REVIEW

P4 or O4 Medicine? Hippocrates Provides the Answer

Clare Fiala,1 Jennifer Taher,2,3 and Eleftherios P. Diamandis1,2,3*

Background: The term P4 medicine (predictive, preventative, personalized, participatory) was coined Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 by Dr. Leroy Hood of the Institute for Systems Biology to demonstrate his framework to detect and prevent through extensive biomarker testing, close , deep statistical analysis, and patient health coaching. Methods: In 2017, this group published the results of their “100 Person Wellness Project.” They performed and 218 clinical laboratory tests, measured 643 metabolites and 262 proteins, quantified 4616 operational taxonomic units in the microbiome, and monitored exercise in 108 partici- pants for 9 months. The study was also interventional, as members were paired with a coach who gave lifestyle and supplement counseling to improve biomarker levels between each sampling period. Results: Using this study as a basis, we here analyze the Hippocratic roots and the advantages and disadvantages of P4 medicine. We introduce O4 medicine (overtesting, overdiagnosis, overtreatment, over- charging) as a counterpoint to P4 medicine to highlight the drawbacks, including possible harms and cost. Conclusions: We hope this analysis will contribute to the discussion about the best use of limited health-care resources to produce maximum benefit for all patients.

IMPACT STATEMENT New technological advancements now allow for extensive testing, sometimes done outside traditional laboratories, aiming to diagnose early disease. The premise is that this testing can lead to better health outcomes. We here draw attention that such testing may also have harmful effects. We introduce the concept of O4 medicine, which stresses overtesting, overdiagnosis, overtreat- ment, and overcharging. We hope that by moderating the enthusiasm of technology-driven testing we will help to facilitate optimal use of current resources, reap the benefits, and minimize harms.

1Department of and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 3Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada. *Address correspondence to this author at: Mount Sinai Hospital and University Health Network, 60 Murray St., Box 32, Fl. 6, Rm. L6-201, Toronto, ON, M5T 3L9, Canada. E-mail [email protected]. DOI: 10.1373/jalm.2018.028613 © 2019 American Association for 4 Nonstandard abbreviations: ISB, Institute for Systems Biology; HPV, human papilloma virus; PSA, prostate-specific antigen. 5 Human : APOE, apolipoprotein E; MTHFR, methylenetetrahydrofolate reductase; HFE, homeostatic iron regulator.

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In 2000, Dr. Leroy Hood founded the Institute received the same advice that is widely given for Systems Biology (ISB)4, an American nonprofit without such testing: take vitamin D supplements, research institution. Systems biology espouses a exercise frequently, and eat healthily (6). One computational and modeling approach to com- symptomatic individual received significant benefit plex biological systems, particularly the human directly derived from the study: A combination of body (1). The ISB aims to harness this framework to limited mobility, high ferritin levels, and a genetic accelerate biomarker discovery, drug develop- risk of developing hemochromatosis led investiga- ment, targeted invention, and even drive tors to refer the 65-year-old man to a policy change (2). P4 medicine is the clinical mani- who discovered cartilage damage and confirmed Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 festation of systems biology and stands for predic- the diagnosis of hereditary hemochromatosis (6). tive, preventative, personalized, and participatory Despite lukewarm results and some method- medicine (3, 4). ological weaknesses (e.g., lack of a control group), The 100K Wellness Project is the ISB's flagship this study formed the basis for the spin-out com- venture to affirm P4 medicine's 2 broad goals of pany Arivale. Founded in 2015, the firm bills itself “quantifying wellness and demystifying disease” as a pioneer of the nascent “scientific wellness” (5). The project aims to revolutionize health care industry. It now offers similar, although reduced, and showcase the ISB's systems biology vision by services to customers, including biannual blood amassing and analyzing vast amounts of partici- testing for more than 40 blood markers, genome pant biological data and providing actionable in- sequencing, activity monitoring, and monthly coach- sights through individualized coaching (5). In 2017, ing for $199/month (7). this group published the results of a preliminary longitudinal study, the 100 Person Wellness Proj- ROOTS OF P4 MEDICINE ect, which tracked 108 individuals for 9 months (6). The investigators compiled what the article calls The founding of Arivale represents a significant “personal, dense, dynamic data clouds” including a investment into P4 medicine, but limited analysis participant's full genome sequence and analysis of has been conducted on the P4 medicine concept blood, urine, saliva, and microbiome (stool) sam- itself. Furthermore, although the term P4 medicine ples, which were tested for 643 metabolites and was introduced in the literature in 2011 (3), many 262 proteins every 3 months. Participants were of its principles can be connected to Hippocratic also equipped with a Fitbit for exercise and sleep fourth century BCE teachings (8). monitoring and completed health history forms Hippocrates's conception of the human body and surveys. The study was also interventional was not unlike that of system biologists today; he given that individuals received test results and life- described it as “one unified organism to be consid- style advice from dieticians or nurses in monthly ered as one coherent and integrated whole.” This coaching sessions to try to improve their bio- framework allowed him to interpret disease in a marker levels between testing rounds (6). novel way and view health and sickness as a con- However, the reams of this extensive and expen- tinuum, just like P4 medicine proponents. Hippo- sive testing and coaching, in our estimation, did crates wrote “ never affect only one part of not produce particularly groundbreaking results. the body, they affect the health balance of all [the] The study identified 81 participants with increased body” (8). Consequently, he focused on interpret- mercury levels, 95 with relatively low vitamin D lev- ing present trends of each sickness and the pa- els, and 52 were considered prediabetic, all to be tient's physical and social environment to predict expected in an American population. Yet, they illness progression. In doing so, he declared, “the

