 6 COL6A6 PIO0001712 Isoform 1 of Catenin alpha-3 CTNNA3 PIO0847237 Conserved hypothetical protein - PIO0295999 Isoform 2 of Collagen alpha-1(DX) chain precursor COL9A1 PIO0217831 Ankyrin repeat domain-containing protein 13A ANKRD13A PIO0296.196 Dimethylglycine dehydrogenase, mitochondrial precursor DMGDH PIO0396145 FYVE finger-containing phosphoinositide kinase PIPSK3 PIOO478.110 Probable G-protein coupled receptor 135 GPR135 PIO0335.168 Isoform Non-muscle of Myosin light polypeptide 6 MYL6 PIO0030037 Agouti-signaling protein precursor ASIP PIO0013749 Protein kinase Czeta type PRKCZ PIO0002491 Isoform 9 of Sorbin and SH3 domain-containing protein 1 SORBS1 PIO0240793 Probable phospholipid-transporting ATPase IF ATP11 B PIO0168995 Olfactory receptor 4D9 OR4D9

US 2013/0237454 A1 Sep. 12, 2013 50

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIOO4797.22 Proteasome activator complex subunit 1 PSME1 PIO0006236 Platelet-derived growth factor receptor-like protein PDGFRL precursor PIO0177878 Isoform 3 of Transmembrane protein 16D TMEM16D PIO0291796 BTB (POZ) domain containing 12 BTBD12 PIO0104907 Isoform 1 of Uncharacterized potential DNA-binding C14Orf106 protein C14orf106 PIOO400795 54 kDa protein - PIO0303622 Olfactory receptor OR9–23 OR 1 N2 PIO0031554 ATP-dependent RNA helicase DDX50 DDX50 PIO0005107 Niemann-Pick C1 protein precursor NPC1 PIO0023860 Nucleosome assembly protein 1-like 1 NAP1L1 PIO0028520 Isoform 1 of NADH dehydrogenase [ubiquinone] NDUFV1 flavoprotein 1, mitochondrial precursor PIO0009070 Isoform 1 of HBS1-like protein HBS1 L PIO0375225 Olfactory receptor 2AE1 OR2AE1 PIO0235622 Isoform 3 of CUB domain-containing protein 1 precursor CDCP1 PIO0742031 similar to golgi autoantigen, golgin subfamily a, 8G LOC645137 PIOO480159 inositol polyphosphate-5-phosphatase F NPP5E PIO0221372 Isoform 2 of 1-acyl-sn-glycerol-3-phosphate acyltransferase AGPAT2 betà PIO0386576 Ig lambda chain V-IV region MOL - PIO0022295 Platelet factor 4 variant precursor PF4V1 PIO0747420 Melanoma-derived protein (Fragment) - PIOO432226 AVLL5809 - PIO0796972 62 kDa protein ETV5 PIO0171874 Ras guanyl-releasing protein 3 RASGRP3 PIO0010807 Frizzled-8 precursor FZD8 PIO00067.46 Ermin ERMN PIO0178894 Zinc finger and BTB domain-containing protein 20 ZBTB20 PIO0878436 24 kDa protein SLC2A11 PIO0640810 6 kDa protein CTDP1 PIO0003921. Isoform 1 of Protein 4.1 EPB41 PIO0031410 FKBP12-rapamycin complex-associated protein FRAP1 PIO0019848 Isoform 1 of Host cell factor HCFC1 PIO0306549 CDNA FLJ11065 fis, clone PLACE1004868, weakly MLSTD1 Similar to MALE STERILITY PROTEIN 2 PIO0306611 TRAF-interacting protein TRAIP PIO0003392 Transmembrane protein 5 TMEMS PIOO153031 Isoform 1 of Uncharacterized protein C17orf&O C17orf&O PIO0289097 Isoform 1 of Ras-GEF domain-containing family member RASGEF1B B PIOO425404 Isoform 1 of Kinesin-like protein KIF21A ÇIF21A PIO0293361 Isoform 2 of Small G protein signaling modulator 2 SGSM2 PIOO4772.62 Uncharacterized protein TRIM41 (Fragment) TRIM41 PIO0021753 Kinesin-like protein KIF13B KIF13B PIO0030703 Motor neuron and pancreas homeobox protein 1 MNX1 PIO0025974 Charged multivesicular body protein 4b CHMP4B PIOO413655 ankyrin repeat domain 55 isoform 1 ANKRD55 PIO0253281 Isoform 2 of Epidermal growth factor receptor kinase EPS8L1 substrate 8-like protein 1 PIO0005607 Isoform 1 of Deleted in bladder cancer protein 1 precursor DBC1 PIO0027984 Putative uncharacterized protein DNAJC11 PIO0026497 Isoform 1 of Poly [ADP-ribose] polymerase 2 PARP2 PIO0296441 Adenosine deaminase ADA PIO0329605 DNA mismatch repair protein Msh:3 MSH3 PIO0032425 Receptor activity-modifying protein 3 precursor RAMP3 PIO0061206 Polyadenylate-binding protein 5 PABPC5 PIO0289758 Calpain-2 catalytic subunit precursor CAPN2 PIO0001568 Vacuolar proton pump subunit D ATP6V1D PIOO465177 Transforming growth factor-alpha variant I TGFA PIO0020470 Isoform 1 of Glycosyltransferase 8 domain-containing GLT8D1 protein 1 PIO0718821 Isoform 1 of Uncharacterized protein C190rf55 C 1901.f55 PIO0018387 Furin precursor FURIN PIO0398229 similar to deubiquitinating enzyme 3 LOC392197 PIO0027248 Tumor suppressor candidate 2 TUSC2 PIO0163851 Isoform 1 of Eukaryotic translation initiation factor 2-alpha EIF2AK4 kinase 4 PIOO438286 Isoform 1 of Protein LAP2 ERBB2IP PIO0023780 Isoform 2 of DnaJ homolog subfamily C member 5 DNAJCS US 2013/0237454 A1 Sep. 12, 2013 51

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0018027 Isoform 1 of Angiogenic factor with G patch and FHA AGGF1 domains 1 PIO0180305 Isoform 5 of E3 ubiquitin-protein ligase UBR4 |UBR4 PIO0010442 Phospholemman precursor FXYD1; FXYD7 PIO0292657 NADP-dependent leukotriene B4 12- LTB4DH hydroxydehydrogenase PIOO434711 Putative uncharacterized protein FP6679 - PIO0020329 Potassium voltage-gated channel subfamily S member 2 KCNS2 PIO0019244 Isoform 1 of RNA-binding protein Nova-1 NOVA1 PIO0009101 Isoform 2 of Helicase SRCAP SRCAP PIO0184650 Class B basic helix-loop-helix protein 4 BHLHB4 PIO0328.298 Isoform 2 of Structural maintenance of chromosomes SMC4 protein 4 PIO0782992 Isoform 1 of Serine/arginine repetitive matrix protein 2 SRRM2 PIO000.6663 Aldehyde dehydrogenase, mitochondrial precursor ALDH2 PIO0014340 Isoform 1 of Protein phosphatase 1 regulatory subunit 12C PPP1R12C PIO0807675 ZNF440 protein ZNF440 PIO0104050 Thyroid hormone receptor-associated protein 3 THRAP3 PIO0386284 olfactory receptor, family 2, subfamily AK, member 2 OR2AK2 PIOO411480 hypothetical protein LOC729461 PIO0018429 Paired mesoderm homeobox protein 2 PRRX2 PIO0646423 Isoform 2 of Transcription initiation factor TFIID subunit TAF4B 4B PIOO387004 PNAS-146 MCM7 PIOO446312 CDNA FLJ42271 fis, clone TKIDN2O15788 - PIO0218667 Stathmin-2 STMN2 PIO0179298 482 kDa protein HUWE1 PIO0299547 Neutrophil gelatinase-associated lipocalin precursor LCN2 PIO0016006 Isoform 1 of Gephyrin GPHN PIO0395630 Putative uncharacterized protein pp.6170 SCRIB PIO000947.1 WD repeat-containing protein 3 WDR3 PIOO455967 Uncharacterized protein ENSP00000353619 (Fragment) - PIO0100067 Isoform 1 of Tumor necrosis factor receptor superfamily TNFRSF19 member 19 precursor PIO0299263 ADP-ribosylation factor GTPase-activating protein 3 ARFGAP3 PIO0186966 Isoform IIA of Myc box-dependent-interacting protein 1 BIN1 PIO0220308 Isoform 2 of Merlin NF2 PIO0045939 2-aminoethanethiol dioxygenase ADO PIO0789476 7 kDa protein - PIO0014537 Isoform 1 of Calumenin precursor CALU PIO0165009 Isoform 3 of MBT domain-containing protein 1 MBTD1 PIO0306749 Kanadaptin SLC4A1AP PIO0001922 Suppressor of tumorigenicity protein 14 ST14 PIO0374670 hypothetical protein isoform 2 LOC388588 PIO0005809 Serum deprivation-response protein SDPR. PIOO453473 Histone H4 HIST2H4A: HIST1H4E: HIST1H4H; HIST4H4; HIST1H4C; HIST1H4A: HIST1H4B; HIST1H4.J.; HIST1H4F; HIST1H4K; HIST1H4L; HIST2H4B; HIST1H4I: HIST1H4D PIOO464980 Isoform 1 of Paired amphipathic helix protein Sin?b SIN3B PIO0289837 Coiled-coil domain-containing protein 85A CCDC85A PIO0878962 10 kDa protein - PIO0103891 Putative uncharacterized protein MTMR14 PIO0328709 Gremlin-2 precursor GREM2 PIO0744932 Conserved hypothetical protein ZDHHC1 PIO0398154 actin filament associated protein 1 AFAP1 PIO0291939 Structural maintenance of chromosomes protein 1A SMC1A PIOO444272 Leukemia inhibitory factor receptor precursor LIFR PIO0641181 MARCKS-related protein MARCKSL1 PIO0022799 Isoform 2 of Aquaporin-4 AQP4 PIOO445750 CDNA FLJ43142 fis, clone CTONG3007870 - PIO0006077 Protein Jade-3 PHF16 PIOO151990 Isoform 1 of Thioredoxin domain-containing protein 15 TXNDC15 precursor PIO0061148 Sodium bicarbonate cotransporter NBC4d SLC4A5 PIO0004944 Isoform 1 of Sodium-driven chloride bicarbonate SLC4A10 exchanger PIO0304587 Protein dispatched homolog 2 DISP2 PIO0219703 Parvalbumin alpha PVALB US 2013/0237454 A1 Sep. 12, 2013 52

TABLE 6c-continued CSF Proteins Absent in Chronic Fatigue but Present in Neurologic Lyme or Normals CleanTPI Protein Gene PIO0003384 Isoform 1 of Cadherin EGF LAG seven-pass G-type CELSR1 receptor 1 precursor PIO0007750 Tubulin alpha-4A chain TUBA4A PIO0015988 HLA class I histocompatibility antigen, alpha chain G HLA-G jite Cui SOjº PIO0001813 Isoform 1 of RING and PHD-finger domain-containing KIAA1542 protein KIAA1542 PIO0171412 Isoform 1 of Sulfatase-modifying factor 2 precursor SUMF2 PIO0005981 Transgelin-3 TAGLN3 PIO0032826 Hsc70-interacting protein ST13 PIO0025447 Elongation factor 1-alpha EEF1A1 PIO0152326 glutathione S-transferase M1 isoform 2 GSTM1 PIO0044751 Isoform 1 of M-phase phosphoprotein 1 MPHOSPH1 PIO0028.193 192 kDa protein KNDC1 PIO0000775 Isoform 1 of Leucine-rich repeats and immunoglobulin-like LRIG1 PIO0329593 Isoform 2 of ADP-dependent glucokinase ADPGK PIO0296461 Isoform 1 of Sphingomyelin phosphodiesterase precursor SMPD1 PIOO65 6052 SPANX-C SPANXB2; SPANXB1; SPANXF1 PIO0658109 Creatine kinase, ubiquitous mitochondrial precursor CKMT1A: CKMT1B PIO0376383 Centrosomal protein 110 kDa CEP110 PIO0019904 Isoform 1 of Beta-adducin ADD2 PIOO413266 Isoform 1 of IQ and AAA domain-containing protein IQCA PIO0015973 Band 4.1-like protein 2 EPB41 L2 PIO0166807 Isoform 3 of Oxidation resistance protein 1 OXR1 PIOO472374 zinc finger protein 98 ZNF98 PIO0032.187 mischarin NISCH PIOO420014 Isoform 1 of U5 small nuclear ribonucleoprotein 200 kDa ASCC3L1 helicase PIO0386.314 FLJO0064 protein (Fragment) CNDP2 PIO0021766 Isoform 1 of Reticulon-4 RTN4 PIO0221006 Isoform 4 of Transcription factor 7-like 2 TCF7L2

(2) indicates text missing or illegible when filed

TABLE 7L Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion. 692 proteins in list.

CleanTPI Protein Gene 00:55 1062 soform 1 of Protein canopy homolog 3 precursor CNPY3 00017551 soform 1 of Regucalcin RGN 00006663 Aldehyde dehydrogenase, mitochondrial precursor ALDH2 00412977 Prothymosin alpha 00384280 Prenylcysteine oxidase 1 precursor PCYOX1 00247295 soform 4 of Nesprin-1 00007800 Angiopoietin-related protein 2 precursor 00553215 00002707 soform 1 of Spastin 00005563 soform 1 of Tubulointerstitial nephritis antigen-like precursor 00827486 Rheumatoid factor light chain variable region precursor (Fragment) 00004671 Golgin subfamily B member 1 00465.345 soform 3 of Pre-mRNA-processing factor 40 homolog B 000101.30 Glutamine synthetase 00477763 Serine/threonine-protein kinase MRCK beta 00328268 EIF4G3 protein 00305477 Cystatin-SN precursor 00070070 Novel protein 008:52619 soform A of Probable phospholipid-transporting ATPase VB 00000203 Low-density lipoprotein receptor-related protein 6 precursor 00021473 59 kDa protein BFA2T3 00016703 24-dehydrocholesterol reductase precursor HCR 24 0002888.1 NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3 DUFA3 00.1521.57 Isoform 1 of Zinc finger protein 509 NF509 0032882.5 Isoform 1 of NEDD4-binding protein 2 4 BP2 00060569 Isoform 2 of Abhydrolase domain-containing protein 12 BHD12 00412298 Isoform 1 of Serine/threonine-protein kinase ATR TR

US 2013/0237454 A1 Sep. 12, 2013 55

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein 0023.2891 soform 3 of Fibronectin type III domain-containing protein 1 00018402 Tubulin-specific chaperone E 00030404 Transcriptional repressor NF-X1 00219661 soform 1 of Myelin proteolipid protein 00.186853 pecanex-like 2 00395376 soform 1 of Semaphorin-5B 00555621 p21-activated kinase 2 variant (Fragment) 00746.232 coiled-coil domain containing 112 isoform 2 00022020 Type II inositol-3,4-bisphosphate 4-phosphatase 00418236 Factor in the germline alpha 00328762 soform 1 of ATP-binding cassette sub-family A member 13 00748342 Beclin-1 BECN1 00739423 similar to c11.1 CG12132-PA isoform 11 LOC377711 00026970 FACT complex subunit SPT16 SUPT16H 00549384 soform 1 of Bromodomain-containing protein 9 RD9 004.7989.3 soform 2 of Uncharacterized protein C10orf18 0orf18 00876910 soform 1 of Ankyrin repeat and SOCS box-containing protein 18 00477766 Soform 3 of Protein PTHB1 0030.1503 soform 1 of Splicing factor, arginine/serine-rich 10 0042.5688 soform 1 of RUN and SH3 domain-containing protein 1 00787427 ankyrin repeat domain 36 00.167241 Zinc finger protein 283 002.20325 soform Short of Insulin receptor precursor 00032541 Keratin type II cuticular Hbs 00384874 soform 1 of ATP-binding cassette sub-family A member 10 00019690 death-inducing-protein 00027723 Elastase-2B precursor 00015737 5 kDa protein 00641954 22 kDa protein 007396.76 Soform 2 of Protein DDX26B 00402006 Similar to DNA-binding protein 00477949 soform 1 of Zinc finger MYM-type protein 4 00737448 similar to heat shock 70 kD protein binding protein LOC338805 00383.261 Peroxin Pexop PEX6 00022735 Synaptotagmin-4 SYT4 00026058 soform 1 of Leucine zipper putative tumor suppressor 1 LZTS1 00479789 soform 1 of Uncharacterized protein Clorf103 C1 Orf103 0041 1637 Galactose-3-O-sulfotransferase 4 GAL3ST4 00.154834 soform 1 of Neighbor of punce11 precursor NOPE 00007360 Zinc finger protein 238 ZNF238 007.93585 57 kDa protein OC90 000291.33 ATP synthase subunit b, mitochondrial precursor ATP5F1 00218271 soform 3 of MAGUK p55 subfamily member 2 MPP2 00003949 Ubiquitin-conjugating enzyme E2 N |UBE2IN 00304992 soform 1 of Zinc finger protein 503 ZNF503 00006612 soform 1 of Clathrin coat assembly protein AP180 SNAP91 00642305 MCM8 protein MCM8 00026320 E3 ubiquitin-protein ligase UBR5 |UBR5 000101.42 Ubiquitin-conjugating enzyme E2 G2 |UBE2G2 00029769 soform p59-HCK of Tyrosine-protein kinase HCK HCK 004461.38 CDNA FLJ42768 fis, clone BRAWH3003522 00449071 soform 5a of Paired box protein Pax-6 PAX6 0043289.3 INPP5E protein (Fragment) INPP5E 002.20039 soform 1 of Transmembrane protein 16K TMEM16K 00000270 Ribonuclease 7 precursor RNASE7 00479430 soform 2 of Complement C1q tumor necrosis factor-related protein 9 C1QTNF9 jite Cui SOjº 00296798 soform 1 of Fibrinogen C domain-containing protein 1 FIBCD1 00003483 soform 1 of Neuralized-like protein 1 NEURL 00419575 Protein of unknown function DUF410 family protein C7orf20 00019090 Collagen alpha-1 COL19A1 00011756 Homeobox protein Meis1 MEIS1 0001.2687 27 kDa protein C1 Orfè3 0033,2106 soform 1 of Pre-B-cell leukemia transcription factor-interacting protein 1 PBXIP1 00418426 Metal transporter CNNM4 CNNM4 00002524 ATP-sensitive inward rectifier potassium channel 14 KCNJ 14 00000110 Zinc finger protein 337 ZNF337 00297767 Casein kinase I isoform gamma-2 CSNK1 G2 00007207 Isoform 1 of Lysosomal acid lipase/cholesteryl ester hydrolase precursor LIPA 000238.68 Canalicular multispecific organic anion transporter 1 ABCC2 US 2013/0237454 A1 Sep. 12, 2013 56

