Special Article Phenotyping, Etiological Factors, and Biomarkers: Toward Precision Medicine in Autism Spectrum Disorders David Q. Beversdorf, MD; MISSOURI AUTISM SUMMIT CONSORTIUM* ABSTRACT: Despite the progress made in understanding the biology of autism spectrum disorder (ASD), effective biological interventions for the core symptoms remain elusive. Because of the etiological hetero- geneity of ASD, identification of a “one-size-fits-all” treatment approach will likely continue to be chal- lenging. A meeting was convened at the University of Missouri and the Thompson Center to discuss strategies for stratifying patients with ASD for the purpose of moving toward precision medicine. The “white paper” presented here articulates the challenges involved and provides suggestions for future solutions. (J Dev Behav Pediatr 37:659–673, 2016) Index terms: autism, biomarkers, precision medicine. Significant progress has been made in understanding Phase II clinical trials.5 This perceived “failure” is likely the biology of autism spectrum disorder (ASD) over the due to the etiological heterogeneity of the subjects with past decade. However, effective biological interventions ASD who received the specific treatment. A review of the for the core symptoms remain elusive. Instead of a single data for the arbaclofen study suggests a strong positive or even a small set of causes, a consensus has emerged response for at least a subset of fragile X and patients with that genetic and environmental causes of ASD are likely ASD. Positive responses in some individuals, but other- multifactorial. The genetic architecture of ASD has be- wise statistically nonsignificant beneficial group effects, come increasingly clear and increasingly complex with are characteristic of most of these early pharmacological estimates of at least 1000 genetic alterations associated treatment trials of ASD. Thus, a critical challenge is to with the risk for ASD.1 These findings hint at starting identify those individuals (or a subset of individuals) who points for patient stratification and precision medicine for may benefit from a particular treatment in a clinical trial. A ASD, and indeed, gene targeting has spawned efforts at meeting was convened on October 18, 2014, at the Uni- clinical trials. For example, research exploring the syn- versity of Missouri and the Thompson Center to foster aptic mechanisms impacted by the fragile X gene in discussions on strategies for stratifying patients with ASD multiple preclinical animal models has led to trials in for the purpose of translating this information to targeted fragile X and ASD with negative modulators of metabo- and individualized experimental therapies, a core princi- tropic glutamate 5 receptors.2 Evidence from other case ple of precision medicine. Attendees agreed that the ul- series3,4 has fostered clinical trials that aim to modulate timate development of biomarkers would allow for glutamatergic and GABAergic functions. Despite the patient stratification in treatment trials and could translate promise of targeted therapies based on a biological ratio- into safer and more effective individualized treatments. nale, much heralded trials with agents such as the GABA B The “white paper” presented here articulates the chal- receptor agonist arbaclofen failed to reveal significant lenges involved in developing better diagnostics and effects for the selected primary outcome measures in treatments based on individual biomarkers, and provides some suggestions for future solutions. From the Departments of Radiology, Neurology, and Psychological Sciences, and the Thompson Center for Autism and Neurodevelopmental Disorders, and COMPLEXITIES OF AUTISM SPECTRUM William and Nancy Thompson Endowed Chair in Radiology, University of DISORDER Missouri, Columbia, MO. Received March 2016; accepted July 2016. Autism spectrum disorder (ASD) encompasses a wide The meeting at University of Missouri and the Thompson Center from which this range of clinical presentations.6,7 Heterogeneity can article was produced was funded by grants from Mizzou Advantage, The Uni- even be observed in the former nomenclature for autism versity of Missouri Chancellor’s Distinguished Visitors Program, the University of Missouri Institute for Clinical and Translational Science (iCATS), and the spectrum disorder, consisting of autistic disorder (im- Thompson Center for Autism and Neurodevelopmental DIsorders. paired communication and socialization, repetitive Disclosure: Since completion of the paper, Daniel Smith has taken a position with behaviors, and onset before age 3), Asperger disorder Blackthorn Therapeutics. The other contributors declare no conflict of interest. (without delays in language or cognitive