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best physician is one who can prevent and predict (9). Although certainly knowing a patient's geno- diseases,” which bears strong parallels with 21st type would generally be far less useful than under- century P4 medicine's emphases on prediction standing their symptoms through an examination and prevention (8). or medical history, this dramatic decrease in price With his emphasis on careful examination and provides context to the increasing use of genetic deep knowledge of the patient's past and environ- testing and its pride of place in P4 medicine and ment, Hippocrates revolutionized medicine. He . In the next section, we saw each person as an individual case and focused break P4 medicine down into its components and on gathering as much information about each pa- explore each P's benefits and fallacies, with exam- Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 tient as possible, proclaiming “he who administers ples of both success and failures. therapy must first know the whole man as a unique psychosomatic entity in relation to his social and ANALYSIS OF P4 MEDICINE natural environment” (8). In these ways, he was practicing personalized medicine, millennia before P4 systems biology and other highly publicized Preventive personalized medicine initiatives. The first “P” of P4 medicine is preventive, in Finally, patient and family participation was an- which individuals are equipped to recognize early other key element of Hippocrates's practice. He disease when it could be reversed or more easily saw the physician as fighting the disease concur- treated (10). Some preventative measures have rently with their patient (participatory) and advised been highly successful. Healthy eating and exer- other to continually consult with pa- cise habits have been linked with decreased tients and their families (8). disease incidence since Hippocrates's time; he be- Hippocrates espoused 2 more properties not lieved that walking is the best form of exercise. covered in P4 medicine—safety and affordabil- These conclusions are echoed in emerging re- ity—by not charging or refusing medical care. search on the link between obesity and the devel- Safety is enshrined in the Hippocratic oath to “do opment of certain cancers. A 2007 US study no harm.” However, we later argue that P4 medi- estimated that 16000 cases of endometrial can- cine's mandate of comprehensive testing can be cer, 13000 of postmenopausal , and damaging because of stress and potential false re- 9000 of colorectal cancers could be attributed to sults. Additionally, this testing compromises P4 obesity (11, 12). Several studies have shown that medicine's affordability, making it available for only dramatic weight loss (e.g., through bariatric sur- the rich. gery) leads to a significant decrease in cancer The examples from Hippocrates show P4 medi- incidence (13–15). Weight loss through lifestyle cine at its core is not a 21st century invention. changes has also been linked to lower rates of en- However, the acronym and usage of modern tech- dometrial and breast cancer (16, 17). nologies is original. Indeed, during the past de- Another preventative measure is smoking ces- cades, medicine has begun to diverge dramatically sation, which dramatically lowers an individual's from Hippocrates's time with the invention of new risk of developing cancer (18–20). Five years after technologies such as genomic, proteomic, and quitting smoking, ex-smokers are half as likely as other omics assays. According to Lu et al., it has current smokers to develop cancers of the mouth, recently become less expensive to sequence a pa- throat, esophagus, and bladder (21, 22). Within this tient's genome (genotyping) than to perform phe- time, their cervical cancer risk falls to that of a non- notyping (e.g., physical examination and history) smoker (21, 22). After 10 smoke-free years, the