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene 00031.522 Trifunctional enzyme subunit alpha, mitochondrial precursor HADHA 00329.142 Glutamate-rich protein 1 ERICH1 00:16925.3 Olfactory receptor OR1-45 OR5 AT1 00045801 Flt3-interacting zinc finger protein 1 FIZ1 00017802 Isoform 1 of Methylglutaconyl-CoA hydratase, mitochondrial precursor AUH 00384.549 TTC31 protein (Fragment) TTC31 0001.2756 Interferon-induced protein with tetratricopeptide repeats 5 IFIT5 00297.985 Uncharacterized protein C60rf103 C6Orf103 005.14394 Family with sequence similarity 120A opposite strand FAM120AOS 00034088 Interleukin-27 beta chain precursor EBIG 00305.856 Homeobox protein Hox-D11 HOXD11 00797859 10 kDa protein LOC64371.1 00385.737 similar to Nonhistone chromosomal protein HMG-17 LOC646853 000151.95 Cleavage stimulation factor 77 kDa subunit CSTF3 00006158 Lymphoid-restricted membrane protein LRMP 00008554 Angiogenin precursor ANG 000281.58 Neurotensin/neuromedin N precursor NTS 00384393 Myosin-reactive immunoglobulin heavy chain variable region (Fragment) 00021129 soform 1 of AP-3 complex subunit beta-1 AP3B1 0001.3871 Ribonucleoside-diphosphate reductase large subunit RRM1 00020039 Cylicin-1 CYLC1 00737712 CCDC125 protein CCDC125 00219036 dicer1 DICER1 00297212 Paladin ÇIAA1274 00418185 Putative uncharacterized protein FLJ20097 CCDC132 0042.3562 soform 1 of Ubiquitin carboxyl-terminal hydrolase 6 USP6 00008475 Hydroxymethylglutaryl-CoA synthase, cytoplasmic HMGCS1 00412.107 FLJ43980 protein FLJ43980 00328793 Sterol regulatory element-binding protein 2 SREBF2 00004563 Protein FAM105A FAM105A 00013257 Single-stranded DNA-binding protein 4 SSBP4 00.158804 basic, immunoglobulin-like variable motif containing BIVM 00.1666.06 KIAA0913 protein (Fragment) ÇIAA0913 00329014 soform 1 of Ankyrin repeat domain-containing protein 46 ANKRD46 00395.603 soform 3 of Uncharacterized protein C18Orf34 C18Orf}4 00303.980 soform 1 of Uncharacterized protein C14orfø3 precursor C14Orfø3 0043,3499 rhomboid, veinlet-like 6 isoform 1 RHBDF2 000061.96 soform 2 of Nuclear mitotic apparatus protein 1 NUMA1 00004446 Sushi repeat-containing protein SRPX2 precursor SRPX2 0001.0448 soform 2 of Rho GTPase-activating protein 24 ARHGAP24 007.37392 similar to proline-rich protein BstNI subfamily 3 precursor LOC646352 00219503 soform 1 of F-box only protein 24 FBXO24 00414591 Flavoprotein oxidoreductase MICAL2 00018240 soform 1 of Protein SDA1 homolog SDAD1 00657892 Factor VIII 003.86651 LOC404266 protein LOC404.266 00.166933 Uncharacterized protein C10orf12 C10orf12 00005254 soform 1 of E3 ubiquitin-protein ligase parkin PARK2 00065378 soform 1 of DC-STAMP domain-containing protein 1 DCST1 00.163718 soform 4 of Vacuolar protein sorting-associated protein 54 VPS54 004148.19 Helicase SKI2W SKIV2L 00041588 Ral guanine nucleotide exchange factor RalGPS1A RALGPS1 00.100787 RANBP2-like and GRIP domain-containing protein 7 RGPD5; RGPD7 008.737.59 Uncharacterized protein ENSP00000381675 (Fragment) 0001.2390 Homeobox protein Hox-D4 HOXD4 00027694 soform 3 of Homeobox protein Hox-A1 HOXA1 00747264 Gamma-aminobutyric-acid receptor subunit rho-1 precursor GABRR1 00337544 soform 2 of Myomegalin PDE4DIP 00020795 R33083. 1 (Fragment) DPP.9 00010740 soform Long of Splicing factor, proline- and glutamine-rich 0001924.3 soform Long of Matrix metalloproteinase-16 precursor MMP16 00749338 Hypothetical gene supported by BC063892 hCG 1651889 0022.1009 soform 7 of Transcription factor 7-like 2 TCF7L2 003.98725 soform 1 of Zinc finger protein 644 ZNF644 00745832 Q calmodulin-binding region domain containing protein 00007067 Golgi-associated plant pathogenesis-related protein 1 C9Crf19 0041 0616 soform 1 of Endonuclease VIII-like 2 NEIL2 00005978 Splicing factor, arginine/serine-rich 2 SFRS2 00844512 RHOV protein (Fragment) RHOV US 2013/0237454 A1 Sep. 12, 2013 57

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene 008793.89 20 kDa protein ZMYND11 00329251 Isoform 1 of Transmembrane protein 146 precursor TMEM146 00465087 Ubiquitin carboxyl-terminal hydrolase BAP1 BAP1 00.103812 PWWP domain-containing protein 2B PWWP2B 00010953 CDNA FLJ11251 fis, clone PLACE1008813 EXOC6 006.39924 97 kDa protein LOC374920 00292579 Stabilin-2 precursor STAB2 00067920 FXYD domain-containing ion transport regulator 7 FXYD7 0087,916.2 Uncharacterized protein ENSP00000374866 00009804 DNA-binding protein SATB1 SATB1 00215925 Glycine N-methyltransferase GNMT 00006675 Multidrug resistance-associated protein 4 ABCC4 00442.551 CDNA FLJ26989 fis, clone SLV03395 ATP9B 00027436 Tumor necrosis factor receptor superfamily member 16 precursor NGFR 00.1661.90 soform 1 of Uncharacterized protein C190rf19 C1901.fl. 9 00.154567 soform 2 of Spermatogenesis-associated protein 20 precursor SPATA20 00008495 NADH-ubiquinone oxidoreductase chain 4 MT-ND4 00179172 soform 2 of Liprin-beta-1 PPFIBP1 00872928 Several ankyrin repeat protein transcript variant 2 (Fragment) ANKRD42 00412647 CDNA: FLJ21792 fis, clone HEP00441 THADA 00032929 soform 1 of Thrombospondin type-1 domain-containing protein 1 THSD1 jite Cui SOjº 00.154451 MMS19 nucleotide excision repair homolog MMS 19 00.1861.45 soform 1 of Protein phosphatase 1.L PPM1L 00386.364 Olfactory receptor 2L2 OR2L2 00218823 soform 1 of WW domain-binding protein 7 MLL4 00060379 Integrator complex subunit 12 NTS12 00444706 CDNA FLJ45007 fis, clone BRAWH301.2005 |

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene 00647254 7 kDa protein 00328118 Sperm-associated antigen 5 SPAG5 00094740 soform 1 of RING finger protein 31 RNF31 003833.18 PRO2272 0029.2470 dapper, antagonist of beta-catenin, homolog 2 DACT2 00215.884 soform ASF-1 of Splicing factor, arginine/serine-rich 1 SFRS1 00013488 soform Alpha-2 of N-chimaerin CHN1 00030909 BB1 family protein 005522.13 soform 6 of Disks large homolog 1 DLG1 00397358 Similar to ribosomal protein S27 00021786 RAF proto-oncogene serine/threonine-protein kinase RAF1 00003438 DnaJ homolog subfamily C member 8 DNAJC3 003989.00 Homeobox protein HMX2 HMX2 00031960 polymerase (RNA) 1 polypeptide A, 194 kDa POLR1A 002988.70 Transmembrane protein 1 TMEM1 00017991 jumonji domain containing 2D JMJD2D 00.151366 soform TRPM6a of Transient receptor potential cation channel TRPM6 subfamily M member 6 00011488 soform 1 of Serine/threonine-protein kinase 4 STK4 00.101405 Farnesyl diphosphate synthase FDPS 00786867 Dual Intracellular Von Willebrand factor domain A DIVA 00006904 Cell death regulator Aven AVEN 00376213 soform 1 of G-protein coupled receptor 120 GPR120 0001 0420 ADP/ATP translocase 4 SLC25A31 00004419 Zinc finger protein 646 ZNF646 008:47409 hypothetical protein LOC440338 00005024 soform 1 of Myb-binding protein 1A MYBBP1A 001778.90 54 kDa protein SMARCD2 0002363.5 soform 1 of Inositol monophosphatase 2 IMPA2 00304.885 Centromere protein C 1 CENPC1 007840.13 anus kinase JAK1 00216139 soform I of Septin-6 SEPT6 002899.54 Heparan sulfate glucosamine 3-O-sulfotransferase 6 HS3ST6 00018134 Soform 4 of Protein SOLO FLJ10357 00855742 sterile alpha motif domain containing 12 isoform a SAMD12 00415037 soform 12L of ADAM 12 precursor ADAM12 0041 1298 Connector enhancer of kinase suppressor of ras 3 CNKSR3 00031288 Claudin-14 CLDN14 O0867582 Similar to SCAN domain-containing protein 2. Isoform 2 ZNF496 00418885 Epididymal-specific lipocalin-10 precursor LCN10 007.95992 Hypothetical short protein 008:47373 hypothetical protein LOC54627 ÇIAA1383 00030070 Gap junction beta-5 protein GJB5 00418.238 soform 1 of HIV-1 Rev-binding protein-like protein HRBL 002934.09 Zinc finger protein 81 ZNF81 00003927 40 kDa peptidyl-prolyl cis-trans isomerase PPID 00024801 E3 ubiquitin-protein ligase NRDP1 RNF41 00.103356 Uncharacterized protein ITGB2 TGB2 00604798 Bitter taste receptor T2R2 (Fragment) 0001.3887 Beta-galactoside alpha-2,6-sialyltransferase 1 00384971 hypothetical protein LOC643155 00025721 COP9 signalosome complex subunit 3 00855747 hypothetical protein LOC57481 00445054 CDNA FLJ44715 fis, clone BRACE3021430 002.20503 003281.59 soform 1 of Uncharacterized protein Clorf&8 00003881 Heterogeneous nuclear ribonucleoprotein F 00003990 soform 2 of Valacyclovir hydrolase precursor 008:47485 Similar to PFIV protein 00007300 BTB/POZ domain-containing protein 3 00217490 soform 1 of Fibronectin type III domain-containing protein 3B 008:48330 Conserved hypothetical protein 00000787 soform LMP2.L of Proteasome subunit beta type-9 precursor 00004379 Homeobox protein HMX1 00375820 Interferon-induced transmembrane protein 5 0041 1635 80 kDa protein 007.95566 6 kDa protein 00217117 soform 1 of Glycerate kinase 00300086 Nicotinate-nucleotide pyrophosphorylase US 2013/0237454 A1 Sep. 12, 2013 59

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene

00235167 Profilin-3 PFN3 00026126 Mammaglobin-B precursor SCGB2A1 0022.0167 Isoform 1 of Putative methyltransferase NSUN7 NSUN7 00.1551.68 Leukocyte common antigen precursor (EC 3.1.3.48) (L-CA) (T200) PTPRC (CD45 antigen). Isoform 2 00384268 XRCC6BP1 protein 0029.9507 Condensin complex subunit 2 00445643 CDNA FLJ43684 fis, clone TBAES2001492 00.165591 Isoform 4 of Transmembrane channel-like protein 6 TMC6 00.152149 CENP-B, N-terminal DNA-binding domain containing protein 00029643 Isoform 2 of Mitogen-activated srotein kinase kinase kinase MLT ZAK 00000875 Elongation factor 1-gamma EEF1G 00215948 Isoform 1 of Catenin alpha-1 CTNNA1 00022918 Isoform 2 of Protein FAM125B FAM125B 00007208 Probable ATP-dependent RNA helicase DDX41 DDX41 00855922 Isoform 4 of DENN domain-containing protein 3 DENND3 00031056 Zinc finger MYND domain-containing protein 15 ZMYND15 00641.614 47 kDa protein AKAP8L 00002134 26S proteasome non-ATPase regulatory subunit 5 PSMD5 0005 6040 Neuritin 1-like NRN1 L 008:56045 AHNAK nucleoprotein 2 AHNAK2 000093:29 Utrophin UTRN 0021.8235 dehydrogenase/reductase member 2 isoform 2 DHRS2 00297.315 Alpha-2B adrenergic receptor ADRA2B 00107855 Hephaestin precursor HEPH 00217662 Uncharacterized protein C11orf.35 C11orf.35 00025489 Serine/threonine-protein kinase MAK MAK 00027774 THAP domain-containing protein 2 THAP2 000274.15 soform 1 of Probable ATP-dependent RNA helicase DHX36 00.1761.25 Collagen XXIX alpha 1 00016046 Protein MGR2 homolog 0000284.1 Sodium/hydrogen exchanger 2 004.72712 Coiled-coil domain containing 7 00061355 Soform 3 of Protein ZNF673 ZNF673 00445804 Uncharacterized protein ENSP00000374264 DKFZp761B107 00790.813 8 kDa protein RAD51AP1 00061780 soform 1 of E3 ubiquitin-protein ligase Itchy homolog ITCH 000300.99 Adenylate cyclase type 9 ADCY9 00016095 Transcription termination factor, mitochondrial precursor MTERF 00004521 Ewing's tumor-associated antigen 1 ETAA1 00171525 Sentrin-specific protease 3 SENP3 00373824 Testis serine protease 1 precursor TESSP1 002997.29 Transcobalamin-1 precursor 00007444 Epiphycan precursor 00.167014 EID2 protein (Fragment) 00007327 soform 1 of Tapasin precursor 00244346 Troponin I, cardiac muscle 00009066 similar to protein tyrosine phosphatase, receptor type, Q isoform 1 jite Cui SOjº 003031.95 Syncoilin-1 SYNC1 00031812 Nuclease sensitive element-binding protein 1 YBX 00018854 Coiled-coil domain-containing protein 68 CCDC68 000.84582 soform 7 of Collagen alpha-1(XIII) chain COL13A1 00216815 soform 2 of DNA topoisomerase 3-beta-1 TOP3B 00062599 71 kDa protein 00060549 G-protein coupled receptor-associated sorting protein 1 GPRASP1 007.95943 7 kDa protein 0.0642.204 Thioredoxin domain-containing protein 16 precursor TXNDC16 0.0646199 Zinc finger, MYM-type 2 ZMYM2 007.91447 Pseudogene candidate LOC3399.29 00745433 eukaryotic translation initiation factor 2C, 2 EIF2C2 00.103090 Isoform 1 of RNA polymerase-associated protein LEO1 LEO1 00101186 Isoform 1 of RRP12-like protein RRP12 00013404 Mothers against decapentaplegic homolog 4 SMAD4 002.20038 Isoform B of Arsenite-resistance protein 2 ARS2 00385683 Ig heavy chain V-III region GAR 00006030 Dynein intermediate chain 1, axonemal DNAI1 00024714 Isoform 1 of Regulator of G-protein signaling 12 RGS12 00259671 Taste receptor type 2 member 44 00335581 Isoform 1 of E3 ubiquitin-protein ligase UBR3 US 2013/0237454 A1 Sep. 12, 2013 60

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene 00004416 Charged multivesicular body protein 2a CHMP2A 00028828 Isoform Beta of Zinc finger protein 202 ZNF202 00514795 Isoform 1 of Tubulin--tyrosine ligase-like protein 7 TTLL7 00.101987 Uncharacterized protein C190rf62 C190rf62 00853224 START domain containing 7 STARD7 00001141 Mitochondrial import inner membrane translocase subunit Tim22 TIMM22 00514975 Chromosome 1 open reading frame 133 C1 Orf133 007.44029 Similar to Zinc finger, FYVE domain containing 21 00399320 Transmembrane protein 59 precursor TMEM59 00217687 Isoform 1 of Coiled-coil domain-containing protein 135 CCDC135 00829745 Cellular titin isoform PEVK variant 2 (Fragment) 00216544 Isoform 2 of Protein hairless 00646323 Isoform 1 of Uncharacterized protein C10orf76 00386797 Isoform 1 of Folliculin-interacting protein 1 00304589 Isoform 1 of 182 kDa tankyrase 1-binding protein 00002857 Isoform CSBP2 of Mitogen-activated protein kinase 14 0001.7630 Nuclear fragile X mental retardation-interacting protein 1 00019992 Myb-related protein A 00.168848 UDP-GlcNAc:beta Gal beta-1,3-N-acetylglucosaminyltransferase 7 00216917 Isoform 1 of Uncharacterized protein C22Orfø 00043499 Probable urocanate hydratase 00056507 Isoform 1 of F-box/WD repeat-containing protein 5 0001745.1 Splicing factor 3 subunit 1 00465273 UHRF1-binding protein 1 00738999 similar to ubiquitin-conjugating enzyme E2 variant 1 00031047 CDNA: FLJ23571 fis, clone LNG12303 00022256 AP-2 complex subunit mu-1 00.151141 soform 1 of Serine/threonine-protein kinase WNK4 000272.32 Insulin-like growth factor 1 receptor precursor 00328.748 Protein ARMET precursor 00553006 Probable prolyl-tRNA synthetase, mitochondrial precursor 00102803 Ankyrin repeat domain-containing protein 22 0003015.3 Tudor domain-containing protein 6 00010212 U6 snRNA-specific terminal uridylyltransferase 1 00844501 MG44 protein 00456060 Protein 00016480 soform 1 of NACHT, LRR and PYD domains-containing protein 2 0041 1545 soform 3 of Thrombopoietin precursor 00.168239 Zinc finger protein GLIS1 LIS1 00.165990 soform 4 of Transcription factor RFX4 FX4 007494.89 fibrocystin L ÇHD1 L1 00059144 Protein FAM46B AM46B 00787697 similar to Oligophrenin 1 isoform 4 E LJ328.10 00043237 CDNA FLJ32095 fis, clone OCBBF2000998 LOC730193; STX6 00028641 soform 4 of Protein phosphatase 1 regulatory subunit 12B PPP1R12B 008791.59 9 kDa protein 00018099 E3 ubiquitin-protein ligase FANCL FANCL 004:55.076 Double C2-like domain-containing protein alpha DOC2A 00295940 Protein unc-84 homolog B UNC84B 00002970 Beta-sarcoglycan SGCB 008:78142 68 kDa protein 00554488 cAMP-dependent protein kinase type I-beta regulatory subunit PRKAR1B 00030279 soform 1 of Zinc finger Ran-binding domain-containing protein 3 ZRANB3 00074656 soform 1 of Coiled-coil domain-containing protein C60rf65 C6Orf65 00014903 soform 1 of FGFR1 oncogene partner 2 FGFR1OP2 0001 1961 soform 1 of Sialoadhesin precursor SIGLEC1 00.170770 soform 1 of PHD finger protein 3 PHF3 00000057 Conserved oligomeric Golgi complex component 2 COG2 004.35928 PP13187 RASGRF1 00013721 Serine/threonine-protein kinase PRP4 homolog PRPF4B 007.48607 Conserved hypothetical protein 00021266 60S ribosomal protein L23a RPL23A; ho(; 16001 00031228 soform 2 of Pleckstrin homology domain-containing family B member 2 PLEKHB2 00337415 Guanine nucleotide-binding protein G(i), alpha-1 subunit GNAI1 00745396 Stromal RNA regulating factor HNRPLL 00604752 soform 3 of Sterile alpha motif domain-containing protein 13 SAMD13 00382534 g heavy chain V-II region OU 00008.444 soform 1 of Cytidine and dcMP deaminase domain-containing protein 1 CDADC1 00792.933 zinc finger protein 462 ZNF462 00402005 Similar to DNA-binding protein ZNF528 US 2013/0237454 A1 Sep. 12, 2013 61

