Game theoretic centrality: a novel approach to prioritize disease candidate genes by combining biological networks with the Shapley value.
2020; 21 (1): 356
BACKGROUND: Complex human health conditions with etiological heterogeneity like Autism Spectrum Disorder (ASD) often pose a challenge for traditional genome-wide association study approaches in defining a clear genotype to phenotype model. Coalitional game theory (CGT) is an exciting method that can consider the combinatorial effect of groups of variants working in concert to produce a phenotype. CGT has been applied to associate likely-gene-disrupting variants encoded from whole genome sequence data to ASD; however, this previous approach cannot take into account for prior biological knowledge. Here we extend CGT to incorporate a priori knowledge from biological networks through a game theoretic centrality measure based on Shapley value to rank genes by their relevance-the individual gene's synergistic influence in a gene-to-gene interaction network. Game theoretic centrality extends the notion of Shapley value to the evaluation of a gene's contribution to the overall connectivity of its corresponding node in a biological network.RESULTS: We implemented and applied game theoretic centrality to rank genes on whole genomes from 756 multiplex autism families. Top ranking genes with the highest game theoretic centrality in both the weighted and unweighted approaches were enriched for pathways previously associated with autism, including pathways of the immune system. Four of the selected genes HLA-A, HLA-B, HLA-G, and HLA-DRB1-have also been implicated in ASD and further support the link between ASD and the human leukocyte antigen complex.CONCLUSIONS: Game theoretic centrality can prioritize influential, disease-associated genes within biological networks, and assist in the decoding of polygenic associations to complex disorders like autism.
View details for DOI 10.1186/s12859-020-03693-1
View details for PubMedID 32787845
Feature Selection and Dimension Reduction of Social Autism Data.
Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing
2020; 25: 707–18
Autism Spectrum Disorder (ASD) is a complex neuropsychiatric condition with a highly heterogeneous phenotype. Following the work of Duda et al., which uses a reduced feature set from the Social Responsiveness Scale, Second Edition (SRS) to distinguish ASD from ADHD, we performed item-level question selection on answers to the SRS to determine whether ASD can be distinguished from non-ASD using a similarly small subset of questions. To explore feature redundancies between the SRS questions, we performed filter, wrapper, and embedded feature selection analyses. To explore the linearity of the SRS-related ASD phenotype, we then compressed the 65-question SRS into low-dimension representations using PCA, t-SNE, and a denoising autoencoder. We measured the performance of a multilayer perceptron (MLP) classifier with the top-ranking questions as input. Classification using only the top-rated question resulted in an AUC of over 92% for SRS-derived diagnoses and an AUC of over 83% for dataset-specific diagnoses. High redundancy of features have implications towards replacing the social behaviors that are targeted in behavioral diagnostics and interventions, where digital quantification of certain features may be obfuscated due to privacy concerns. We similarly evaluated the performance of an MLP classifier trained on the low-dimension representations of the SRS, finding that the denoising autoencoder achieved slightly higher performance than the PCA and t-SNE representations.
View details for PubMedID 31797640
Data-Driven Diagnostics and the Potential of Mobile Artificial Intelligence for Digital Therapeutic Phenotyping in Computational Psychiatry.
Biological psychiatry. Cognitive neuroscience and neuroimaging
Data science and digital technologies have the potential to transform diagnostic classification. Digital technologies enable the collection of big data, and advances in machine learning and artificial intelligence enable scalable, rapid, and automated classification of medical conditions. In this review, we summarize and categorize various data-driven methods for diagnostic classification. In particular, we focus on autism as an example of a challenging disorder due to its highly heterogeneous nature. We begin by describing the frontier of data science methods for the neuropsychiatry of autism. We discuss early signs of autism as defined by existing pen-and-paper-based diagnostic instruments and describe data-driven feature selection techniques for determining the behaviors that are most salient for distinguishing children with autism from neurologically typical children. We then describe data-driven detection techniques, particularly computer vision and eye tracking, that provide a means of quantifying behavioral differences between cases and controls. We also describe methods of preserving the privacy of collected videos and prior efforts of incorporating humans in the diagnostic loop. Finally, we summarize existing digital therapeutic interventions that allow for data capture and longitudinal outcome tracking as the diagnosis moves along a positive trajectory. Digital phenotyping of autism is paving the way for quantitative psychiatry more broadly and will set the stage for more scalable, accessible, and precise diagnostic techniques in the field.