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chance of developing lung cancer is halved, and decrease disease mortality and morbidity (31–36). the risk for cancers of the larynx and pancreas is A recent ex post analysis of 28797 patients decreased (23, 24). showed that detecting cervical cancer at stage 1 Vaccination for disease prevention represents cytology screening can save the health system another of the triumphs of modern medicine, with $4000 per case compared with a later stage diag- the eradication of once-deadly diseases and con- nosis (37). Cervical cancer screening programs are trol of others. The human papilloma virus (HPV) common worldwide, and innovative approaches vaccine has shown promising results for cervical are being introduced to bring this life-saving inter- cancer prevention. A recent major review of 26 vention to countries with less funded health sys- Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 studies encompassing 73428 women showed that tems (38, 39) and underserved populations (40, vaccines reduced the risk of cervical precancer as- 41). sociated with HPV16/18 from 341 to 157 per However, some screening programs have 10000 in women 15 to 26 years of age (25). HPV achieved less than optimal results. Prostate can- vaccination also decreased the risk for any precan- cer is a leading cause of in men. Prostate- cer lesions from 559 to 391 per 10000 women (25) specific antigen (PSA) screening has been widely and may also reduce the risk of anal cancer, par- available since the 1980s, but there is growing con- ticularly in men who have sex with men (26, 27). troversy about its utility (42, 43). It has been shown Novel vaccines are also being discussed. There is that increased PSA levels do not necessarily indi- currently investigation to develop vaccines for pre- cate cancer and low PSA levels do not always indi- vention of atherosclerosis that target the enzyme cate the patient is cancer free (44). A recent study PCSK9 (proprotein convertase subtilisin/kexin) in- of 408825 men, 50 to 69 years of age, detected volved in regulating circulating cholesterol levels prostate cancer in 4.3% of men who received PSA (28). testing and in 3.6% of the control group who did Despite these encouraging statistics, other can- not receive a PSA test. However, a 10-year follow-up cer and noncancer preventative measures have period showed there was no significant impact on been far less effective. Although preventive medi- prostate cancer mortality (45). cine has been practiced for millennia, a major rea- This study is another addition to the growing son it is not used more often is that there are no body of evidence against PSA testing for prostate effective preventive measures against some seri- cancer. Even if cancer is accurately detected, there ous diseases (e.g., Alzheimer disease). are still conflicting opinions about how to address the tumor and whether to engage in watchful wait- Predictive ing and active surveillance or pursue treatment Predictive medicine involves identifying genetic that can have significant side effects (46, 47). and other risks for disease and knowing and plan- Personalized ning for the effects of illnesses in advance (10). There have been some significant successes in this In personalized medicine, care and treatments effort. Neonatal screening for are heavily focused on the individual (10). They are and congenital hypothyroidism has resulted in sig- often guided by the patient's genome, particularly nificant decreases in infant mortality and morbidity now that it can be sequenced for $1000 (48). This (29). Additionally, prenatal screening for aneup- approach has had some impressive successes in loidies is also highly accurate (30). precision with the development of tar- Cervical cancer screening through Pap smears geted cancer treatments. The approval of the in asymptomatic women has long been known to breast cancer drug Herceptin (trastuzumab) in