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene 00020036 Neuronal acetylcholine receptor subunit alpha-4 precursor CHRNA4 00329054 Osteopetrosis-associated transmembrane protein 1 precursor OSTM1 00028864 Neurexophilin-3 precursor NXPH3 00023757 soform 1 of X-linked retinitis pigmentosa GTPase regulator RPGR. 00000663 soform Mitochondrial of Malonyl-CoA decarboxylase, mitochondrial jite Cui SOjº MLYCD 00739387 hypothetical protein LOC401478 FLJ45872 00164352 zinc finger protein 292 ZNF292 00008913 Alpha-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 ST6CALNAC 5 00020454 Deoxycytidine kinase DCK 005.14028 21 kDa protein RNF207 00024292 Low-density lipoprotein receptor-related protein 2 precursor LRP2 00028357 Exportin-4 XPO)4 00438355 Fibrillin-3 precursor FBN3 00009043 Apoptotic-related protein PCAR (Fragment) 00027442 Alanyl-tRNA synthetase, cytoplasmic AARS 00014845 soform 1 of Ciliary dynein heavy chain 8 DNAH8 00385687 similar to Ubiquinol-cytochrome c reductase complex 14 kDa protein 00794829 6 kDa protein ACADS 00216423 soform 4 of Intersectin-2 TSN2 00303870 Seven transmembrane helix receptor 00848229 EGF, latrophilin and seven transmembrane domain-containing protein 1 ELTD1 jite Cui SOjº 00293.857 soform 1A of Beta-arrestin-1 ARRB1 00293565 ms-related tyrosine kinase 4 isoform 1 FLT4 00022471 minor histocompatibility antigen HA-1 HMHA1 00848.252 hypothetical protein LOC285501 LOC2.85501 00288939 soform 3 of Coiled-coil domain-containing protein 40 CCDC40 00065057 Putative uncharacterized protein CXorf58 CXOrfs 8 00073769 48 kDa protein PALM2 000655.20 soform 1 of Protein phosphatase 1M PPM1M 004365.18 Benzodiazepine receptor ligand 00015.345 Cadherin EGF LAG seven-pass G-type receptor 3 precursor CELSR3; SLC26A6 008:47391 soform 1 of Zinc finger protein 276 ZNF276 00001654 soform 3 of Pericentriolar material 1 protein PCM1 00028493 soform 1 of Tuberin TSC2 00332.583 chorionic somatomammotropin hormone 1 isoform 2 CSH1; CSH2: GH1 0.030.1844 Zinc fingers and homeoboxes protein 3 00013788 HIV Tat-specific factor 1 HTATSF1 00001151 soform 2 of Uncharacterized MFS-type transporter C20orf59 00847237 Conserved hypothetical protein 00295.999 soform 2 of Collagen alpha-1 (DC) chain precursor COL9A1 002961.96 Dimethylglycine dehydrogenase, mitochondrial precursor DMGDH 003961.45 FYVE finger-containing phosphoinositide kinase PIPSK3 004:781 10 Probable G-protein coupled receptor 135 GPR135 00.168995 Olfactory receptor 4D9 OR4D9 000591.90 soform 1 of SLAM family member 9 precursor SLAMF9 00043467 Tigger transposable element-derived protein 1 TIGD1 00235842 Zinc finger protein 483 ZNF483 002.20473 soform 2 of Calcium-transporting ATPase type 2C member 1 ATP2C1 00382831 Cerebral protein-13 BAP1 00477692 Uncharacterized protein ENSP00000330808 LOC131 149 00301583 soform 1 of Zinc finger protein 691 ZNF691 00790.447 2 kDa protein 008.29904 Uncharacterized protein ENSP00000374814 00020533 Protein BEX1 BEX1 00376436 soform 4 of Vacuolar protein sorting-associated protein 13B VPS13B 000291 62 soform 2 of Cell division cycle 2-like protein kinase 5 CDC2L5 00065500 BRO1 domain-containing protein BROX C1 Orfs 8 007.403.36 ormin 1 FMN1 00017203 Protein RMI1 homolog RMI1 0029.3431 WUGSC:H DJ0855D21.2 protein MGC708.63 002954.00 Tryptophanyl-tRNA synthetase, cytoplasmic WARS 00444330 CDNA FLJ45693 fis, clone FEBRA2012625 00.170509 soform 3 of Calcium/calmodulin-dependent protein kinase kinase 2 CAMKK2 00017533 Cytochrome c oxidase subunit 3 MT-CO3 00419922 soform 1 of IQ domain-containing protein E IQCE 00005710 Heparan sulfate glucosamine 3-O-sulfotransferase 2 HS3ST2 00744872 soform 1 of Uncharacterized protein KIAA0423 KIAA0423 US 2013/0237454 A1 Sep. 12, 2013 62

TABLE 7L-continued Table 7L. Qualitative List of CSF Proteins Identified (Present) in Patients with Neurologic Lyme disease and not found in True Normals or Chronic Fatigue. All with with immunoaffinity depletion, 692 proteins in list.

CleanTPI Protein Gene

00787412 similar to Protein C11orf2 LOC441 616 00.168607 tetratricopeptide repeat domain 21A isoform 1 TTC21 A 004.193.85 olfactory receptor, family 52, subfamily E, member 8 OR52E8 00006236 Platelet-derived growth factor receptor-like protein precursor PDGFRL 0029.1796 BTB (POZ) domain containing 12 BTBD12 00400795 54 kDa protein 00031554 ATP-dependent RNA helicase DDX50 DDX50 00023860 Nucleosome assembly protein 1-like 1 NAP1L1 00375225 Olfactory receptor 2AE1 OR2AE1 00235622 soform 3 of CUB domain-containing protein 1 precursor CDCP1 00742031 similar to golgi autoantigen, golgin subfamily a, 8G LOC645137 002.21372 soform 2 of 1-acyl-sn-glycerol-3-phosphate acyltransferase beta AGPAT2 00796972 62 kDa protein ETV5 00010807 Frizzled-8 precursor FZD8 00031410 FKBP12-rapamycin complex-associated protein FRAP1 00019848 soform 1 of Host cell factor HCFC1 0030661 1 TRAF-interacting protein TRAIP 00.153031 soform 1 of Uncharacterized protein C17orf&O C17orf&O 00289097 soform 1 of Ras-GEF domain-containing family member 1B RASGEF1B 004:25.404 soform 1 of Kinesin-like protein KIF21A ÇIF21A 00477,262 Uncharacterized protein TRIM41 (Fragment) TRIM41 00030703 Motor neuron and pancreas homeobox protein 1 MNX1 00025974 Charged multivesicular body protein 4b CHMP4B 00413655 ankyrin repeat domain 55 isoform 1 ANKRD55 00026497 soform 1 of Poly [ADP-ribose] polymerase 2 PARP2 00061206 Polyadenylate-binding protein 5 PABPC5 00289758 Calpain-2 catalytic subunit precursor CAPN2 00465177 Transforming growth factor-alpha variant I TGFA 00.180305 soform 5 of E3 ubiquitin-protein ligase UBR4 |UBR4 00019244 soform 1 of RNA-binding protein Nova-1 NOVA1 00009101 Soform 2 of Helicase SRCAP SRCAP 00782992 soform 1 of Serine/arginine repetitive matrix protein 2 SRRM2 00807675 ZNF440 protein ZNF440 00.104050 Thyroid hormone receptor-associated protein 3 THRAP3 0041 1480 hypothetical protein LOC729461 0064.6423 soform 2 of Transcription initiation factor TFIID subunit 4B TAF4B 00446312 CDNA FLJ42271 fis, clone TKIDN2015788 00.1792.98 482 kDa protein HUWE1 0001 6006 soform 1 of Gephyrin GPHN 00395630 Putative uncharacterized protein ppó170 SCRIB 00.100067 soform 1 of Tumor necrosis factor receptor superfamily member 19 TNFRSF19 jite Cui SOjº 00789476 7 kDa protein 00306749 Kanadaptin 00001922 Suppressor of tumorigenicity protein 14 00464980 soform 1 of Paired amphipathic helix protein Sin?b 00744932 Conserved hypothetical protein 00445750 CDNA FLJ43142 fis, clone CTONG3007870 00006077 Protein Jade-3 PHF16 00061 148 Sodium bicarbonate cotransporter NBC4d SLC4A5 00004944 soform 1 of Sodium-driven chloride bicarbonate exchanger SLC4A10 00304587 Protein dispatched homolog 2 DISP2 00219703 Parvalbumin alpha PVALB 0065 6052 SPANX-C SPANXB2; SPANXB1; SPANXF1 00413266 soform 1 of IQ and AAA domain-containing protein IQCA 00472.374 zinc finger protein 98

TABLE 81 Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins IPI Protein Gene IPIO0216704 Isoform 2 of Spectrin beta chain, erythrocyte SPTB IPIO0022361 Band 3 anion transport protein SLC4A1 US 2013/0237454 A1 Sep. 12, 2013 63

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene

PIO0003921. Isoform 1 of Protein 4.1 EPB41 PIO001.4592 Chondroadherin precursor CHAD PIO0028614 erythrocyte membrane protein band 4.2 isoform 2 EPB42 PIO0246058 PDCD6IP protein PDCD6IP PIO0027462 Protein S100-A9 S100A9 PIO0019502 Myosin-9 MYH9 PIO0005981 Transgelin-3 TAGLN3 PIO0024094 Rhesus blood group-associated glycoprotein RHAG PIO0251507 Isoform IB of Synapsin-1 SYN1 PIO0218345 Isoform 2 of Tubulin alpha-3C/D chain TUBA3C: TUBA3D: LOC654264 PIO0023576 Leucine-rich repeat transmembrane neuronal protein 2 precursor LRRTM2 PIO0871227 Isoform 1 of Hemicentin-1 precursor HMCN1 PIO0005652 Isoform 1 of WSC domain-containing protein 2 WSCD2 PIO0217466 Histone H1.3 HIST1H1D PIO0031789 Isoform 1 of Interleukin-1 receptor accessory protein precursor L1RAP PIO0007102 Uncharacterized protein C17orf25 GLOD4 PIO0257508 Dihydropyrimidinase-related protein 2 DPYSL2 PIOO168520 Isoform 2 of Matrilin-2 precursor MATN2 PIOO410585 Isoform 1 of Crumbs homolog 2 precursor CRB2 PIO0217465 Histone H1.2 HIST1H1 C PIO0217467 Histone H1.4 HIST1H1E PIO0007709 Isoform 1 of ADAM 28 precursor ADAM28 PIO0219930 Cellular retinoic acid-binding protein 1 CRABP1 PIO0302944 Isoform 4 of Collagen alpha-1(XII) chain precursor COL12A1 PIO0017567 Isoform Long of Endoglin precursor ENG PIO0005809 Serum deprivation-response protein SDPR. PIO0022774 Transitional endoplasmic reticulum ATPase VCP PIO0028082 Reversion-inducing cysteine-rich protein with Kazal motifs precursor RECK PIO0219910 22 kDa protein - PIO0012510 EMILIN-2 precursor EMILIN2 PIO0029928 Elastin ELN PIOO472754 Polycystic kidney disease 1-related protein ÇIAA03.19.L. PIOO441344 Beta-galactosidase precursor GLB1 PIO0396378 Isoform B1 of Heterogeneous nuclear ribonucleoproteins A2/B1 HNRNPA2B1 PIOO411656 Isoform 1 of Protein piccolo PCLO PIO0021347 Ubiquitin-conjugating enzyme E2 L3 UBE2I.3 PIO0007047 Protein S100-A8 S100A8 PIO0024689 Aquaporin-1 AQP1 PIO0025812 Carbonic anhydrase-related protein 11 precursor CA11 PIO0646689 Thioredoxin domain-containing protein 17 TXNDC17 PIO0.220281 Guanine nucleotide-binding protein G(o) subunit alpha 1 G.NAO1 PIO0024067 Isoform 1 of Clathrin heavy chain 1 CLTC PIO0217005 Ankyrin repeat domain-containing protein 18A ANKRD18A PIO0294.713 Isoform 1 of Mannan-binding lectin serine protease 2 precursor MASP2 PIO0004488 Vacuolar proton pump subunit F ATP6V1 F PIO0007812 Vacuolar ATP synthase subunit B, brain isoform ATP6V1B2 PIO0219806 Protein S100-A7 S100A7 PIO0011865 Isoform 2 of Platelet-derived growth factor D precursor PDGFD PIO0009439 Synaptotagmin-1 SYT1 PIO0219682 Erythrocyte band 7 integral membrane protein STOM PIO000.4047 Isoform 1 of Exostosin-2 EXT2 PIO0384016 Full-length cDNA 5-PRIME end of clone CSODJ009YL13 of T cells DLST (Jurkat cell line) of Homo sapiens (Fragment) PIO0152524. Isoform 3 of Neuropilin and tolloid-like protein 1 precursor NETO1 PIO0552943 V1-11 protein GLV1–36 PIO0031718 Isoform 1 of Ectonucleoside triphosphate diphosphohydrolase 4 ENTPD4 PIO0300623 Pro-MCH precursor PMCH PIO0008756 Isoform 1 of Bullous pemphigoid antigen 1, isoforms 1/2/3/4/5/8 DST (Fragment) PIO0002511 Cyclic AMP-dependent transcription factor ATF-6 alpha ATF 6 PIO0216699 Isoform 2 of Unc-112-related protein 2 FERMT3 PIO0023942 Isoform 2 of Syndecan-3 SDC3 PIO00093.96 Isoform 1 of Cannabinoid receptor 1 CNR1 PIOO426727 Isoform 1 of Methyl-CpG-binding domain protein 4 MBD4 PIO0018879 Alpha-L-iduronidase precursor DUA PIO0788258 similar to lysyl oxidase-like 1 preproprotein LOXL1 PIO0019904 Isoform 1 of Beta-adducin ADD2 PIO0020407 Alpha-1,6-mannosylglycoprotein 6-beta-N- MGAT5 acetylglucosaminyltransferase A PIO0295767 Noelin-2 precursor OLFM2 PIO0216694 plastin 3 PLS3 PIO0306844 Corticotropin-releasing factor-binding protein precursor CRHBP

US 2013/0237454 A1 Sep. 12, 2013 65

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0013978 Speckle-type POZ protein SPOP PIO0335946 Family with sequence similarity 120B FAM120B PIO0033600 Isoform 1 of Protein phosphatase 1 regulatory subunit 7 PPP1RT PIO0216774 Cerebellin-2 CBLN2 PIO0152769 Isoform 1 of Trpc4-associated protein TRPC4AP PIO0647217 Superkiller viralicidic activity 2-like 2 SKIV2L2 PIOOO27438 Flotillin-1 FLOT1 PIO0013933 Isoform DPI of Desmoplakin DSP PIO0003406 Isoform 1 of Drebrin DBN1 PIO0744811 Low-density lipoprotein receptor-related protein 5 precursor LRP5 PIOO465178 Isoform 1 of Vacuolar proton translocating ATPase 116 kDa subunit a ATP6V0A1 isoform 1 PIO0018275 Prion-like protein doppel precursor PRND PIO0046057 Isoform 2 of Syntaxin-binding protein 1 STXBP1 PIO0008580 Antileukoproteinase precursor SLPI PIO0003348 Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2 GNB2 PIO0008998 Protein tyrosine phosphatase-like protein PTPLAD1 PTPLAD1 PIO0847759 DENN domain-containing protein 4B DENND4B PIO02949.10 Protein PARM-1 precursor DKFZP564O0823 PIO00084.33 40S ribosomal protein S5 RPS5 PIO0827745 Isoform 1 of RNA-binding protein 24 RBM24 PIO000.9532 4-aminobutyrate aminotransferase, mitochondrial precursor ABAT PIO0030876 diaphanous 1 isoform 2 DLAPH1 PIO014.5805 Isoform 1 of TRAF2 and NCK-interacting protein kinase TNIK PIO0296374 Zinc finger protein-like 1 ZFPL1 PIO0373823 Cytochrome P450 26C1 CYP26C1 PIO0815893 Isoform 1 of Chromodomain-helicase-DNA-binding protein 2 CHD2 PIO0021907 Isoform 1 of Myelin basic protein MBP PI00027626 T-complex protein 1 subunit zeta CCT6A PIO0398992 Isoform 1 of Chromodomain-helicase-DNA-binding protein 8 CHD8 PIO0215746 Fatty acid-binding protein, adipocyte FABP4 PIO0215914 ADP-ribosylation factor 1 ARF1 PIO0399.180 Serine/threonine-protein kinase SBK1 SBK1 PIO0027547 Dermcidin precursor DCD PIOO4453.15 Protein FAM47C FAM47C PIO0746666 hypothetical protein LOC728262 PIO0290854 A-kinase anchor protein 3 AKAP3 PIO0604551 Isoform 1 of Cell division cycle-associated protein 7 CDCAT PIO0787083 similar to peptidylprolyl isomerase A isoform 1 LOC256374 PIO0001712 Isoform 1 of Catenin alpha-3 CTNNA3 PIO0217831 Ankyrin repeat domain-containing protein 13A ANKRD13A PIO0024920 ATP synthase subunit delta, mitochondrial precursor ATP5D PIO0028520 Isoform 1 of NADH dehydrogenase [ubiquinone] flavoprotein 1, NDUFV1 mitochondrial precursor PIO00067.46 Ermin ERMN PIO0003392 Transmembrane protein 5 TMEMS PIO0186966 Isoform IIA of Myc box-dependent-interacting protein 1 BIN1 PIO0165009 Isoform 3 of MBT domain-containing protein 1 MBTD1 PIO0641181 MARCKS-related protein MARCKSL1 PIO0018342 Adenylate kinase isoenzyme 1 AK1 PIO0394712 Granulocyte inhibitory protein - PIO0141938 H2A histone family, member V isoform 2 H2AFV PIO0028786 Isoform 3 of Polycystin-1 precursor PKD1 PIO0299778 Serum paraoxonase/lactonase 3 PON3 PIOO456683 Isoform 3 of Transcription elongation factor SPT6 SUPT6H PIO001.2391 Isoform Long of Adenomatous polyposis coli protein APC PIO0185088 immunoglobulin superfamily, member 11 isoform b IGSF11 PIO0152182 Isoform 1 of Kelch domain-containing protein 4 KLHDC4 PIO003.3030 Protein ADRM1 ADRM1 PIO0185661 Ubiquitin carboxyl-terminal hydrolase 32 USP32 PIO0218292 Isoform Short of Ubiquitin fusion degradation protein 1 homolog |UFD1 L, PIO0000104 Isoform 1 of mRNA-capping enzyme RNGTT PIO0514893 Disheveled-associated activator of morphogenesis 2 DAAM2 PIO0025363 Isoform 1 of Glial fibrillary acidic protein GFAP PIO0743898 Uncharacterized protein ENSP00000357890 (Fragment) - PIO0023359 Isoform 1 of Malonyl CoA-acyl carrier protein transacylase, MCAT mitochondrial precursor PIO0021274 Ephrin type-A receptor 8 precursor EPHA8 PIOO410013 Isoform 1 of Zinc finger CCCH domain-containing protein 3 ZC3H3 PIOO454910 Serine/threonine-protein kinase MRCK gamma CDC42BPG PIO0302133 Transient receptor potential cation channel subfamily V member 5 TRPV5 PIO0010207 Ubiquitin-fold modifier 1 precursor |UFM1