View details for DOI 10.1016/j.bpsc.2019.11.015
View details for PubMedID 32085921
Validity of Online Screening for Autism: Crowdsourcing Study Comparing Paid and Unpaid Diagnostic Tasks.
Journal of medical Internet research
2019; 21 (5): e13668
BACKGROUND: Obtaining a diagnosis of neuropsychiatric disorders such as autism requires long waiting times that can exceed a year and can be prohibitively expensive. Crowdsourcing approaches may provide a scalable alternative that can accelerate general access to care and permit underserved populations to obtain an accurate diagnosis.OBJECTIVE: We aimed to perform a series of studies to explore whether paid crowd workers on Amazon Mechanical Turk (AMT) and citizen crowd workers on a public website shared on social media can provide accurate online detection of autism, conducted via crowdsourced ratings of short home video clips.METHODS: Three online studies were performed: (1) a paid crowdsourcing task on AMT (N=54) where crowd workers were asked to classify 10 short video clips of children as "Autism" or "Not autism," (2) a more complex paid crowdsourcing task (N=27) with only those raters who correctly rated ≥8 of the 10 videos during the first study, and (3) a public unpaid study (N=115) identical to the first study.RESULTS: For Study 1, the mean score of the participants who completed all questions was 7.50/10 (SD 1.46). When only analyzing the workers who scored ≥8/10 (n=27/54), there was a weak negative correlation between the time spent rating the videos and the sensitivity (rho=-0.44, P=.02). For Study 2, the mean score of the participants rating new videos was 6.76/10 (SD 0.59). The average deviation between the crowdsourced answers and gold standard ratings provided by two expert clinical research coordinators was 0.56, with an SD of 0.51 (maximum possible SD is 3). All paid crowd workers who scored 8/10 in Study 1 either expressed enjoyment in performing the task in Study 2 or provided no negative comments. For Study 3, the mean score of the participants who completed all questions was 6.67/10 (SD 1.61). There were weak correlations between age and score (r=0.22, P=.014), age and sensitivity (r=-0.19, P=.04), number of family members with autism and sensitivity (r=-0.195, P=.04), and number of family members with autism and precision (r=-0.203, P=.03). A two-tailed t test between the scores of the paid workers in Study 1 and the unpaid workers in Study 3 showed a significant difference (P<.001).CONCLUSIONS: Many paid crowd workers on AMT enjoyed answering screening questions from videos, suggesting higher intrinsic motivation to make quality assessments. Paid crowdsourcing provides promising screening assessments of pediatric autism with an average deviation <20% from professional gold standard raters, which is potentially a clinically informative estimate for parents. Parents of children with autism likely overfit their intuition to their own affected child. This work provides preliminary demographic data on raters who may have higher ability to recognize and measure features of autism across its wide range of phenotypic manifestations.
View details for DOI 10.2196/13668
View details for PubMedID 31124463
Outgroup Machine Learning Approach Identifies Single Nucleotide Variants in Noncoding DNA Associated with Autism Spectrum Disorder
WORLD SCIENTIFIC PUBL CO PTE LTD. 2019: 260–71
View details for Web of Science ID 000461866400024
Analysis of Sex and Recurrence Ratios in Simplex and Multiplex Autism Spectrum Disorder Implicates Sex-Specific Alleles as Inheritance Mechanism
IEEE. 2018: 1470–77
View details for Web of Science ID 000458654000258