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1998 and leukemia drug Gleevec (imatinib) in 2001 The conditions screened for by P4 medicine in led to a burst in the development of targeted ther- the 100 Person Wellness Project are vaguely de- apies, some that work across multiple tumor types fined as arising from “transition from wellness to (49). A 2018 study of 610000 patients with meta- disease” (6). To detect these “transitions,” the study static cancer found that 15.4% of patients were screened for scores of biomarkers with the aim of eligible for a genome-targeted drug approved by detecting any discrepancy. However, not screen- the US Food and Drug Administration (50). How- ing for a defined condition violates the Wilson and ever, the analysis also showed that only 6.6% likely Jungner criteria, given that there is no recognizable benefitted because the drugs do not work for all latent or early symptomatic stage, nor an agreed- Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 eligible patients. More research and investment are upon policy regarding whom to treat as patients. clearly needed for personalized medicine to reach its Moreover, randomly testing for disease is also full potential. The real benefits of personalized can- not an important problem with a known natural cer treatments in terms of cost-effectiveness are still history. hotly debated, as some argue that despite the hype, The 100 Person Wellness Project continues to the benefits are small, and treatments are expensive fail the Wilson and Jungner screening criteria be- or unsustainable (51). cause there is no evidence for the efficacy of this approach beyond the 1 study. Thus, there can be Participatory no indication of screening program effectiveness Participatory is the final component of P4 medi- or a suitable acceptable test. The overall benefits cine. Patients are well involved and actively partic- of this approach cannot outweigh the harms, as ipate in their own care, making medicine more the lack of a clear disease would likely lead to overt- efficient (10). A major benefit of this approach is esting and overdiagnosis. In this way, P4 medicine empowering patients, which can benefit the pa- of the 100 Person Wellness Project also fails the tient–physician relationship by inspiring trust and Wilson and Jungner quality assurance criterion be- cooperation. Recently, most institutions allow pa- cause there are no mechanisms to minimize the tients to view their laboratory and other results potential risks of screening. This analysis points to online, contemporaneously with the attending cli- some crucial flaws in the P4 medicine paradigm nician and discuss with them for management that we address in our O4 medicine concept. In planning. Nowadays, clinicians consider patients short, despite potential benefits, the concept of P4 as part of the care team and use full transparency. medicine is based on intuition that it should work, These recent developments represent a triumph but the evidence for its effectiveness is still lacking. of participatory medicine. INTRODUCTION TO O4 MEDICINE P4 MEDICINE AS SCREENING Here, we introduce O4 medicine (overtesting, Testing asymptomatic individuals as per Arivale's overdiagnosis, overtreatment, overcharging) as a framework is equivalent to population screening. counterpoint to the P4 concept. This framework In 1968, Wilson and Jungner developed the original aims to elucidate the possible downsides and dis- World Health Organization criteria for population advantages of embracing P4 medicine. The criti- screening (52). We use the only published study on cism is not intended to bash new technology, resist P4 medicine, from the 100 Person Wellness Proj- progress, or antagonize pioneers, but rather to ect, as an indicator of what P4 medicine looks like prompt an informed discussion about the current in practice (6). limitations of genetic and wellness testing (53, 54).

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Table 1. Glossary of terms discussed in O4 medicine section.

Term Definition Overtesting Testing done because it is technically possible, not because it is proven useful Overdiagnosis Diagnosis of a disease that would otherwise never become clinically apparent or pose a threat to patient's life Overtreatment The consequences of overdiagnosis; treatment of a disease that would otherwise never become clinically apparent or pose a threat to patient's life Incidental findings Findings unveiled during testing for alternative reasons

Indolent disease A disease that would otherwise never become clinically apparent Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021

Table 1 contains a glossary of terms discussed in he had a linked to Lynch syndrome, which this section, and the caveats of screening asymp- increased his chance of developing several types of tomatic individuals are summarized in Fig. 1. cancers. Fortunately, he had the medical insight to know that false-positive findings were common with Overtesting these tests, as well as the means to send another Overtesting occurs when (often healthy) individ- sample to a company with experience in diagnostics. uals receive tests that are unlikely to be useful to He eventually received the reassuring news that he them. This increases the risk of stress induced by did not have the mutation. This is a classic example false-positive results and requires additional, often showing how overtesting can be expensive, stressful, invasive and expensive, testing to resolve. and simply inaccurate. The medical resident was 1 of The New York Times recently reported the dis- likely thousands, if not millions, of similar cases that turbing case of an American medical resident who occurred or will occur in the future because of wide- sent his saliva to a commercial genome sequenc- spread patient-initiated testing. ing service to discover his predisposition to various In 2014, an analysis of 406 published severe dis- genetic diseases (55). The firm's results indicated ease was performed. It was found that

Fig. 1. Results from screening asymptomatic individuals. Green represents benefits, and orange represents disadvantages.