US 2013/0237454 A1 Sep. 12, 2013 67

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene

PIO0744825 Conserved hypothetical protein - PIO0005675 NF-kappa-B-repressing factor NKRF PIO0218628 Isoform 2 of Integrin alpha-IIb precursor ITGA2B PIO0217989 Isoform 1 of Protein-associating with the carboxyl-terminal domain of SCYL3 €Zijil PIO0217405 Isoform 1 of E3 ubiquitin-protein ligase UBR1 |UBR1 PIO0217258 CCDC100 protein CCDC100 PIOO456670 Isoform 13 of Peroxisomal N(1)-acetyl-spermine?spermidine oxidase PAOX PIO0186621 Orofacial clefting chromosomal breakpoint region 1 OFCC1 PIO0295098 Signal recognition particle receptor subunit beta SRPRB PIO0071824 Isoform 1 of Cytoskeleton-associated protein 2 CKAP2 PIO0747494 Glutamate receptor delta-2 subunit precursor GRID2 PIO0879409 28 kDa protein - PIOO169259 Small VCP/p07-interacting protein SVIP PIO0106506 Isoform 1 of Evolutionarily conserved signaling intermediate in Toll ECSIT pathway, mitochondrial precursor PIO0006900 Something about silencing protein 10 UTP3 PIOO472332 similar to polyhomeotic 1-like isoform 4 LOC653441 PIO0789245 Isoform 2 of Probable organic cation transporter protein C60rf&5 SLC22A23 PIO0291922 Proteasome subunit alpha type-5 PSMA5 PIO0152145 Protein odd-skipped-related 1 OSR1 PIO0021770 Isoform 1 of 3-hydroxy-3-methylglutaryl-coenzyme A reductase HMGCR PIOO465045 DIP2 disco-interacting protein 2 homolog B DIP2B PIO0018803 homeobox D12 HOXD12 PIO0021594 Isoform 1 of Glycosylphosphatidylinositol anchor attachment 1 GPAA1 protein PIO0010360 Isoform 1 of Collagen alpha-3(IV) chain precursor COL4A3 PIOO465044 Protein RCC2 RCC2 PI00013847 Cytochrome b-c1 complex subunit 1, mitochondrial precursor UQCRC1 PIO0026665 Glutaminyl-tRNA synthetase QARS PIO0180386 Isoform GN-1L of Glycogenin-1 GYG1 PIO0167638 Isoform 1 of GTP-binding protein 10 GTPBP10 PIO0384861 Isoform 1 of ARF GTPase-activating protein GIT1 GIT1 PIO02962.19 Glutaminase liver isoform, mitochondrial precursor GLS2 PIO0376087 putative binding protein 7as 7A5 PIO0794679 Major histocompatibility complex, class I, B MICA; HLA-B; HLA A; LOC730410; HLA-C, HLA A29.1 PIO0008282 Isoform 1 of Calcium/calmodulin-dependent 3',5'-cyclic nucleotide PDE1A phosphodiesterase 1A PIO0007277 Isoform 1 of Leucine-rich repeat flightless-interacting protein 2 LRRFIP2 PIO0294519 Isoform 1 of Telomerase protein component 1 TEP1 PIO0179589 Myotrophin MTPN PIO0031485 Mitochondrial ribosomal protein 63 MRP63 PIOO429191 Eukaryotic peptide chain release factor subunit 1 ETF1 PIO0514594 Isoform 1 of Protein FAM5B precursor FAMSB PIO0853376 additional sex combs like 3 ASXL3 PIO0216914 Vitelline membrane outer layer protein 1 homolog precursor VMO1 PIO0166010 Isoform 1 of CCR4-NOT transcription complex subunit 1 CNOT1 PIO0399252 Isoform 1 of Protein Jade-1 PHF17 PIO0144243 Human immunodeficiency virus type I enhancer-binding protein 2 HIVEP2 PIO0291463 Radical S-adenosyl methionine domain-containing protein 2 RSAD2 PIO0007040 Zinc finger protein 222 ZNF222 PIO0220578 Guanine nucleotide-binding protein G GNAI3 PIO0740191 similar to Forkhead box protein L1 LOC651986 PIO0044607 Protein phosphatase inhibitor 2-like protein 1 PPP1R2P1 PIO0301923 Isoform 1 of Cell division protein kinase 9 CDK9 PIO0255145 hypothetical protein LOC342346 PIO0010737 Thrombomodulin precursor THED PIO0030319 Forkhead box protein F2 FOXF2 PIO0168806 Isoform 1 of Myeloid/lymphoid or mixed-lineage leukemia protein 3 MLL3 homolog PIO0015285 Ethanolamine-phosphate cytidylyltransferase PCYT2 PIO0302850 Small nuclear ribonucleoprotein Sm D1 SNRPD1 PIOO478.124 61 kDa protein UCKL1 PIO0013681 N-terminally extended type 3 canonical transient receptor potential TRPC3 channel PIO0019208 Similar to 60S ribosomal protein L29 - PIO0012895 Isoform 1 of Carbonic anhydrase 12 precursor CA12 PIO0023513 Isoform 1 of E3 ubiquitin-protein ligase CHFR CHFR PIO0025019 Proteasome subunit beta type-1 precursor PSMB1 PIOO166817 Zinc finger protein 561 ZNF561 US 2013/0237454 A1 Sep. 12, 2013 68

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0375174 Ankyrin repeat and sterile alpha motif domain-containing protein 1B ANKS1B PIO0296866 interphotoreceptor matrix proteoglycan 2 IMPG2 PIO0040730 protocadherin 21 precursor PCDH21 PIO0013508 Alpha-actinin-1 ACTN1 PIO0644231 Isoform 1 of Cytoplasmic FMR1-interacting protein 1 CYFIPI PIO0013466 Arsenical pump-driving ATPase ASNA1 PIO0016605 Uncharacterized protein C10rf123 C1 orf123 PIO0872861 PTDO16 protein LOC51136 PIOO166619 Isoform 2 of Putative transporter SVOPL SVOPL PIO0796647 HIG1 domain family, member 1C HIGD1 C PIO0852758 Similar to Ankyrin repeat domain-containing protein 26. Isoform 2 ANKRD18B PIO0023087 Ubiquitin-conjugating enzyme E2 T UBE2T PIO0161119 Isoform 1 of NF-kappa-B inhibitor beta NFKBIB PIO0016577 CDNA: FLJ22814 fis, clone KAIA3004 CD22 PIO0852633 16 kDa protein RABL2B PIOO163391 Isoform 1 of Putative methyltransferase METT10D METT10D PIO0299679 Isoform B of Ral guanine nucleotide dissociation stimulator-like 1 RGL1 PIO0797699 20 kDa protein - PIOO794119 13 kDa protein ABCC8 PIO0816274 Chemokine-like factor superfamily 1 transcript variant 26 CMTM1 PIO0171737 Isoform 2 of Leucine-rich repeat and death domain-containing protein LRDD PIO0385003 Putative transposase TIGD1 PIO0029123 Isoform A of Endothelin B receptor precursor EDNRB PIO0158992 snRNA-activating protein complex subunit 4 SNAPC4 PIO0184997 cDNA FLJ78771, highly similar to Homo sapiens discs, large DLG7 homolog 7 (Drosophila), mRNA PIO0001869 Pappalysin-1 precursor PAPPA PIO0027834 heterogeneous nuclear ribonucleoprotein L isoform a HNRNPL PIO0062730 Uncharacterized protein C16orf.45 C16orf245 PIO0298258 UNC13B protein UNC13D PIO0744366 Conserved hypothetical protein - PIO0000792 Quinone oxidoreductase CRYZ PIO0008905 UDP-glucuronosyltransferase 2B15 precursor UGT2B15 PIO0186581 amplified in osteosarcoma isoform 2 precursor OS9 PIOO445364 CDNA FLJ44171 fis, clone THYMU2036058 - PIO0166071 B-cell CLL/lymphoma 6 member B protein BCL6B PIO0218130 Glycogen phosphorylase, muscle form PYGM PIO0034006 Tyrosine-protein phosphatase non-receptor type 23 PTPN23 PIOO419253 Isoform 1 of Nck-associated protein 5 NAP5 PIO0292393 Sodium channel protein type 4 subunit alpha SCN4A PIO0029012 Eukaryotic translation initiation factor 3 subunit A EIF3A. PIO0385042 Nucleolar GTP-binding protein 1 GTPBP4 PIO0.402144 Isoform 1 of Zinc finger protein 555 ZNF555 PIOO478986 Similar to 40S ribosomal protein S4 LOC126235 PIOO478521 lsoform 1 of UPF0475 protein RILPL1 PIO0025700 Isoform CD6A of T-cell differentiation antigen CD6 precursor CD6 PIO0061507 Isoform 3 of Ester hydrolase C11orf54 C11orfs 4 PIO0016949 Isoform 4 of Electrogenic sodium bicarbonate cotransporter 1 SLC4A4 PIO0031547. Desmoglein-3 precursor DSG3 PIO0382756 Isoform 2 of Pleiotropic regulator 1 PLRG1 PIO0743284 Methionine synthase MTR PIO0021363 Histone demethylase JARID1A ARID1A PIO0216683 M-phase inducer phosphatase 3 CDC25C PIO0737969 microtubule associated monoxygenase, calponin and LIM domain MICAL3 containing 3 PIO0015522 Growth/differentiation factor 5 precursor GDF5 PIO0877084 Isoform 1 of Coiled-coil domain-containing protein 144C CCDC144C PIO0060265 Zinc finger protein 775 ZNF175 PIO0024802 TATA-binding protein-associated factor 172 BTAF1 PIO0374039 Conserved hypothetical protein C1 orf189 PIOO44.2121 delta-aminolevulinic acid dehydratase isoform a ALAD PIO0013455 CLIP1 protein CLIP1 PIO0026299 Isoform Glycophorin C of Glycophorin-C GYPC PIO0845508 BAH domain and coiled-coil containing 1 BAHCC1 PIO0745300 31 kDa protein NAT11 PIOO186826 Ephrin receptor EPHB4 PIO0787932 similar to zinc finger protein 10 hCG 1646157 PIOO1661 61 Protein SIX6C)S1 C14Orf}9 PIO0180426 Isoform 3 of G protein-coupled receptor kinase 4 GRK4 PIO001.3219 Integrin-linked protein kinase ILK PIO0796906 8 kDa protein ABCF3 PIO0028932 Microtubule-associated serine/threonine-protein kinase 3 MAST3

US 2013/0237454 A1 Sep. 12, 2013 70

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0027685 C-C chemokine receptor type 1 CCR1 PIO0009335 Brain protein 16 C8orf$0A PIOO432755 PPRR6495 FAM124A PIO0796777 17 kDa protein CRYAA PIO0008894 Carboxypeptidase A4 precursor CPA4 PIO0031005 Protein kinase-like protein Sgkl96 FLJ23356 PIO0787414 Uncharacterized protein ENSP00000381388 MGC34829 PIO0019988 N-sulphoglucosamine sulphohydrolase precursor SGSH PIO0873740 Uncharacterized protein ENSP00000383832 (Fragment) - PIO0032416 Isoform Long of Protein jagged-2 precursor JAG2 PIO0335589 RNA methyltransferase-like protein 1 RNMTL1 PIO0843819. Similar to Dual specificity protein kinase CLK2 - PIO0065276 Isoform 2 of Tether containing UBX domain for GLUT4 ASPSCR1 PIO0644522 PNKP protein PNKP PIO0045511 Isoform 1 of Chloride channel CLIC-like protein 1 precursor CLCC1 PIO0604763 Transmembrane protein 66 precursor TMEM66 PIO0235647 similar to fibrillarin LOC345 630 PIOO470805 Isoform 2 of Mediator of DNA damage checkpoint protein 1 MDC1 PIO0167089 Isoform 2 of Activated CDC42 kinase 1 TNK2 PIO0783753 UPF0235 protein C15orf10 C150rf240 PIO0030919 Mitogen-activated protein kinase kinase 1-interacting protein 1 MAP2K1 IP1 PIO0394879 Leucine-rich repeat-containing protein 9 LRRC9 PIOO401852 Conserved hypothetical protein DKFZP434L187 PIOO442865 CDNA FLJ26488 fis, clone KDNO5770, highly similar to Bumetamide- SLC12A1 sensitive sodium-(potassium)-chloride cotransporter 2 PIO0748891 hypothetical protein LOC283635 isoform 1 C14orf24 PIOO414320 Annexin A11 ANXA11 PIO08740.23 Uncharacterized protein ENSP00000379699 - PI00827584 similar to kinesin family member 27 KIF27 PIO0020199 Alpha-2,8-sialyltransferase 8B ST8SIA2 PIOO791513 CDNA FLJ16614 fis, clone TESTIA013365 CTA-216E10.6 PIO0002884 CDNA: FLJ22222 fis, clone HRCO1658 FLJ22222 PIO0003363 Isoform 1 of Protein phosphatase 1 regulatory subunit 1B PPP1R1B PIO0005705 Isoform Gamma-1 of Serine/threonine-protein phosphatase PP1- PPP1CC gamma catalytic subunit PIO0164949 Isoform NELF-C of Negative elongation factor C/D TH1 L PIO0029647 Zymogen granule membrane protein 16 precursor ZG 16 PIOO414481 GTF3C1 protein GTF3C1 PIOO154528 Isoform 1 of Structural maintenance of chromosomes protein 6 SMC6 PIO0164861 Isoform 3 of Kinesin-like protein KIF13A ÇIF13A PIOO411674 Isoform 1 of Zinc finger protein 254 ZNF254 PIO0249982 Isoform 1 of Death-inducer obliterator 1 DIDO1 PIO0328270 Neuronal PAS domain-containing protein 2 NPAS2 PIOO442544 CDNA FLJ27034 fis, clone SLV07984 - PIO0175019 similar to Temporarily Assigned Gene name family member LOC643677 PIO0027898 Isoform A of Uncharacterized protein C21orf70 C21 Orf70 PIO0023340 Histone acetyltransferase MYST3 MYST3 PIO0300052 Keratin type II cuticular Hb4 ÇRT84 PIO0019158 ADAM metallopeptidase domain 8 precursor ADAM8 PIO0045928 Sodium/hydrogen exchanger 7 SLC9A7 PIO0306332 60S ribosomal protein L24 RPL24 PIO0023184 Isoform 1 of Poly [ADP-ribose] polymerase 3 PARP3 PIO0872739 Uncharacterized protein C18Orf2 C18Orf2 PIO0241409 hypothetical protein LOC55747 FAM21B PIO0090764 Toll-like receptor 1 precursor TLR1 PIO0024253 Isoform 1 of Fibroblast growth factor 14 FGF14 PIO0218637 Major histocompatibility complex, class II, DQ beta 2 HLA-DQB2 PIO0216921 Isoform 2 of Stathmin-4 STMN4 PIO0011416 Delta(3,5)-Delta(2,4)-dienoyl-CoA isomerase, mitochondrial ECH1 jite Cui SOjº PIO0260755 similar to Rho GTPase activating protein 18 C20orfø5 PIO0337385 Isoform 1 of Pre-mRNA-processing factor 40 homolog A PRPF40A PIO0304527 Protein FAM83H FAM83H PIO0030741 Uncharacterized protein C21orf13 LCASL PIO0399.296 hypothetical protein LOC3901.10 LOC3901.10 PIO0233358 islet cell autoantigen 1, 69 kDa-like isoform 2 CA1 L. PIO0879842 6 kDa protein - PIO0021476 Eukaryotic translation initiation factor 4E-binding protein 3 EIF4FBP3 PIO0028383 Uncharacterized protein C16orf24 C16orf24 PIOO298.337 cDNA FLJ17671 SLC14A1 PIO0044842 Isoform 2 of RAB3A-interacting protein RAB3IP PIO001.3004 Isoform 1 of Pyridoxal kinase PDXK US 2013/0237454 A1 Sep. 12, 2013 71