development), Address for reprints: David Q. Beversdorf, MD, Department of Radiology, Uni- and pervasive developmental disorder—not otherwise versity of Missouri School of Medicine, DC069.10, One Hospital Drive, Columbia, MO 65212; e-mail: [email protected]. specified (features of ASD but not meeting criteria for either autistic disorder or Asperger disorder).8 As a re- Copyright Ó 2016 Wolters Kluwer Health, Inc. All rights reserved. sult, multiple studies have attempted to suitably cluster Vol. 37, No. 8, October 2016 www.jdbp.org | 659 Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. symptoms in large populations. A number of studies have Another approach looked at genetic profiles of specific explored factor analysis to determine the structure of symptoms, such as impaired social communication,28 symptoms, focusing on “core features” of ASD, revealing and yet others have found evidence that the core deficits a variety of sets of clusters, but overall suggesting that are genetically heterogeneous.29 social/communication issues may be distinct from re- Clearly, subtyping of ASD according to the cause or stricted and repetitive behaviors and interests.9 Another pathobiology could be highly relevant to individualized recent study identified 4 phenotypic clusters and found treatment. With at least several hundred to 1000 that they varied in short-term prognosis regarding di- different genes1,30 estimated to play a role in ASD risk, agnostic stability.10 To understand how ASD-related development of a “one-size-fits-all” pharmacological in- characteristics are manifested in the general pop- tervention would be tremendously challenging. Some of ulation, one recent study clustered 2343 cases based on these genes contain rare variants with high penetrance the autism spectrum quotient (AQ), revealing 2- and 3- and are directly involved in the cause of ASD, whereas factor solutions varying in combinations of severity of other genes serve as risk factors for ASD that may act in impairments in socialization, mentalizing, and orienta- concert with other genetic or environmental risk fac- tion to detail.11 tors.1,31–34 Some individuals who harbor such variable Autism spectrum disorder can also be associated with penetrance variants develop ASD, whereas others har- a range of co-occurring medical and/or psychiatric con- boring the same variants do not. In most cases, no genetic ditions, including seizures, gastrointestinal conditions, factor is identified to contribute to the diagnosis. In- sleep disturbances, aggressive behaviors, anxiety symp- creasing recognition of environmental factors that seem to toms, and attentional deficits. These conditions may or contribute to ASD may impact a cause–phenotype map. may not be associated with cognitive impairment. One Therefore, a detailed assessment of factors in ASD that recent study also incorporated co-occurring medical and would be potentially meaningful in guiding a precision biological variables in the generation of data-driven medicine approach must also explore a range of factors phenotypic clusters, revealing clusters for (1) circadian beyond genotype and clinical phenotype.35 Finally, it is and sensory dysfunction, (2) immune abnormalities, (3) not yet known whether the heterogeneity of ASD in this neurodevelopmental delay, and (4) stereotypic behaviors context is represented by continuous variability on mul- in one analysis of ASD-associated features.12 Although tiple dimensions or is represented by clusters, which may the best course of treatment is clear for some of these also have implications for treatment. conditions (i.e., treat seizures with antiepileptic drugs), it is not known how these various co-occurring pheno- WHAT IS A “BIOMARKER”? ARE BIOMARKERS typic aspects might relate to potential targeted treatment FOR A BEHAVIORAL CONDITION SUCH AS ASD of the core features. Several studies have assembled a rich phenotypic da- DEFINED THE SAME WAY AS THOSE FOR A tabase in cases in which genetic information is available, DISEASE SUCH AS CANCER? yielding a set of genotype–phenotype clusters.13–15 Ad- Biological markers, or “biomarkers,” are broadly de- ditionally, “complex autism,” characterized by the pres- fined as a characteristic that is objectively measured and ence of prominent dysmorphic features suggesting evaluated as an indicator of normal biological processes, altered early morphogenesis, has been found to be as- pathogenic processes, or pharmacological responses to sociated with greater impairment and a markedly higher a therapeutic intervention.36 For autism spectrum disor- rate of chromosomal disorders or broader syndromic der (ASD), a broad range of candidates could be con- conditions in which ASD is a common manifestation.16,17