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122 (27%) were either common polymorphisms or programs: For example, between 35% and 51% of lacked sufficient evidence for pathogenicity (56). men have microfoci of prostate cancer at autopsy Numerous supposed disease-causing mutations (61–63). If these tumors had been discovered while were also found in the genomes of “healthy” con- the men were alive, it could have led to unwar- trols. Thus, there are fundamental problems that ranted expensive interventions such as reach beyond the tests themselves, regardless of and imaging. Although the findings may some- false-positive or -negative findings. This introduces times be useful (e.g., finding an early-stage pancre- new concerns that even if an assay functions cor- atic cancer), overdiagnosis generally does more Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 rectly, it will likely yield many results of unknown harm than good and leads to overtreatment. significance, confusing the patients on what to do next. Overtreatment Moreover, even if 100% accurate and testing for the correct variants, whole genome sequencing Overtreatment stems from overdiagnosis. A typ- may not accurately predict disease risk. It is widely ical example of overtreatment would be a radical known that for most diseases environmental fac- prostatectomy in an 80-year-old man with low- tors are at least as important, if not more domi- grade prostate cancer. Not only is the itself nant, than genetic predisposition. In short, painful and unpleasant, but the patient may also pathogenic variants can produce highly variable experience incontinence and impotence. All this, phenotypes for which treatments may not be ben- and the patient will likely receive no therapeutic eficial and may provoke anxiety in patients and benefit from the procedure (64). their families, as well as put stress on the medical Less treatment is often more beneficial and has system (57, 58). fewer side effects. A recent study of 731 prostate cancer patients recorded a 50% reduction in over- Overdiagnosis all mortality in patients who underwent radical Overdiagnosis is a side effect of testing and oc- prostatectomy and a 47% reduction in those ran- curs when a patient is diagnosed with a “disease” domized for observation (64). Active surveillance that is asymptomatic and will never cause prob- has been shown as a safe management option for lems in their lifetime (59). men ≥55 years of age with Gleason 6/low tumor A classic example of overdiagnosis is the inci- volume for at least 10 to 15 years (64, 65). Similarly, dentaloma: a mass found on an imaging study un- in breast cancer, it has been shown that lumpec- related to the symptoms for which the scan was tomy and mastectomy do not differ in terms of ordered. This phenomenon is applicable to labo- outcome for women with stage I or stage II disease ratory medicine when incidental findings are dis- (66). covered when screening (e.g., blood tests) for other reasons. Similar to incidentalomas, inciden- Overcharging tal findings are becoming common with next- generation sequencing tests (60). Finally, overcharging is the compound result of Although screening may uncover clinically signif- overtesting, overdiagnosis, and overtreatment. In- icant cases that can benefit from early treatments, appropriate tests and procedures burden the even established screening programs report large medical system and waste clinician time. To re- numbers of positive results with uncertain signifi- ceive these unserviceable interventions, patients cance (59). Other examples of overdiagnosis can must generally take off time from work or other be found outside of traditional screening activities, resulting in a loss of productivity.

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CHOOSING WISELY informatic research has also shown that coding key security is often deceptive, and participants are not The Choosing Wisely movement was founded in adequately informed of risks to confidentiality (70). 2012 in the US by the American Board of Internal The affordability issues surrounding P4 medi- Medicine (67, 68). It grew out of the concerns that cine have been discussed in some depth in the overtesting, overdiagnosing, overtreating, and over- previous sections. We would like to mention an- charging were having on tax payers, the health-care other concern: Not being able to afford the most system, and patients. The organization educates cli- suitable diagnostic path may lead to correlated fi- nicians, health-care professionals, and patients on nancial discrimination and inequitable medicine. Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 reducing unnecessary tests and procedures. More Would the resulting absence of these data owing than 540 specialty societies have contributed lists on to affordability undermine the complex computa- interventions that are generally overprescribed and tional system that interprets genotypes and meta- clinically unwarranted. bolic pathways? Could it worsen the gap between The recommendations from the American medical care received by individuals at different College of and are rel- income brackets? evant to this discussion as well. They advise against Furthermore, a central pillar of P4 medicine in ordering APOE5 testing as a predictive test for the 100 Person Wellness Project is individualized Alzheimer disease, MTHFR testing as a risk assess- coaching (10). We do not think that it would be ment for hereditary thrombophilia, HFE genetic feasible to extend this to the general population. testing unless indicated by iron overload or family Without coaching, it would be challenging for pa- history, and duplicate unless there tients to understand the reams of data created by is ambiguity about the validity of the test result P4 medicine. This could lead to confusion and (69). In the P4 proof-of-concept study, all 108 par- stress that would require significant health practi- ticipants were screened for the HFE mutation re- tioner time and resources to assuage. gardless of family history or predisposition to To maximize physician time, Choosing Wisely, hereditary hemochromatosis (6). This is just 1 ex- the Society of General , and the ample showing how the P4 medicine approach College of Family Physicians of Canada have rec- and other wellness initiatives could be wasteful to ommended eliminating routine annual checkups, the health-care system (6). including a physical examination and laboratory tests for healthy asymptomatic individuals who do GENERAL PROBLEMS WITH P4 MEDICINE not have a chronic medical condition or other health concerns or risk factors (71–73). In 2017, the Although espousing P4 medicine could be ben- Canadian Task Force on Preventative Health Care eficial, there are also fundamental problems with concluded that “Annual checkups do not result in the framework, such as data confidentiality and af- better health outcomes” and instead advise that fordability. Just a decade ago, patient information health-care providers prioritize “periodic visits to was exclusively kept as hard copies in physician primary care physicians for specific prevention ac- offices. Now, the huge amount of data required for tivities” (74). P4 medicine presents new challenges for patient privacy. First, DNA in itself is an individual identifier. CONCLUSION Increasingly detailed genotypic and phenotypic information is now being collected and widely It is important to evaluate the work of pioneers shared among investigators. Some medical by carefully analyzing their premise, costs, findings,