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene

PIOO328260 Protein FAN NSMAF PIO0807418 Isoform 9 of Lymphoid-specific helicase HELLS PIO0183002 Isoform 1 of Protein phosphatase 1 regulatory subunit 12A PPP1R12A PIOO163601 Putative uncharacterized protein FLJ10213 FLJ102.13 PIOO4287.41 LP2477 FLJ35348 PIO0006252 Multisynthetase complex auxiliary component p43 SCYE1 PIO0007321 Isoform 1 of Acyl-protein thioesterase 1 LYPLA1 PIO0217617 palmitoylated membrane protein 7 MPP7 PIO0024662 Chromobox protein homolog 5 CBX5 PIO0550364 Phosphoglucomutase-2 PGM2 PIO0169331 Phosphatidylcholine:ceramide cholinephosphotransferase 2 SGMS2 PIO0028450 Isoform 1 of Sodium/calcium exchanger 1 precursor SLC8A1 PIO0010405 Isoform Long of Tyrosine-protein kinase transmembrane receptor ROR1 ROR1 precursor PIO0873774 Uncharacterized protein ENSP00000383488 (Fragment) - PIO0847335 FLJ45422 protein - PIO0217740 C20orf12 protein C20orf12 PIO0008497 Ornithine decarboxylase ODC1 PIO0010808 Interferon-gamma receptor alpha chain precursor IFNGR1 PIO0872550 Uncharacterized protein PRDM2 PRDM2 PIO0514622 Ran-binding protein 6 RANBP6 PIO0009203 Sorting nexin-7 SNX7 PIO0790021 Zinc finger protein 652 ZNF652 PIO0855918 mucin 5, subtype B, tracheobronchial MUCSB PIO0008.404 Isoform Long of Segment polarity protein dishevelled homolog DVL- DVL1L1 -like PIO0658025 Putative novel transcript - PIO0022958 PROO 149 C16orf72 PIO0032313 Protein S100-A4 S100A4 PIO0027009 Isoform 1 of Protein kinase C and casein kinase substrate in neurons PACSIN2 protein 2 PIO0023162 UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase GNE PIO0789181 115 kDa protein PLCL1 PIO0005132 Guanine nucleotide-binding protein-like 3-like protein GNL3L PIO0742725 Conserved hypothetical protein LOC3.88564 PIO0878755 43 kDa protein - PIO0152050 ataxin 2-binding protein 1 isoform 3 A2BP1 PIO0385480 Caskin-1 CASKIN1 PIOO465123 KIAA0415 gene product KIAA04.15 PIO001.2441 Isoform 1 of Synaptojanin-1 SYNJ1 PIO0006054 Syntaphilin SNPH PIO0385918 CDNA FLJ90582 fis, clone PLACE1000442, moderately similar to ZNF627 ZINC FINGER PROTEIN ZFP-36 PIO0008438 40S ribosomal protein S10 RPS10 PIO0152849 Isoform 1 of G2/mitotic-specific cyclin-B3 CCNB3 PIO0029556 Uncharacterized protein C10rf105 C1 Orf105 PIO0217012 pleckstrin and Sec7 domain containing PSD PIO0015980 Isoform 2 of Multiple PDZ domain protein MPDZ PIO0102678 Isoform 1 of Pecanex-like protein 1 PCNX PIO0020356 331 kDa protein MAP1A PIO0008226 73 kDa protein THSD3 PIO0010903 Dopey family member 1 DOPEY1 PIO0735934 similar to capicua homolog LOC646070 PIOO465234 Cytokine receptor common beta chain precursor CSF2RB PIO0010303 Serpin B4 SERPINB4 PIO0008091 Putative DNA helicase INO80 complex homolog 1 [NOC1 PIO0016112 peroxidasin homolog PXDN PIO0329791 cDNA FLJ78679, highly similar to Homo sapiens DEAD (Asp-Glu- DDX46 Ala-Asp) box polypeptide 46 (DDX46), mRNA PIOO152344 Pyridoxal phosphate phosphatase PHOSPHO2 PHOSPHO2 PIO0028601 Putative metallothionein C20orf127 MT1P3 PIOO4791.25 SLIT-ROBO Rho GTPase-activating protein 2 SRGAP2 PIOO455852 Isoform 1 of Rho guanine nucleotide exchange factor 15 ARHGEF15 PIO0550876 Protein maestro MRO PIOOO64296 PROO633 - PIO0216651 Isoform 1 of Interleukin-28 receptor alpha chain precursor IL28RA PIOO792945 38 kDa protein CHFR PIO014.9375 Isoform 2 of Uncharacterized protein C11orf56 C11orf S6 PIO0015913 5,6-dihydroxyindole-2-carboxylic acid oxidase precursor TYRP1 PIO0007512 Glutathione transferase omega-2 GSTO2 PIO0016576 Isoform 1 of Grainyhead-like protein 2 homolog GRHL2 PIO0290308 Tribbles homolog 1 TRIB1

US 2013/0237454 A1 Sep. 12, 2013 73

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0032597 RNA-binding motif protein, X-linked 2 RBMX2 PIO0783855 neighbor of BRCA1 gene 1 NBR1 PIO0746987 Ribosomal protein S1 family protein - PIO0295469 Copine-6 CPNE6 PIOO456599 hypothetical protein LOC84792 MGC12966 PIOO607831 PRAME family member 3 PRAMEF3 PIO0399254 Isoform 1 of OTU domain-containing protein 4 OTUD4 PIO0719505 RABL2A protein RABL2A PIO0784880 Cancer/testis antigen 75 LOC440934 PIO0884353 Ets-1 transcript variantets-1 delta - PIO0852725 Isoform 7 of Prolactin receptor precursor PRLR PIO0005600 Isoform 1 of Bifunctional heparan sulfate N-deacetylase/N- NDST2 sulfotransferase 2 PIO0791593 8 kDa protein GLYCAM1 PIO0024346 snRNA-activating protein complex subunit 3 SNAPC3 PIO0293396 adaptor-related protein complex 1, gamma 1 subunit isoform a AP1 G1 PIO0018914 Tyrosine-protein phosphatase non-receptor type 14 PTPN14 PIO0296913 ADP-sugar pyrophosphatase NUDT5 PIO0185.146 Importin-9 IPO9 PIO0217791 Coiled-coil domain-containing protein 105 CCDC105 PIO0167006 Uncharacterized protein C130rf26 C13orf26 PIO00284.81 Ras-related protein Rab-8A RAB8A PIO0294215 Uncharacterized protein KIAA0232 KIAA0232 PIO007.1185 Isoform SV1 of PITSLRE serine/threonine-protein kinase CDC2L1 CDC2L.1 PIOO166776 Protein CREG2 precursor CREG2 PIO0001796 Tumor necrosis factor receptor superfamily, member 18 (Fragment) TNFRSF18 PIO0549972 LIM domain-containing protein 2 LIMD2 PIO0029107 Werner syndrome ATP-dependent helicase WRN PIOO470468 Isoform 3 of Protein EFR3 homologA EFR3A PIO0382515 CDNA FLJ30384 fis, clone BRACE2008114 - PIO085.3312 Uncharacterized protein ENSP00000324580 - PIO0217871 Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial ALDH4A1 jite Cui SOjº PIOO470490 Isoform 1 of Nuclear receptor coactivator 1 NCOA1 PIO0001433 Protocadherin beta 15 precursor PCDHB15 PIO0220156 Isoform B of Transforming growth factor beta-2 precursor TGFB2 PIO0024818 Isoform 1 of Ubiquitin-specific peptidase-like protein 1 |USPL1 PIO0335437 Ankyrin repeat and zinc finger domain-containing protein 1 ANKZF1 PIO0000076 Beta-nerve growth factor precursor NGFB PIO0100980 EH domain-containing protein 2 EHD2 PIO0215610 55 kDa erythrocyte membrane protein MPP1 PIO0015148 Ras-related protein Rap-1b precursor RAP1B PIOO410657 Isoform 2 of mRNA cap guanine-N7 methyltransferase RNMT PIO0552591 V1-20 protein IGLV10–54 PIO0022277 Coiled-coil domain-containing protein 56 CCDC56 PIO0216.288 Isoform 3 of Lethal L3MBTL PIO0025499 Isoform Tau-F of Microtubule-associated protein tau MAPT PIO085.6012 collagen type VI alpha 6 COL6A6 PIO0335.168 Isoform Non-muscle of Myosin light polypeptide 6 MYL6 PIO0030037 Agouti-signaling protein precursor ASIP PIO0013749 Protein kinase Czeta type PRKCZ PIO0002491 Isoform 9 of Sorbin and SH3 domain-containing protein 1 SORBS1 PIO0240793 Probable phospholipid-transporting ATPase IF ATP11 B PIO0376237 Isoform 2 of Transcription factor LBX2 LBX2 PIO0020966 Isoform 1 of Phosphatidylinositol N-acetylglucosaminyltransferase PIGA subunit A PIOO456827 Protein FAM22G precursor FAM22G PIO0747657 Similar to Rod cº?P-specific 3',5'-cyclic phosphodiesterase subunit PDE6B beta precursor PIO0215777 Isoform B of Phosphate carrier protein, mitochondrial precursor SLC25A3 PIO0028912 zinc finger protein 161 VEZF1 PIO0019242. Matrix metalloproteinase-15 precursor MMP15 PIO0024664 Isoform Long of Ubiquitin carboxyl-terminal hydrolase 5 USP5 PIO0786946 similar to Tektin-3 LOC642249 PIOO166257 CDNA FLJ37614 fis, clone BRCOC2011769 - PIOO442745 CDNA FLJ26780 fis, clone PRSO3837 - PIO0017256 Ras suppressor protein 1 RSU1 PIO0374301 hypothetical protein - PIO0023217 Isoform 1 of Ryanodine receptor 2 RYR2 PIO0018843 Isoform 1 of D(3) dopamine receptor DRD3

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TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene

PIOO746459 CDNA FLJ34517 fis, clone HLUNG2006781 - PIOO444234 CDNA FLJ45743 fis, clone KIDNE2016464 FLJ457.43 PIO0002534 Isoform 1 of Purine-rich element-binding protein gamma PURG PIO0556.253 Isoform 1 of Coiled-coil domain-containing protein C60rfl.99 C6Orf199 PIO0017592 Leucine zipper-EF-hand-containing transmembrane protein 1, LETM1 mitochondrial precursor PIO001.6007 Myosin-Vc MYOSC PIO0744927 gastrotropin isoform 1 FABP6 PIO0024319 Forkhead box protein J1 FOXJ1 PIO0339297 Polypeptide N-acetylgalactosaminyltransferase 4 GALNT4 PIO0254408 bromodomain PHD finger transcription factor isoform 1 BPTF PIO0304324 Histone deacetylase 11 HDAC11 PIOO477693 fatty acid binding protein LOC646486 PIO0025310 Zinc finger protein 217 ZNF217 PIOO427808 Isoform 1 of Uncharacterized protein C10orf71 C10orf71 PIO0735313 similar to Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 - PIO0384013 Polypeptide N-acetylgalactosaminyltransferase-like protein 2 GALNTL2 PIO0382495 Ig heavy chain V-III region ZAP - PIOO477820 Isoform 1 of FRAS1-related extracellular matrix protein I precursor FREM1 PIO0024776 Calmegin precursor CLGN PIO0023110 Potassium channel subfamily K member 3 KCNK2 PIO0182833 Coiled-coil alpha-helical rod protein 1 CCHCR1 PIO0394994 Isoform 1 of Nesprin-3 C14orf249 PIOO419992 Isoform 1 of Acyl-CoA synthetase family member 4 AASDH PIO0004445 Gamma-2-syntrophin SNTG2 PIO0878015 12 kDa protein - PIO0328094 Isoform 1 of Forkhead box protein P3 FOXP3 PIO0873348 63 kDa protein A1 CF PIOO640240 59 kDa protein SPTLC3 PIO0002824 Cysteine and glycine-rich protein 2 CSRP2 PIO0398.272 Isoform 1 of Collagen alpha-1(XVII) chain COL17A1 PIO0061009 Isoform 1 of WD repeat-containing protein 67 WDR67 PIO0299301 Isoform 1 of Desmuslin DMN PIO0152011 PTPL1-associated RhoGAP 1 ARHGAP29 PIO0847790 Protein of unknown function DUF1725 domain containing protein - PIO0065121 Isoform 2 of Coiled-coil domain-containing protein 36 CCDC36 PIO0373867 glycolipid transfer protein domain containing 2 GLTPD2 PIO0872354 armadillo repeat containing 2 ARMC2 PIO0152975 Isoform 1 of Coiled-coil domain-containing protein 90A, CCDC90A mitochondrial precursor PIO0374804 Isoform 1 of Diacylglycerol kinase delta DGKD PIO0292894 Pre-rRNA-processing protein TSR1 homolog TSR1 PIO0028232 Putative uncharacterized protein FGF4 PIO00272.69 E3 ubiquitin-protein ligase CBL CBL PIO0797567 9 kDa protein GNAI2 PIO0032958 Isoform 2 of Actin-binding protein anillin ANLN PIO0057815 intestinal facilitative glucose transporter 7 SLC2A7 PIO0014367 Isoform 1 of Non-SMC element 4 homolog A NSMCE4A PIO0884022 Similar to Immunglobulin heavy chain variable region - PIOO465319 Chondroitin sulfate synthase 2 CHPF PIO0549844 Isoform 1 of Protein FAM134B FAMI34B PIOO457114 Isoform 1 of IQ motif and Sec7 domain-containing protein 1 IQSEC1 PIO0002773 Isoform 2 of Tyrosine-protein kinase JAK3 JAK3 PIO0005667 NEDD4-binding protein 1 N4BP1 PIOO300594 CDNA FLJ35435 fis, clone SMINT2002620 SPATA13 PIO0103142 Nudo domain-containing protein 2 NUDCD2 PIO0290785 Isoform 1 of SET domain-containing protein 6 SETD6 PIO0297763 Retinal-specific ATP-binding cassette transporter ABCA4 PIO0000861 Isoform 1 of LIM and SH3 domain protein 1 LASP1 PIOO168255 hypothetical protein LOC400451 LOC4004:51 PIO0015990 Isoform 1 of Eyes absent homolog 3 EYA3 PIO0171500 Uncharacterized protein C14orf.45 C14orf245 PIO0170765 Isoform 3 of Alanine--glyoxylate aminotransferase 2-like 2 AGXT2L2 PIO0099977 platelet-derived growth factor C precursor PDGFC PIO0292953 Isoform 2 of Ankycorbin RAI14 PIOO159072 57 kDa protein ROD1 PIOO305692 Thioredoxin-like protein 1 TXNL1 PIO003.1630 Melanocyte protein Pmel 17 precursor SILV PIOO167446 Isoform 2 of Uncharacterized protein C17orf78 C17orf78 PIOO479625 Isoform 1 of ELAV-like protein 4 ELAVL4 PIO0745395 Conserved hypothetical protein KIAA0508 PIO0043069 Ankyrin repeat domain-containing protein 30A ANKRD30A US 2013/0237454 A1 Sep. 12, 2013 77

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0014316 Cyclin-dependent kinase 5 activator 1 precursor CDK5R1 PIO0301726 Isoform 1 of Uncharacterized protein C3orf20 C3orf20 PIOO185361 ATP-dependent RNA helicase DDX55 DDX55 PIO0293867 D-dopachrome decarboxylase DDT PIOO794779 DNA polymerase theta POLQ PIOO478354 Putative uncharacterized protein CXorf31 CXOrf} 1 PIO0166414 Coiled-coil domain-containing protein 96 CCDC96 PIO0300053 Keratin type II cuticular Hb2 KRT82 PIO0749062 Conserved hypothetical protein - PIOO452161 Isoform 1 of Mucolipin-1 MCOLN1 PIOO384546 CDNA FLJ25883 fis, clone CBR02735 - PIOO412272 SH3 domain-binding glutamic acid-rich-like protein 2 SH3BGRL2 PIO0006298 Isoform 1 of Peptidyl-prolyl cis-trans isomerase G PPIG PIO0031497 Conserved hypothetical protein C7orf.49 PIO0022061 Sodium/hydrogen exchanger 6 SLC9A6 PIO0217418 Isoform 2 of Rho GTPase-activating protein 12 ARHGAP12 PIO0743545 Conserved hypothetical protein - PIO0328156 Amine oxidase [flavin-containing] B MAOB PIOO644785 Protein PLXNB3 PIOO654693 Protein FAM44C FAM44C PIO0880011 116 kDa protein - PIO0018583 Isoform 1 of Intracellular hyaluronan-binding protein 4 HABP4 PIO0030986 Isoform Long of Kelch repeat and BTB domain-containing protein 10 KBTBD10 PIO0045503 Isoform 2 of Protein phosphatase 1 regulatory subunit 14A PPP1R14A PIO0793408 6 kDa protein ADAMTS9 PIO0024255 G patch domain and KOW motifs-containing protein GPKOW PIO0028262 67 kDa protein ÇIAA 1754 PIO0027212 Insulin receptor-related protein precursor [NSRR PI00009724 Isoform 1 of EF-hand calcium-binding domain-containing protein 6 EFCAB6 PIO0868835 Similar to Heterogeneous nuclear ribonucleoproteins C1/C2 (hnRNP - C1/hnRNP C2). Isoform 4 PIO0396658 Isoform 2 of Protein ITFG3 TFG3 PIO0742127 Similar to Heterogeneous nuclear ribonucleoprotein A1 (Helix- - destabilizing protein) (Single-strand RNA-binding protein) (hnRNP core protein A1). Isoform A1-A PIO0398586 hypothetical protein LOC1998.00 LOC1998.00 PIOO418164 Novel protein RP4-692D3.1: LOC731440 PIO0033019 Potassium voltage-gated channel subfamily B member 1 KCNB1 PIO0032598 Isoform 1 of ETS translocation variant 3 ETV3 PIO0217494 Isoform 1 of Protein SMG7 SMG7 PIO0000837 Metabotropic glutamate receptor 3 precursor GRM3 PIO0296535 2-hydroxyacyl-CoA lyase 1 HACL1 PIO0062882 ATP-binding domain-containing protein 3 ATPBD3 PIOO445167 CDNA FLJ44499 fis, clone UTERU3000665, highly similar to Homo SRCAP sapiens Snf2-related CBP activator protein PIOO442582 CDNA FLJ26893 fis, clone RCT00305 - PIO001 1274 Isoform 1 of Heterogeneous nuclear ribonucleoprotein D-like HNRPDL PIO0002791 Isoform Wnt-16b of Protein Wnt-16 precursor WNT16 PIO0290432 Natural resistance-associated macrophage protein 1 SLC11A1 PIO001.2540 Prominin-1 precursor PROM1 PIOO477396 Uncharacterized protein ZNF324B (Fragment) ZNF584; ZNF324B PIO0853149 RW1 protein TMEM131 PIO0168977 Olfactory receptor 6J1 OR6 J1 PIO0165955 Isoform 1 of Mitogen-activated protein kinase 15 MAPK15 PIO0377211 Isoform 3 of Cadherin-like protein 26 precursor CDH26 PIO0736.558 THAP domain containing 4 THAP4 PIOO470518 Mitotic spindle assembly checkpoint protein MAD1 MAD1 L1 PIO0005087 Tropomodulin-3 TMOD3 PIO0029.227 LOC93622 protein LOC93622 PIO0218839 Cytochrome P450 1A1 CYP1A1 PIO0006356 Isoform 1 of Patatin-like phospholipase domain-containing protein 5 PNPLA5 PIO0005616 Isoform 1 of Trace amine-associated receptor 2 TAAR2 PIO07894.94 8 kDa protein TUSC4 PIO0745346 Isoform 11 of Peroxisomal N(1)-acetyl-spermine?spermidine oxidase PAOX PIO0027596 Secreted frizzled-related protein 2 precursor SFRP2 PIO0008455 Isoform 2 of Myosin-VI MYO6 PIO0217850 Isoform 1 of GRAM domain-containing protein 1C GRAMD1 C PIO0020771 Isoform 3 of Ensconsin MAP7 PIO0170800 Isoform 1 of Otoancorin precursor OTOA PIO0063181 CDKN2A interacting protein N-terminal like CDKN2 AIPNL PIO0328225 Isoform 1 of T-box transcription factor TBX20 TBX20 PIO0166331 Ankyrin repeat domain-containing protein 35 ANKRD35 US 2013/0237454 A1 Sep. 12, 2013 78

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0294386. Myosin-Ia MYO1A PIO0061680 SAGA-associated factor 29 homolog CCDC101 PIOO220901 TBC1D4 protein TBC1D4 PIO0059139 Vacuolar proton pump subunit E 2 ATP6V1 E2 PIO0010893 Left-right determination factor 2 precursor LEFTY2 PIO0746222 ATP-binding cassette, sub-family B (MDR/TAP), member 5 ABCB5 PIO0010843 Isoform 1 of Amyloid beta A4 precursor protein-binding family B APBB1 member 1 PIO001.2353 Mitochondrial 39S ribosomal protein L3 MRPL3 PIO0385065 Isoform 1 of Coiled-coil domain-containing protein 46 CCDC46 PIOO413930 Elongation of very long chain fatty acids protein 2 ELOVL2 PIO00067.15 Double-strand-break repair protein rad21 homolog RAD21 PIO0787189 similar to thioredoxin domain containing 4 LOC727,931 PIO0215965 Isoform A1-B of Heterogeneous nuclear ribonucleoprotein A1 HNRNPA1 PIO0030237 Isoform 1 of Uncharacterized protein Clorf.49 C1 orf249 PIO0088953 Phosphoinositide 3-kinase regulatory subunit 6 C17orf28 PIO0031490 Isoform 1 of Collectin-11 precursor COLEC11 PIOO430079 Isoform 2 of PHD finger protein 8 PHF PIO0296942 Cadherin-12 precursor CDH12 PIO0852688 Isoform 1 of Low density lipoprotein receptor-related protein 5-like LRP5 L protein PIO0060440 Zinc finger protein GLI4 GLI4; ZFP41 PIO0845299 Putative uncharacterized protein LOC285733 LOC285733 PIO0003897 Isoform 1 of Protocadherin gamma B6 precursor PCDHGB6 PIOO1522.57 Enkurim C10orf63 PIO0043526 Uncharacterized protein C14orf.44 C14orf244 PIO001.3373 Orexin precursor HCRT PIO0829925 Uncharacterized protein ENSP00000365090 ELA2A PI00009333 Transmembrane protein 9 precursor TMEM9 PIOO470917 Isoform 2 of Uncharacterized protein KIAA1529 ÇIAA1529 PIO0013269 Isoform 1 of Uncharacterized protein C60rf106 C6orf106 PIO0022433 Heat-shock protein beta-6 HSPB6 PIO0179694 Beta-klotho ÇLB PIO0027642 Isoform 1 of JmjC domain-containing histone demethylation protein MJD2C 3C PIO0797832 Isoform 3 of Acyl-CoA dehydrogenase family member 10 ACAD10 PIOO410464 Isoform 1 of Zinc finger protein 324B ZNF324B; ZNF584 PIO0166863 Isoform 2 of Coiled-coil domain-containing protein 123, CCDC123 mitochondrial precursor PIO0008832 Growth arrest-specific protein 1 precursor GAS1 PIO0014958 Isoform 1 of Serum paraoxonase/arylesterase 2 PON2 PIO071966.9 Myosin regulatory light chain MRLC2 PIO0299084 Transmembrane protein 33 TMEM33 PIO0029737 Isoform Long of Long-chain-fatty-acid--CoA ligase 4 ACSL4 PIO0005661 Isoform Gamma of Max-like protein X MLX PIO0217683 A-kinase anchor protein 12 isoform 2 AKAP12 PIOO418966 hypothetical protein LOC123688 isoform 2 LOC123688 PIO03284.09 Armadillo repeat-containing protein 4 ARMC4 PIOOO65457 OTTHUMP00000018353 FLJ32682 PIOO444502 CDNA FLJ45482 fis, clone BRTHA2001953 FLJ45482 PIO0001780 Ubiquitin carboxyl-terminal hydrolase 16 USP16 PIO0552840 Probable G-protein coupled receptor 112 GPR112 PIO0016373 Ras-related protein Rab–13 RAB13 PIO0552434 Myosin, heavy chain 7B, cardiac muscle, beta MYHTB PIO0876962 Isoform 2 of Inverted formin-2 INF2 PIO0026512 Isoform HERA-A of GTP-binding protein era homolog ERAL.1 PIO0180375 Isoform 1 of Beta-arrestin-2 ARRB2 PIO0297407 Solute carrier family 45 member 4 SLC45A4 PIOO152879 Monocarboxylate transporter 10 SLC16A10 PIO02901.55 66 kDa protein ZNF148 PIO0747017 Putative uncharacterized protein DKFZp686D06121 NEK1 PIO0793836 11 kDa protein ARHGDIB PIO0382422 Ig lambda chain V-I region NEWM - PIO0328842 ARHGAP4 protein ARHGAP4 PIO0008632 Isoform 1 of Putative homeodomain transcription factor 1 PHTF1 PIO0065253 Uncharacterized protein C3orf50 C3orf20 PIO0883751 RNA-directed DNA polymerase (Reverse transcriptase), related - domain containing protein PIO0216137 Synaptonemal complex protein 1 SYCP1 PIO0005621 7.h3 protein (Fragment) SYDE1 PIO0001933 Coiled-coil domain-containing protein 113 CCDC113 PIO0383294 Putative uncharacterized protein pp.7518 MNT US 2013/0237454 A1 Sep. 12, 2013 79

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0016861 102 kDa protein GTF3C2 PIO0020903 Isoform 1 of AF4/FMR2 family member 2 AFF2 PIOO465247 Isoform 1 of Stimulated by retinoic acid gene 6 protein homolog STRA6 PIO0382394 Isoform 5 of Cytosolic phospholipase A2 beta PLA2C4E PIO0167913 Isoform 1 of Spermatid-associated protein SPERT PIO0874276 Putative uncharacterized protein DKFZp761N1814 EPB41L4B PIOO446767 Isoform 3 of Transducin-like enhancer protein 4 TLE4 PIOOO2O754 PRO1751 - PIO0300060 WD repeat-containing protein 70 WDR70 PIO0021979 Peroxisomal membrane protein 11A PEX11 A PIO0031768 Hook homolog 3 HOOK3 PIO0216986 Isoform C of Complement receptor type 2 precursor CR2 PIOO470771 SAMD4B protein SAMD.4B PIO0021143 Class B basic helix-loop-helix protein 2 BHLHB2 PIO0297931 Isoform 1 of AP1 subunit gamma-binding protein 1 AP1 GBP1 PIO0018691 28S ribosomal protein S18a, mitochondrial precursor MRPS18A PIO0010604 Isoform 1 of 1-phosphatidylinositol-4,5-bisphosphate PLCE1 phosphodiesterase epsilon-1 PIO0022438 Isoform Long of Transcription factor Maf MAF PIO0396527 Isoform 1 of Coiled-coil domain-containing protein 128 CCDC128 PIO0291840 Isoform 1 of Zinc finger protein 90 homolog ZFP90 PIO0646410 Isoform 2 of Flavin-containing amine oxidase domain-containing AOF1 protein 1 PIOO451413 Intersectin 1 isoform 7 TSN1 PIO0787410 similar to Polypeptide N-acetylgalactosaminyltransferase 9 GALNT9 PIO0552601 Putative uncharacterized protein DKFZp686M12165 (Fragment) - PIO0166833 LAG1 longevity assurance homolog 5 LASS5 PIO0183425 CDKN1A interacting zinc finger protein 1 CIZ1 PI000272.28 Probable glutamyl-tRNA(Gln) amidotransferase subunit B, PET112]. mitochondrial precursor PIO0007917 Collectin-10 precursor COLEC10 PIO0552787 similar to Matrin-3 RBM20 PIO0065484 CDNA FLJ32471 fis, clone SKNMC2000322, weakly similar to PTRH2 MAJOR CENTROMERE AUTOANTIGEN B PIO0384447 Sarcoma antigen NY-SAR-22 (Fragment) NEXN PIO0830073 Isoform 1 of RING finger protein 207 RNF207 PIO001.2411 Zinc finger protein 32 ZNF32 PIO0760993 IQ motif and Sec7 domain 2 isoform 2 QSEC2 PIO0004527 Uncharacterized protein KIAA0355 ÇIAA0355 PIO0018956 ALX homeobox protein 1 ALX1 PIOO154553 Centrosomal protein of 76 kDa CEP76 PIOO444208 CDNA FLJ45771 fis, clone NETRP2003103 RNF44 PIO0001641 Origin recognition complex subunit 6 ORC6L PIO0216484 Isoform 2 of LisH domain-containing protein ARMC9 ARMC9 PIO0170961 Isoform 2 of WD repeat-containing protein 16 WDR16 PIO0786880 Myosin-XVB - PIOO152722 Protein CCDC35 CCDC35 PIO0298447 Probable methyltransferase TARBP1 TARBP1 PIOO293.200 OTTHUMP00000016423 PARC PIO0550272 Integrator complex subunit 10 [NTS10 PIO0514197 similar to Nonhistone chromosomal protein HMG-17 LOC648822 PIO0156804 cDNA FLJ77550, highly similar to Homo sapiens zinc finger protein ZNF665 665 (ZNF665), mRNA PIO0384140 Full-length cDNA clone CSODAO05YA22 of Neuroblastoma of Homo ESR2 sapiens (Fragment) PIOO410564 CDNA FLJ45248 fis, clone BRHIP20068.19 FLJ45248 PIO0023586 Isoform 1 of Sentrin-specific protease 6 SENP6 PIO0028579 Transcription initiation factor TFIID subunit 6 TAF6 PIO0253323 Ankyrin repeat domain-containing protein 57 ANKRD57 PIOO166361 Putative uncharacterized protein FLJ33590 FLJ33590 PIO0294810 CDNA FLJ10824 fis, clone NT2RP4001086 (Fragment) FAM21 A PIOO418408 Cytochrome P450 CYP2D7P 1 PIOO168627 Uncharacterized protein CXorf20 CXOrf20 PIO0026952 Plakophilin-3 PKP3 PIO0014852 Isoform 1 of Phosphoglucomutase-like protein 5 PGM5 PIO0332628 Otopetrin-3 OTOP3 PIO0296830 Isoform 1 of Leucine zipper protein 1 LUZP1 PIO0306127 THUMP domain-containing protein 3 THUMPD3 PIO0022881 Isoform 1 of Clathrin heavy chain 2 CLTCL1 PIO0397015 A.T hook DNA-binding motif-containing protein 1 AHDC1 PIO0029184 Hyaluronan and proteoglycan link protein 2 precursor HAPLN2 PIO0795917 126 kDa protein CXOrf245 US 2013/0237454 A1 Sep. 12, 2013 80

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0815976 Transmembrane protein 120B TMEM120B PIO0382671 Isoform 6 of C-type lectin domain family 4 member M CLEC4M PIO0018303 Isoform 2 of Protocadherin-11 X-linked precursor PCDH.11x PIO0176210 hypothetical protein LOC133558 FLJ40243 PIO01661.53 Protein KIAA0082 KIAA0082 PIO0300621 Isoform 2B2 of Synaptojanin-2 SYNJ2 PIO03061.66 germ cell associated 1 isoform 2 GSG1 PIOO401002 Zinc finger protein 740 ZNF140 PIOO607829 Isoform 1 of Ret finger protein-like 2 RFPL2 PIOO402280 Isoform 1 of Small leucine-rich proteoglycan family member CHADL LOC150356 precursor PIO0006800 Isoform Long of Autophagy protein 5 ATG5 PIO0218559 Gamma-sarcoglycan SGCG PIOO479897 Chromosome 9 open reading frame 75 C9Crf75 PIO0216003 Cullin-5 CUL5 PIOO445796 CDNA FLJ43383 fis, clone OCBBF2006058, highly similar to Homo ACAD8 sapiens acyl-Coenzyme A dehydrogenase-8 mRNA PIO0742114 similar to tripartite motif protein 11 LOC653978 PIO0023164 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated HCN4 channel 4 PIOOO12480 FKSG42 RACGAP1 P PIO0004538 similar to nascent polypeptide-associated complex alpha polypeptide NACAD isoform 1 PIO0297462 Uncharacterized protein C10rf65 C1 Orf65 PIO0793454 7 kDa protein USP19 PIO0028392 specifically androgen-regulated protein isoform 1 C1 orf116 PIO0385495 Transmembrane protein 153 LMF2 PIO0017726 Isoform 1 of 3-hydroxyacyl-CoA dehydrogenase type-2 HSD17B10 PI00791509 Neural precursor cell expressed, developmentally down-regulated 1 NEDD1 PIO0289931 Isoform 1 of Mucosal addressin cell adhesion molecule 1 precursor MADCAM1 PIOO442601 CDNA FLJ26817 fis, clone PRS06446 - PIO0012891 Phosphorylase b kinase gamma catalytic chain, testis/liver isoform PHKG2 PIO0021338 Dihydrolipoyllysine-residue acetyltransferase component of pyruvate DLAT dehydrogenase complex, mitochondrial precursor PIOO455083 Uncharacterized protein ENSP00000371558 - PIOO168877 helicase (DNA) B HELE PIO0641214 177 kDa protein ADCY10 PIO0290837 Isoform 2 of F-box/WD repeat-containing protein 10 FBXW10 PIO00092.13 Isoform 1 of B-cell lymphoma/leukemia 11B BCL11B PIO0003421 T-brain-1 protein TBR1 PIO0396314 Isoform 3 of CCR4-NOT transcription complex subunit 10 CNOT 10 PIO0000106 Signal transducer and activator of transcription 4 STAT4 PIO0339217 Ovochymase-1 precursor OVCH1 PIO0395631 Isoform 1 of E3 ubiquitin-protein ligase TRAF7 TRAF7 PIOO455397 DMWD protein DMWD PIO0744557 kazrin isoform E RP1-21 O18.1 PIOO152692 D-tyrosyl-tRNA(Tyr) deacylase 1 DTD1 PIO0397526 Isoform 1 of Myosin-10 MYH10 PIO0640654 RAP1 GTPase activating protein RAP1GAP PIO0791831 10 kDa protein ADRBK1 PIOO479904 Uncharacterized protein COL27A1 COL27A1 PIO001.3256 Isoform 1 of Cleavage stimulation factor 64 kDa subunit CSTF2 PIO00592.79 Exocyst complex component 4 EXOC4 PIO0299402 Pyruvate carboxylase, mitochondrial precursor PC PIO0167639 Vacuolar proton pump subunit d 2 ATP6VOD2 PIO0170855 tetratricopeptide repeat domain 19 TTC 19 PIOO445563 Putative uncharacterized protein MGC21675/FLJ43787 C4Orf242 PIO0884334 Conserved hypothetical protein LOC729968 PIO0007910 Isoform 1 of Sodium-dependent phosphate transport protein 2B SLC34A2 PIO0083708 BAT2-iso BAT2D1 PIOO3287.15 Protein LYRIC MTDH PIO0290035 Isoform 1 of Protocadherin-15 precursor PCDH15 PIO0385511 Uncharacterized protein TNRC6B TNRC6B PIO0006561 Isoform 1 of Protein KIAA0317 ÇIAA0317 PIO0375294 Laminin subunit alpha-1 precursor LAMA1 PIO0375325 Keratin-associated protein 10-10 KRTAP10-10 PIO0640293 23 kDa protein TIMP3 PIO0235003 Tumor necrosis factor receptor superfamily, member 6 isoform 1 FAS variant (Fragment) PIO0216702 Isoform 1 of ATP-binding cassette sub-family A member 9 ABCA9 PIOO167930 ring finger protein 190 MARCH10 00470657 Anti-colorectal carcinoma heavy chain US 2013/0237454 A1 Sep. 12, 2013 81

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIOO413868 hypothetical protein LOC79632 isoform 1 C6Orf60 PIO00663.67 Endothelial cells scavenger receptor precursor SCARF1 PIO0397740 zinc finger protein 749 ZNF749 PIO0300426 Isoform 1 of Tetratricopeptide repeat protein 29 TTC29 PIO0307259 DnaJ homolog subfamily C member 13 DNAJC13 PIO0386113 CDNA: FLJ23412 fis, clone HEP20516 C20orf S9 PIOO153060 Angiopoietin-related protein 4 precursor ANGPTL4 PIO0020354 Interleukin-13 receptor alpha-1 chain precursor L13RA1 PIO0177888 Isoform 1 of Leukocyte receptor cluster member 8 LENG8 PIO010.1267 Isoform 1 of Uncharacterized protein C190rf60 C190rf60 PIO0739927 similar to vasoactive intestinal peptide receptor 2 LOC6454.64 PIO0782965 huntingtin interacting protein 1 HIP1 PIOO444375 Rh blood group, CcEe antigens RHCE PIO0794880 Isoform 1 of Chromodomain-helicase-DNA-binding protein 7 CHD7 PIOO419791 Isoform 1 of Arginine/serine-rich coiled-coil protein 2 RSR C2 PI10100106 resistance to inhibitors of cholinesterase 8 homolog A RIC8A PIO0216593 Isoform NOH-1LV of NADPH oxidase homolog 1 NOX1 PIO0395667 Interferon-related IFRD2 (PC4-B) protein NAT6: IFRD2 PIO0008708 Ribosomal L1 domain-containing protein 1 RSL1 D1 PIO0748649 25 kDa protein - PIO0100362 erythrocyte membrane protein band 4.1 like 4B isoform 1 EPB41L4B PIO0219898 Isoform 2 of Nephrin precursor NPHS1; PRODH2 PIO0872098 Zinc finger protein Pegasus KZF5 PIO0043294 Isoform 1 of Uncharacterized protein C7orf26 C7orf26 PIO0152535 Chromodomain-helicase-DNA-binding protein 5 CHD5 PIO0217507 Neurofilament medium polypeptide NEFM PIO0216356 Isoform 2 of RasGAP-activating-like protein 1 RASAL1 PIO0290562 Nuclear factor interleukin-3-regulated protein NFIL3 PIO0006003 CD83 antigen precursor CD83 PIO0166528 Isoform 3 of Rapamycin-insensitive companion of mTOR RICTOR PIO0221325 E3 SUMO-protein ligase Ranbp2 RANBP2 PIO0084684 similar to Zinc finger protein 469 ZNF469 PIOO643.809 Protein CNTNAP3B PIOO164776 Similar to RIKEN cDNAA230078105 gene TMEM198 PIO0023410 Integrin alpha-8 precursor TGA8 PIOO787593 Similar to CG33300-PA LOC730407 PIO0180781 Isoform 1 of Mixed lineage kinase domain-like protein MLKL PIO0339309 Isoform 1 of Proto-oncogene DBL MCF2 PIO0843923 Phosphodiesterase PDE7B2 PDE7B PIO0640865 Integrin beta-like protein 1 precursor TGBL1 PIO0029144 Isoform PR130 of Serine/threonine-protein phosphatase 2A regulatory PPP2R3A subunit B" subunit alpha PIO0175439 F-box only protein 43 FBXO43 PIO0646485 Protein EFCAB2 PIO0023105 Peptidylglycine alpha-amidating monooxygenase COOH-terminal PAMCI interactor PIO0301144 Isoform 1 of Sulfatase-modifying factor 1 precursor SUMF1 PIOO439935 UDP-glucuronosyltransferase 1-4 precursor UGT1A4; UGT1A6 PIO0001753 Myosin-4 MYH4 PIOO401829 Putative uncharacterized protein ENST00000281581 - PIO0056324 Isoform 1 of Hermansky-Pudlak syndrome 3 protein HPS3 PIO0220493 U6 snRNA-associated Sm-like protein LSms LSMS PIO0386390 Olfactory receptor 6N2 OR6TN2 PIO0044761 Pseudouridylate synthase 7 homolog PUS7 PIO0032342 TRIP12 protein TRIP12 PIO0307536 Isoform 1 of Testis-expressed sequence 11 protein TEX11 PIO0244812 Tetratricopeptide repeat protein 6 TTC6 PIO0030487 CDNA FLJ30993 fis, clone HLUNG1000064, weakly similar to ÇIAA1627 KARYOGAMY PROTEIN KAR4 PIO0787443 similar to Collagen alpha-2(XI) chain precursor LOC730037 PIO001.3371 Protein sprouty homolog 3 SPRY3 PIO0.414259 Isoform 2 of Pregnancy-specific beta-1-glycoprotein 4 precursor PSG4 PIOO410590 Isoform 2 of LSM14 protein homolog A LSM14A PIO0023330 Isoform 2 of LisH domain and HEAT repeat-containing protein ÇIAA 1468 ÇIAA1468 PIO0645614 Isoform 2 of Cadherin-3 precursor CDH3 PIO0744574 Similar to Tropomyosin alpha-4 chain - PIO0737735 similar to cell division cycle 10 isoform 1 LOC646913 PIO0065415 Isoform 1 of Coiled-coil domain-containing protein 138 CCDC138 PIO0376206 Isoform 2 of 17-beta hydroxysteroid dehydrogenase 13 precursor HSD17B13 PIO0011589 Isoform A of Septin-4 SEPT4 PIO0032158 Isoform 2 of NMDA receptor-regulated protein 1 NARG1 US 2013/0237454 A1 Sep. 12, 2013 82