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and applications. O4 medicine (overtesting, overdi- charged to be study participants, to access a ser- agnosis, overtreatment, overpayment) is meant to vice that has currently limited evidence for its ef- highlight the possible problems with P4 medicine fectiveness. (predictive, preventative, participatory, personalized). A larger sample may exacerbate the already ex- The ISB is not the only group seeking to utilize isting problems with the study. More participants big data from large groups of participants to pro- would lead to more false results, rather than fewer. vide insights into health and wellness. In 2017, Moreover, if the disease being screened for is rare, Alphabet (Google's parent company) launched the the positive predictive value will be low even if the Project Baseline study that aims to develop a ref- testing procedure is highly sensitive and specific. Downloaded from https://academic.oup.com/jalm/article/4/1/108/5603054 by guest on 27 September 2021 erence point for good health and identify risk fac- As we described in an earlier commentary (76), tors for disease (75). They are recruiting 10000 the only way to conclusively find the benefitof people who will undergo blood and urine tests, medical revolutions or new technologies is by con- contribute health records, fill out health surveys, ducting prospective, controlled clinical trials and and wear smartwatches and sleep sensors that will not offering testing or services to patients unless transmit exercise and heart rate information to a they are proven to work. This is the essence of central database. NIH is planning a million-person evidence-based medicine (80). To effectively address mega-study with similar goals and methodology to the issue of random testing to identify occult disease, Project Baseline (76). The Lake Nona Life Project is 1 clinician mentioned that the Hippocratic oath centered around a community in Florida and in- should be modified to include this statement against vites residents and workers to fill out yearly sur- overtesting: I will not request an investigation unless veys about their health and wellness to gain Iamconfident that the answer and the actions I take insights into insomnia, , stress, and the on its basis will substantially improve my patient's life long-term benefits of active living (77). (81). The ISB stated that they wished to expand the In closing, we do not exclude the possibility that testing offered in their 100 Person Wellness Study additional technological innovations may one day to a larger cohort to find more “transitions from lead to medicine that predicts most, if not all, dis- wellness to disease for many common diseases, as eases noninvasively within a window that allows well as transitions to improved health” (6). This preventative effective measures. But until that day came to fruition with the founding of Arivale (de- comes, actionable interventions should be se- scribed in the Introduction) (78). Ninety-six percent lected only if there is evidence for their overall ben- of clients have given their anonymized data for ISB efit over harms of the patient. We have no question research (79). Notably, clients are effectively that Hippocrates would agree with this suggestion.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved.

Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Employment or Leadership: None declared. Consultant or Advisory Role: E.P. Diamandis, Abbott Diagnostics. Stock Ownership: None declared. Honoraria: None declared. Research Funding: None declared. Expert Testimony: None declared. Patents: None declared.

Role of Sponsor: No sponsor was declared. Acknowledgments: The authors thank Annie H. Ren for help with conception and design of the figures.

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