TABLE 81-continued ?able 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0013468 Mitotic checkpoint protein BUB3 BUB3 PIO0745955 EBNA1 binding protein 2 EBNA1 BP2 PIOO157237 Isoform 1 of MAGUK p55 subfamily member 4 MPP4 PIO0009040 Ornithine decarboxylase antizyme 3 OAZ3 PIO0383774 Mihl/Tx protein CASP4 PIOO182774 SH3 yL1 protein SH3 YL1 PIO0217691 Isoform 1 of EF-hand domain-containing protein C17orf57 C17orf57 PIO0514843 KIAA0082 KIAA0082 PIO0216346 Isoform 2 of Nucleolar protein 3 NOL3 PIO0644968 Similar to Heterogeneous nuclear ribonucleoprotein A1 - PIOO414122 coiled-coil domain containing 141 CCDC141 PIO0884216 RNA-directed DNA polymerase (Reverse transcriptase), related - domain containing protein PIO0397759 similar to ribosomal protein L21 LOC3886.21 PIO0156871 Isoform 2 of Ubiquitin carboxyl-terminal hydrolase 49 |USP49 PIO0168692 Isoform 2 of Zinc finger protein 318 ZNF318 PIO0187082 Isoform 3 of Multiple C2 and transmembrane domain-containing MCTP1 protein 1 PIO0018805 Uncharacterized protein C14orf105 C14Orfl05 PIOO446685 CDNA FLJ41345 fis, clone BRAWH2002761 - PIOO470515 Isoform 1 of Uncharacterized protein Clorf173 C1 Orf173 PIO0001317 Rho-related BTB domain-containing protein 1 RHOBTB1 PIO0024523 Isoform A of DnaJ homolog subfamily B member 6 DNAJB6 PIO0030814 Fibroblast growth factor 22 precursor FGF22 PIOO441064 Isoform 1 of Uncharacterized protein C15orf26 C150rf26 PIO0867744 Isoform 3 of Pleckstrin homology domain-containing family H PLEKHH2 member 2 PIO0784027 Rod cº?P-specific 3',5'-cyclic phosphodiesterase subunit beta PDE6B jite Cui SOjº PIO0879277 436 kDa protein TRRAP PIO0011631 Centromere/kinetochore protein zwl.0 homolog ZW10 PIO0014186 Isoform A of Zinc finger homeobox protein 3 ZFHX3 PIO0852699 4 kDa protein - PIO0.400834 Mediator of RNA polymerase II transcription subunit 13-like MED1.3L PIO0018203 Isoform SRP55-2 of Splicing factor, arginine/serine-rich 6 SFRS6 PIO0335259 deleted in liver cancer 1 isoform 1 DLC1 PIO023.9405 Isoform 1 of Nesprin-2 SYNE2 PIO0788010 similar to 60S ribosomal protein L21 RPL21; LOC728501 PIO0027487 Creatine kinase M-type CKM PIO0029662 Isoform 1 of Potassium voltage-gated channel subfamily H member 2 KCNH2 PIO0651669 Putative uncharacterized protein - PIO0029446 Isoform 1 of Myotubularin-related protein 5 SBF1 PIO0883929 Conserved hypothetical protein - PIO0641155 20 kDa protein HIRIP3 PIO0030307 Solute carrier family 41 member 2 SLC41A2 PIO0398162 Isoform 2 of Nebulin-related-anchoring protein NRAP PIOO158506 Isoform 3 of Zinc finger protein 688 ZNF688 PIO0003768 Isoform 1 of Pescadillo homolog 1 PES1 PIO0100910 Isoform 2 of Armadillo repeat-containing protein 5 ARMC5 PIOO445894 CDNA FLJ42978 fis, clone BRTHA2004821 - PIO0022325 Isoform 4 of Pro-neuregulin-2, membrane-bound isoform precursor NRG2 PIO0747271 zinc finger protein SBZF3 ZNF695 PIO0006178 Yé encoding protein NPY6R PIO0796745 22 kDa protein PPP1R14D PIO0299880 Isoform 2 of Calcium-activated potassium channel subunit beta-3 KCNMB3 PIO0328885 eEF1A2 binding protein DKFZp-434B1231 PIO0009305 Glucosamine-6-phosphate isomerase GNPDA1 PIOO465054 Putative uncharacterized protein DKFZp686C1054 THUMPD1 PIOO456676 Isoform 1 of F-box only protein 38 FBXO38 PIO0328089 Kappa B and V(D)J recombination signal sequences binding protein HIVEP3 PIO0002506 Dolichyl-phosphate beta-glucosyltransferase ALG5 PIO0.410325 Low-density lipoprotein receptor class A domain-containing protein 3 LDLRAD3 jite Cui SOjº PIOO450358 Putative uncharacterized protein TOP PIO0004472 Isoform 1 of Serine/threonine-protein kinase WNK1 WNK1 PIO0.428677 Putative olfactory receptor (Fragment) - PIO0788014 similar to Opioid growth factor receptor LOC729,015 PIOO442208 CDNA FLJ16344 fis, clone TEST12032643, moderately similar to ADCY4 ADENYLATECYCLASE, TYPE IV PIO0019932 ubiquitin-conjugating enzyme E2D 2 isoform 2 |UBE2D2 PIO0869224 Pseudogene candidate - PIO0000102 Progonadoliberin-1 precursor GNRH1 US 2013/0237454 A1 Sep. 12, 2013 83

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIOO470896 Isoform 2 of Zinc finger FYVE domain-containing protein 26 ZFYVE26 PIO03294.88 Isoform IB of Tyrosine-protein kinase ABL2 ABL2 PIO0219604. Dual specificity mitogen-activated protein kinase kinase 1 MAP2K1 PIO0000030 Isoform Delta-1 of Serine/threonine-protein phosphatase 2A 56 kDa PPP2R5D regulatory subunit delta isoform PIO0017538 Isoform 2 of Separin ESPL1 PIO0787099 similar to SR protein related family member LOC728676 PIOO297235 cDNA FLJ17204 CCPG1 PIO0002405 2'-5'-oligoadenylate synthetase 3 OAS3 PIO001.3205 Isoform 1 of JmjC domain-containing histone demethylation protein JMJD2B 3B PIO0218715 Isoform 2 of ADAM 33 precursor ADAM33 PIOO410666 Isoform 3 of Protein LAP4 SCRIB PIO0827815 Light chain Fab (Fragment) - PIO0013651 Isoform 3 of RNA-binding protein 33 RBM33 PIO0002344 steroid 5 alpha-reductase 3 SRD5A3 PIOO444408 CDNA FLJ45600 fis, clone BRTHA3020369 - PIO0005013 poly(rC) binding protein 4 isoform b PCBP4. PIO0294728 Dmix-like protein 1 DMXL1 PIO0004288 Isoform 1 of Sialic acid-binding Ig-like lectin 7 precursor SIGLEC7 PIO0855960 Integral membrane protein GPR137C GPR137C PIO0003571 Isoform S-CaRP1 of Calcium-binding protein 1 CABP1 PIO0021751 Neurofilament heavy polypeptide NEFH PIO0174347 Inactive dual specificity phosphatase 27 DUSP27 PIO0787774 similar to collagen, type I, alpha 1 LOC730756 PIOO419903 Putative L-aspartate dehydrogenase LOC554235 PIO0165357 Isoform 1 of Metastasis-associated protein MTA3 MTA3 PIO0299406 Pituitary adenylate cyclase-activating polypeptide type I receptor ADCYAP1R1 jite Cui SOjº PIOO401789 Isoform 2 of Highly divergent homeobox HDX PIO0303732 Uncharacterized protein C20orf106 precursor C20orf106 PIO0016425 Isoform 2 of Synaptopodin 2-like protein SYNPO2L PIO0017640 Isoform 1 of Slithomolog 3 protein precursor SLIT3 PIO001.4577 Ras-related protein Rab-18 RAB 18 PIO0023856 Peregrin BRPF1 PIO0294241 Transcription factor IIIA GTF3A PIO0025717 Metaxin-2 MTX2 PIO0023095 Myeloid leukemia factor 2 MLF2 PIO0009645 Ran-binding protein 17 RANBP17 PIO0022629 Isoform 1 of Protein regulator of cytokinesis 1 PRC1 PIO0031082 Putative uncharacterized protein DKFZp761O17121 LDOC1L PIO0788120 similar to CG1418.2-PA LOC7300.94 PIO0396063 C-myc promoter-binding protein DENND4A PIO001.3296 40S ribosomal protein S18 RPS18 PIO00043.62 MORC family CW-type zinc finger protein 1 MORC1 PIO0787625 similar to 60S ribosomal protein L23a LOC389,101 PIO0385020 Putative uncharacterized protein DKFZp686D159 (Fragment) CAPRIN_2 PIO0374223 hypothetical protein LOC389119 C3orf54 PIO00396.26 Isoform D of UPF0318 protein FAM120A FAM120A PIO02952.53 Isoform 1 of Cell surface glycoprotein OX2 receptor precursor CD200R1 PIO0299040 Polycystin-2 PKD2 PIO0307165 Tripartite motif-containing protein 47 TRIM47 PIOO152685 Tetratricopeptide repeat protein 15 TTC15 PIO0013789 SET and MYND domain-containing protein 5 SMYD5 PIO0396025 hypothetical protein LOC254122 FLJ30934 PIO0014232 ADP-ribosylation factor-like protein 6-interacting protein 1 ARL6IP1 PIO0021715 Isoform 1 of Collagen alpha-5(IV) chain precursor COL4A5 PIO0026305 Hook homolog 1 HOOK1 PIOO184160 Isoform 2 of RING finger protein 180 RNF180 PIO0216308 Voltage-dependent anion-selective channel protein 1 VDAC1 PIO0651633 CASKIN1 protein (Fragment) CASKIN1 PIOO247063 Neprilysin MME PIO0398779 Isoform 4 of Plectin-1 PLEC1 PIO0168418 Putative uncharacterized protein C11orf64 C11orfö4 PIOO167764 Transmembrane protein 102 TMEM102 PIOO171716 OTTHUMP00000028696 TTC28 PIO0394818 Isoform 1 of Ankyrin repeat domain-containing protein 47 |

TABLE 81-continued Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Cº Protein Gene PIO0000873 Valyl-tRNA synthetase VARS PIO0386.185 FLJO0370 protein (Fragment) - PIO0829697 Uncharacterized protein ENSP00000375030 - PIO0000690 Isoform 1 of Apoptosis-inducing factor 1, mitochondrial precursor AIFM1 PIO0016988 WD repeat-containing protein 13 WDR.13 PIOO478058 Isoform 2 of NMDA receptor-regulated 1-like protein NARG1 L PIO0782960 Isoform 1 of Leucine-rich repeat and IQ domain-containing protein 3 LRRC44 PIO0103373 Cytoglobin CYGB PIO0646831 34 kDa protein - PIO0384164 Full-length cDNA clone CSODIO75YC18 of Placenta of Homo PGF sapiens (Fragment) PIO073961.1 similar to golgi autoantigen, golgin subfamily a, 8A isoform 3 LOC727909 PIO001.2451 Guanine nucleotide-binding protein subunit beta-4 GNB4 PIO0394960 Isoform 1 of Probable G-protein coupled receptor 133 precursor GPR133 PIO0555595 Ubiquitin carboxyl-terminal esterase L1 (Ubiquitin thiolesterase) - variant (Fragment) PIOO431697 Cancer/testis antigen 45-5 RP13–36C9.6 PIO0028066 class IV alcohol dehydrogenase 7 mu or sigma subunit ADHZ PIO0152960 RNA polymerase 1-specific transcription initiation factor RRN3 RRN3 PIOO792370 6 kDa protein GNAT1 PIOO167762 Isoform 1 of Uncharacterized protein C190rf.47 C1901.f47 PIO0385321 Isoform 2 of Protein kinase C-binding protein 1 ZMYND8 PIOO385153 HUMEEP ATXN10 PIO0337348 Growth differentiation factor 7 GDF7 PIO0060627 Coiled-coil domain-containing protein 124 CCDC124 PIOO401190 LOC155006 protein LOC155006 PIO002503.9 rRNA 2'-O-methyltransferase fibrillarin FBL PIOO479578 similar to Nonhistone chromosomal protein HMG-14 hCG 1659.830 PIO0018245 Isoform 3 of DNA-directed RNA polymerase III subunit RPC5 POLR3E PIOOO20565 PRO1598 - PIOO446711 CDNA FLJ41261 fis, clone BRAMY2034920 - PIO0787990 similar to ribosomal protein S14 LOC644119 PIO0218743 Isoform 2 of Bestrophin-1 BEST1 PIO0736826 similar to Temporarily Assigned Gene name family member LOC402217 PIOO412024 Zinc finger protein 485 ZNF485 PIO0297559 Isoform 1 of USH1C-binding protein 1 |USHBP1 PIO0396147 Protocadherin-20 precursor PCDH2O PIOO478572 Collagen alpha-4(IV) chain precursor COL4A4 PIO0032785 Isoform II of Amyloid beta A4 precursor protein-binding family B APBB3 member 3 PIO0009982 Isoform 1 of Tudor and KH domain-containing protein TDRKH PIO0216164 Peroxisomal bifunctional enzyme EHEIADH PIOO419912 YY2 transcription factor YY2 PIO0735531 proline-rich synapse-associated protein 2 isoform 4 SHANK3 PIO0005104 Inhibitor of nuclear factor kappa-B kinase subunit alpha CHUK PIO0008837 Tyrosine-protein phosphatase non-receptor type 5 PTPN5 PIO0017800 ATP-binding cassette sub-family A member 3 ABCA3 PIO0737972 Transcription factor 24 (Fragment) TCF24 PIO0374074 similar to CG40449-PA.3 LOC388795 PIO0220533 Isoform D of Transmembrane protease, serine 3 TMPRSS3 PIO0302458 Exportin-7 XPO7 PIO0646826 Putative uncharacterized protein FLJ32658 FLJ32658 PIO0016859 Isoform 1 of Transcription factor IIIB 90 kDa subunit BRF1 PIO0031386 Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit PIK3CA alpha isoform PIOOO65547 OTTHUMP00000031495 RP11–93B14.6 PIO0043370 WD repeat-containing protein 52 WDR52 PIO0064767 Isoform 1 of Rho GTPase-activating protein 17 ARHGAP1 7 PIO021.9689 Isoform Beta of Protein vav-3 VAV3 PIO0328.291 Cytoskeleton-associated protein 2-like CKAP2L PIO0647897 RING finger protein 113B RNF113B PIO0024285 similar to testicular serine protease 2 LOC1386.52 PIO0783200 38 kDa protein RAPGEF3 PIO0014877 Isoform 2 of Glutaminyl-peptide cyclotransferase-like protein QPCTL PIOO186554 Uncharacterized protein KIAA1853 KIAA1853 PIOO418336 Isoform 2 of Integrator complex subunit 3 INTS3 PIO0872730 Macrophin 1 isoform MACF1 PIO0303207 ATP-binding cassette sub-family E member 1 ABCE.1 PIO0301609 Serine/threonine-protein kinase Nek9 NEK9 PIO07445.27 Conserved hypothetical protein - PIO0302351 Isoform 1 of Serine/threonine-protein kinase 33 STK33 PIO0878483 30 kDa protein - US 2013/0237454 A1 Sep. 12, 2013 85

TABLE 81-continued

Table 81. Proteins Absent in Neurologic Lyme disease but Present in Normals or Chronic Fatigue. 1597 Proteins

Protein Gene

PIOO744179 Uncharacterized protein ENSP00000370856 (Fragment) PIOO396.279 Soform 1 O CLIP-associating protein 1 CLASP1 PIOOO13378 soform Long of DNA topoisomerase 3-alpha TOP3A PIOO4291.90 Ras-related protein Rab-11A RAB1 1A PIOO464994 Soform 1 O tRNA modification GTPase GTPBP3, mitochondrial GTPBP3 jite Cui SOjº PIOOOO8449 Soform 3 O Pre-mRNA 3’-end-processing factor FIP1 FIP1L1 PIOO414402 Olfactory receptor 2T27 OR2T27 PIOO1689.13 Soform 2 O Limbin EVC2 PIOOOO!931.5 Golgi resident protein GCP60 ACBD3 PIOO871625 cDNA FLJT. 7072, highly similar to Homo sapiens prostaglandin E PTGER3 receptor 3 (subtype EP3) (PTGER3), transcript variant 9, mRNA PIOO4792.96 Soform 1 O ATP-binding cassette sub-family A member 8 ABCA8 PIOO300221 Putative uncharacterized protein DKFZp-434I1916 LL PIOOO26036 Soform 5 O Dipeptidyl peptidase 8 PP8 PIOO647205 Uncharacterized protein C60rf174 precursor 6Orf174 PIOOOO6932 Soform 1 O Putative RNA-binding protein Lucy-like 2 LUC7L2 PIO0017819 Bile acid-CoA:amino acid N-acyltransferase BAAT PIOO 1451.21 GPI mannosyltransferase 3 PIGB PIOO744357 Conserved hypothetical protein PIOO410320 Sodium-dep endent glucose transporter SLC5A11 PIOOO65085 CDNA FLJ25371 fis, clone TSTO1885 FLJ25371 PIOO2.89914 MutS protein homolog 4 MSH4 PIOOO12438 Isoform Long of 52 kDa repressor of the inhibitor of the protein PRKRIR kinase PIOO217895 rai-like protein SHC4 PIOO2946.18 Proline-rich protein PRCC PRCC PIOOOOO784 Isoform MEF2DAB of Myocyte-specific enhancer factor 2D MEF2D PIOO848.180 Conserved hypothetical protein PIO0045208 Zinc finger protein 300-B ZNF300 PIOO871452 Soform 1 O PWWP domain-containing protein 2A PWWP2A PIOO 102820 Soform 3 O Mitochondrial tumor suppressor 1 MTUS 1 PIOO215786 3',5'-cyclic nucleotide phosphodiesterase 10A2 PDE10A PIOO845401 Soform 6 O Neuron navigator 1 NAV1 PIOO217979 Myeloid/lymphoid or mixed-lineage leukemia 5 MLL5 PIOO440764 Soform 1 O Gamma-glutamyltransferase 6 precursor GGT6 PIOO374068 Soform 1 O ADAMTS-like protein 4 precursor ADAMTSL4 PIOO186439 Zinc finger protein 643 ZNF643 PIOOO624.67 Soform 1 O Zinc finger protein 274 ZNF274 PIOOOOO890 Soform 1 O Growth hormone variant precursor GH2 PIOOO65351 Zinc finger protein 354B ZNF354B PIOO55.2455 2 kDa protein INPP5A PIOO395473 Zinc finger protein 135 ZNF135 PIO0003842 Soform 1 O Microtubule-associated protein 2 MAP2 PIOO655760 Envelope polyprotein PIOO38.4767 FLJO0332 protein (Fragment) TBC1D10C PIO0028.050 Selenocysteine-specific elongation factor EEFSEC PIOO152033 soform 1 of Transient receptor potential cation channel subfamily M TRPM8 member 8 PIOO7895.64 soform 3 of Metallophosphoesterase 1 MPPE1 PIO001 1253 40S ribosomal protein S3 RPS3 PIOO454620 1q22.1 provirus ancestral Pol protein PIOO337335 soform 1 of Myosin-14 MYH14 PIOO 103426 soform 1 of Solute carrier family 13 member 3 SLC13A3 PIOO291839 soform 2 of Rap guanine nucleotide exchange factor 6 RAPGEF6 US 2013/0237454 A1 Sep. 12, 2013 86

TABLE 9 Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00217493 18.00 00783.656 6.67 004654.36 6.50 00.161055 6.50 00445.716 5.00 00384395 5.00 00020747 5.00 00291807 5.00 00827978 4.00 00827485 4.00 00024887 4.00 00419442 4.00 00008107 4.00 00022.445 4.00 00002307 4.00 00465070 4.00 00023.604 4.00 00395769 4.00 002.20706 3.60 00382682 3.50 0083.0035 3.33 0046531.5 3.22 00384.407 3.00 0029.6259 3.00 00400986 3.00 00010863 3.00 00005153 3.00 0002013.1 3.06 00.176920 3.00 00.176104 3.00 00019600 3.00 00299435 3.00 00008207 3.00 00830057 3.00 000289.31 3.00 00006.556 3.00 00022674 3.00 00043810 3.00 00.166892 3.00 0039.8007 3.00 0001 6604 3.00 00003469 3.00 00827643 3.00 00741.524 3.00 00.1794.15 3.00 00442002 3.00 00387,099 3.00 00021828 3.00 0041071.4 2.91 00383808 2.75 00182138 2.67 0047301.1 2.67 0044.2909 2.67 00023019 2.55 00021833 2.50 00883772 2.50 0029.3088 2.50 0021 6983 2.50 0041 0079 2.50 00215983 2.45 002.20301 2.40 00024621 2.40 00029275 2.40 00008556 2.33 PIOOOO!9477 2.29 US 2013/0237454 A1 Sep. 12, 2013 87

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00023505 2.25 00654755 2.15 00418960 2.14 0001 0381 2.11 00003907 2.09 00002818 2.00 00002535 2.00 00030757 2.00 00217781 2.00 00382478 2.00 00018352 2.00 00470766 2.00 00007617 2.00 0030.1098 2.00 00000070 2.00 00827788 2.00 00003807 2.00 000101.33 2.00 00099.650 2.00 00.166553 2.00 0022.1080 2.00 00099838 2.00 007.44706 2.00 0029.1987 2.00 00031019 2.00 00387101 2.00 00004480 2.00 00021812 2.00 00008085 2.00 00027972 2.00 004:55.739 2.00 008:83879 2.00 00297.208 2.00 00.151036 2.00 0.0218914 2.00 00328587 2.00 00005517 2.00 00029605 2.00 00009881 2.00 00030431 2.00 00384400 2.00 00008997 2.00 00019755 2.00 00383951 2.00 00000160 2.00 00012048 2.00 00010810 2.00 00020431 2.00 00297.288 2.00 00218474 2.00 0071962.1 2.00 00387110 2.00 00329352 2.00 00399.089 2.00 000272.39 2.00 00783.604 2.00 00008726 2.00 00299.399 2.00 00.16892.1 2.00 00383.603 2.00 00.179851 2.00 00219684 2.00 0.06444.72 2.00 002.20362 2.00 PIO0006130 2.00 US 2013/0237454 A1 Sep. 12, 2013 88

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00550363 2.00 0042007.1 2.00 00.103871 2.00 00218539 2.00 0001894.1 2.00 0043.2766 2.00 00746600 2.00 004:19815 2.00 003761.97 2.00 002936.13 2.00 007965.18 2.00 00007648 2.00 00409659 2.00 002.2011.3 2.00 000151.35 2.00 00306929 2.00 00011092 2.00 00293-616 2.00 006.43747 2.00 00465.173 2.00 00011832 2.00 00:185892 2.00 00.1521.89 2.00 00.176778 2.00 008.29979 2.00 00004970 2.00 00003084 2.00 00025155 2.00 00401776 2.00 00009504 2.00 00015473 2.00 00304533 2.00 00031101 2.00 00402291 2.00 00385799 2.00 00829803 2.00 00033541 2.00 00027220 2.00 00014048 2.00 00329775 .97 00022284 .90 00.165975 .88 007453.13 .86 00016679 .86 0001 6666 .83 00307592 .83 00006803 .83 00382420 .83 00001895 .83 00012887 .80 00397645 .80 00873.544 .80 00479.1.16 .78 0082984.1 .78 0001 0402 .78 00025.426 77 000253.18 .75 00019530 .75 00020906 .75 00375.364 .75 00418471 .75 00013438 .75 00443799 .73 00219131 .71 PIO0059366 .69 US 2013/0237454 A1 Sep. 12, 2013 89

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00003111 .67 00465377 .67 00419565 .67 00025473 .67 00001 610 .67 00007240 .67 00009054 .67 00465.255 .67 00010896 .67 00099670 .67 0041.9966 .67 00031708 .67 00419.720 .67 003824.86 .67 00337351 .67 00008752 .67 00027765 .67 00854589 .67 0029.4193 .65 00218.192 .65 00784154 .62 008441.56 .61 00743963 .60 000183.11 .60 00.152850 .60 00816775 .60 00440932 .60 00470607 .60 004:2851.1 .60 00743.194 .58 00743766 .58 000291.31 .57 0038248.1 .57 00829.701 .57 0029.2732 .57 00827.522 .57 00012075 .57 00298.547 .56 00001506 .55 00027350 .53 00:169383 .53 00008.944 .51 008:54745 .50 00024035 .50 00394.820 .50 0030,1294 .50 00014.964 .50 00412541 .50 00064.652 .50 00883765 .50 00002412 .50 00552852 .50 00736.885 .50 00789234 .50 00.165972 .50 00297180 .50 000085.33 .50 00302962 .50 00045536 .50 00005222 .50 00215.980 .50 00641251 .50 0001.5911 .50 00306322 .50 PIOO301 180 .50

US 2013/0237454 A1 Sep. 12, 2013 91

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00019581 .38 00.166039 .38 00001592 .38 00025.809 .38 00010796 .38 00.183321 .38 0.0218046 .38 00032328 .37 00465016 .37 003346.67 .37 00026.050 .36 00477,992 .36 00032220 .36 002.17345 .36 00472249 .36 00297646 .35 00328.746 .35 00794.450 .35 00026154 .35 00514285 .35 0.0646281 .34 0001917.6 .33 00387113 .33 00011643 .33 00005129 .33 00657936 .33 00387024 .33 00298650 .33 008:84080 .33 004181.25 .33 00789477 .33 00021856 .33 007892.59 .33 0074.1710 .33 00000144 .33 00219.425 .33 0078347.1 .33 00171196 .33 00:160552 .33 008:83855 .33 00006713 .33 00011518 .33 00293303 .33 00031549 .33 002961.97 .33 00554786 .33 00000824 .33 00018396 .33 00.1651.25 .33 00787.265 .33 00299.024 .33 00299299 .33 00009111 .33 00300838 .33 00027497 .33 00006543 .33 00.14253.8 .33 00015614 .33 00786926 .33 00009851 .33 00013895 .33 0001994.3 .33 002.20292 .33 000270.87 .33 PIOO654888 .32 US 2013/0237454 A1 Sep. 12, 2013 92

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00023807 .32 00783.287 .32 00018219 .31 00007778 .31 00022431 .31 00013.682 .30 00456736 .30 00.103175 .30 00025461 .30 00:169276 .30 0039.4992 .30 00.1632O7 .30 00.152847 .29 00005142 .29 00299758 .29 00022608 .29 00294.615 .29 00827829 .29 0085484.1 .29 00008780 .29 00006657 .29 00003865 .29 000271.74 .29 00003176 .29 002.20739 .29 00217966 .29 0087,991.5 .29 0032.8550 .28 00383732 .28 00292.150 .28 00289.204 .28 00.162547 .28 00062037 .27 0001.2283 .27 00382500 .27 00514676 .27 002.20342 .27 00029235 .27 00477597 .27 00029699 .27 0030.1255 .27 0043,2592 .27 00218733 .27 007.95013 .26 003.95488 .26 00783492 .25 00015315 .25 0001 6150 .25 008:16155 .25 0.0884004 .25 00552939 .25 007831.56 .25 00021817 .25 00017557 .25 00000265 .25 00002925 .25 00382493 .25 00033560 .25 00414896 .25 000287.14 .25 00477714 .25 0040 1283 .25 00030847 .25 00006524 .25 PIOO1684.79 .25 US 2013/0237454 A1 Sep. 12, 2013 93

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

002.93757 .25 00024.273 .25 0.0646304 .25 00015964 .25 00001734 .25 00430291 .25 00382426 .25 00328840 .25 00009.997 .25 00009030 .24 00032.293 .24 00556287 .24 008:54743 .24 00022.895 .24 0001958.0 .24 002997.38 .23 002.20562 .23 00.166048 .23 00000044 .23 00787050 .23 00002211 .23 00292.946 .23 00215.894 .23 00007853 .22 00376.689 .22 002.20334 .22 00739827 .22 00744.835 .22 00465248 .22 00829877 .22 0001 1252 .21 00028413 .21 00298828 .21 00004413 .21 007.95055 .21 0001 2503 .21 00027482 .20 000298.19 .20 00387095 .20 00013701 .20 0002981 7 .20 00827.940 .20 00219.465 .20 00749328 .20 00215997 .20 00013096 .20 00478.809 .20 0002801.5 .20 002.90856 .20 0.0218414 .20 004104.87 .20 00029.273 .20 00386418 .20 00303963 .20 00022488 .20 0029.1866 .20 00552.905 .20 0000992.0 .19 001.71473 .19 00022937 .19 00292304 .19 00852979 .19 004653.25 .19 00830047 .19 PIOO827906 .19 US 2013/0237454 A1 Sep. 12, 2013 94

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00386630 00294705 00376394 00:183445 00031030 0030.1364 00.167710 00292950 00413959 00456623 00010949 00007257 00295832 002925.30 00297 124 00022420 00064935 00023824 00.1670.93 00004946 00063048 00022.367 00414717 00328.391 00218493 00329688 00013569 00032311 00009865 00002406 00827.650 00032291 00816555 00027827 00000130 008:16741 00303.16.1 007453.63 00022337 00012058 00027507 003852.53 00217146 003.85985 00216691 002.96537 00017696 00305461 00879.309 0085.3369 00843.910 00798.430 00555812 007.91343 00301143 0001691.5 00013179 0064.2632 00001793 00291.395 00219.301 00021033 00023845 004181 63 PIO002 1854 US 2013/0237454 A1 Sep. 12, 2013 95

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00742696 00019568 00032258 00247243 00328.609 00004440 004.19722 00.176424 00022392 008:79665 002.96777 00022463 00296992 00020996 008:1662.6 00005908 00032292 00032405 00.152418 00021447 00.182944 00816799 00025840 0000719.9 00019954 00219526 00026,216 00021885 00064.607 00000828 00784.119 00289083 00.176221 00029.260 002.96534 00298793 00299059 00783390 00607 600 0029.9724 00011662 00289831 00032.288 00299503 00001399 00376427 00298237 00477804 00020012 00442.297 00607580 00442.294 00218732 00553177 00218834 00020987 00060310 00.168626 00297.263 00219029 00003802 00006166 00022395 00017601 .0 9 PIOOO19591 US 2013/0237454 A1 Sep. 12, 2013 96

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00024966 .09 00552.267 .09 00639.937 .09 0001 1264 .09 00020986 .09 0029.1262 .09 00478003 .09 004:51625 .09 00006608 .09 00785200 .08 0001.2303 .08 00010295 .08 00295414 .08 002895.01 .08 00069058 .08 00828205 .08 00027851 .08 00005292 .08 00003366 .08 00854,644 .08 00550.162 .08 00794.184 .08 008453.54 .07 00241,562 .07 00003351 .07 00102543 .07 00.171411 .07 00219798 .07 00298.388 .07 00299699 .07 00854806 .07 00829.626 .07 00001611 .07 00301812 .07 00026944 .07 00384542 .07 00375,205 .07 00015.346 .07 00382938 .07 00.104074 .07 00027.310 .07 00016,334 .07 00785 196 .07 00827892 .07 00410210 .07 00026.104 .07 00293748 .07 00784773 .06 00.154742 .06 003281.13 .06 00877029 .06 00023814 .06 0047.2961 .06 00301865 .06 00009.950 .06 00853045 .06 00784865 .06 00746963 .06 00784519 .06 00784985 .06 00430808 .06 00440577 .06 00301579 .06 00044369 .06 PIOO306710 .06 US 2013/0237454 A1 Sep. 12, 2013 97

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00387105 .06 0001990.6 .06 00854.667 .06 0029.4834 .06 00000779 .06 00028911 .05 00006601 .05 00028553 .05 00791. 134 .05 00783.689 .05 002.21 224 .05 00550731 .05 00853525 .05 00794070 .05 0001 2440 .05 00011605 .05 002927.91 .05 00219757 .05 00.152540 .05 00426051 .05 0047.9514 .04 00289819 .04 00:178302 .04 00374563 .04 002.20327 .04 004:19595 .04 00026314 .04 00025465 .04 00021842 .04 00218874 .04 00027780 .04 00878576 .03 00.156171 .03 0002233.1 .03 0078.8835 .03 00022229 .03 00470535 .03 0021-8911 .03 00.166766 .03 00216171 .03 00022892 .02 00028908 .02 00022417 .02 00306339 .02 00333140 .02 00022.426 .02 00303.210 .02 00385264 .02 00218875 .02 00218413 .02 00.166729 .01 00022434 .01 00007921 .01 00647027 .01 00878517 .01 00298971 .01 002961.65 .01 00021841 .00 00000027 .00 00830,122 .00 00383.03.2 .00 00297.040 .00 00031008 .00 00218398 .00 PIOOO73763 .00 US 2013/0237454 A1 Sep. 12, 2013 98

TABLE 9-continued Relative Abundance of CSF Proteins Chronic Fatigue compared to Neurologic Lyme Table 9. Quantitative Relative Abundance of CSF Proteins in Chronic Fatigue (CF) compared to Neurologic Lyme Disease. A ratio greater than 1 indicates there is a relative quantitative difference in Chronic Fatigue compared to Neurologic Lyme disease (LD). Ratios near 1 suggest equal relative abundances. Ratios less than 1 indicate the proteins is present in a greater relative abundance in Neurologic Lyme disease compared to Chronic Fatigue. There are 168 proteins in Chronic Fatigue that are 2 fold greater in relative abundance than those proteins Neurologic Lyme disease. There are 1081 proteins that are relatively more abundant in Neurologic Lyme disease compared to Chronic Fatigue with a ratio of 0.5 or less. Blank cell is close to 0 ratio. Clean IPI CF to LD Ratio

00.167619 .00 00004798 .00 00305380 .00 00827846 .00 00025365 .00 0045.5521 .00 00307729 .00 0.0644346 .00 00829980 .00 00219219 .00 00748265 .00 00418169 .00 00171611 .00 00827839 .00 00030634 .00 0001784.1 .00 00011140 .00 0029.0744 .00 00028381 .00 00748890 .00 00816737 .00 00440 153 .00 00298.285 .00 00030877 .00 00024032 .00 00028600 .00 00024107 .00 000261.25 .00 00029061 .00 00006128 .00 00216461 .00 00827929 .00 00830018 .00 00550533 .00 00022389 .00 00382488 .00 00854.624 .00 00477868 .00 00827,580 .00 00328.745 .00 00025,476 .00 00021983 .00 00413641 .00 00394870 .00 00024572 .00 00018769 .00 00024825 .00 00022822 .00 00023751 .00 002898.02 .00 00031765 .00 00004457 .00 00024766 .00 00301631 .00 0047881 6 .00 00.171230 .00 00478997 .00 00306850 .00 0.0218.946 .00 00014371 .00 00305975 .00 0022.1332 .00 0001 6014 .00 00413781 .00 PIOO874156 .00