Nathaniel Stockham

All Publications

• The human "contaminome": bacterial, viral, and computational contamination in whole genome sequences from 1000 families. Scientific reports Chrisman, B., He, C., Jung, J., Stockham, N., Paskov, K., Washington, P., Wall, D. P. 2022; 12 (1): 9863

  Abstract

  The unmapped readspace of whole genome sequencing data tends to be large but is often ignored. We posit that it contains valuable signals of both human infection and contamination. Using unmapped and poorly aligned reads from whole genome sequences (WGS) of over 1000 families and nearly5000 individuals, we present insights into common viral, bacterial, and computational contamination that plague whole genome sequencing studies. We present several notable results: (1) In addition to known contaminants such as Epstein-Barr virus and phiX, sequences from whole blood and lymphocyte cell lines contain many other contaminants, likely originating from storage, prep, and sequencing pipelines. (2) Sequencing plate and biological sample source of a sample strongly influence contamination profile. And, (3) Y-chromosome fragments not on the human reference genome commonly mismap to bacterial reference genomes. Both experiment-derived and computational contamination is prominent in next-generation sequencing data. Such contamination can compromise results from WGS as well as metagenomics studies, and standard protocols for identifying and removing contamination should be developed to ensure the fidelity of sequencing-based studies.

  View details for DOI 10.1038/s41598-022-13269-z

  View details for PubMedID 35701436

• Causal Modeling to Mitigate Selection Bias and Unmeasured Confounding in Internet-Based Epidemiology of COVID-19: Model Development and Validation. JMIR public health and surveillance Stockham, N., Washingon, P., Chrisman, B., Paskov, K., Jung, J. Y., Wall, D. P. 2022

  Abstract

  Selection bias and unmeasured confounding are fundamental problems in epidemiology that threaten study internal and external validity. These phenomena are particularly dangerous in internet-based public health surveillance where traditional mitigation and adjustment methods are inapplicable, unavailable, or out of date. Recent theoretical advances in causal modeling can mitigate these threats, but these innovations have not been widely deployed in the epidemiological community.The purpose of our paper is to demonstrate the practical utility of causal modeling to both detect unmeasured confounding and selection bias and also guide model selection to minimize bias. We implement this approach in an applied epidemiological study of COVID-19 cumulative infection rate in the New York City Spring 2020 epidemic.We collected primary data from Qualtrics surveys of Amazon Mechanical Turk crowd workers residing in New Jersey and New York state across two sampling periods; April 11-14th and May 8-11th 2020. The surveys queried the subjects on household health status and demographic characteristics. We constructed a set of possible causal models of household infection and survey selection mechanisms and ranked them by compatibility with the collected survey data. The most compatible causal model was then used to estimate the cumulative infection rate in each survey period.There were 527 and 513 responses collected for each period. Response demographics were highly skewed toward younger age in both survey periods. Despite the extremely strong relationship between age and COVID-19 symptoms we recovered minimally biased estimates of cumulative infection rate using only primary data and the most compatible causal model, with a relative bias of +3.8% and -1.9% from the reported cumulative infection rate for the first and second survey periods.We successfully recovered accurate estimates of cumulative infection rate from an internet-based crowd sourced sample despite considerable selection bias and unmeasured confounding in the primary data. This implementation demonstrates how simple applications of structural causal modeling can be effectively used to determine falsifiable model conditions, detect selection bias and confounding factors, and minimize estimate bias through model selection in a novel epidemiological context.

  View details for DOI 10.2196/31306

  View details for PubMedID 35605128

• Improved Digital Therapy for Developmental Pediatrics Using Domain-Specific Artificial Intelligence: Machine Learning Study. JMIR pediatrics and parenting Washington, P., Kalantarian, H., Kent, J., Husic, A., Kline, A., Leblanc, E., Hou, C., Mutlu, O. C., Dunlap, K., Penev, Y., Varma, M., Stockham, N. T., Chrisman, B., Paskov, K., Sun, M. W., Jung, J. Y., Voss, C., Haber, N., Wall, D. P. 2022; 5 (2): e26760

  Abstract

  Automated emotion classification could aid those who struggle to recognize emotions, including children with developmental behavioral conditions such as autism. However, most computer vision emotion recognition models are trained on adult emotion and therefore underperform when applied to child faces.We designed a strategy to gamify the collection and labeling of child emotion-enriched images to boost the performance of automatic child emotion recognition models to a level closer to what will be needed for digital health care approaches.We leveraged our prototype therapeutic smartphone game, GuessWhat, which was designed in large part for children with developmental and behavioral conditions, to gamify the secure collection of video data of children expressing a variety of emotions prompted by the game. Independently, we created a secure web interface to gamify the human labeling effort, called HollywoodSquares, tailored for use by any qualified labeler. We gathered and labeled 2155 videos, 39,968 emotion frames, and 106,001 labels on all images. With this drastically expanded pediatric emotion-centric database (>30 times larger than existing public pediatric emotion data sets), we trained a convolutional neural network (CNN) computer vision classifier of happy, sad, surprised, fearful, angry, disgust, and neutral expressions evoked by children.The classifier achieved a 66.9% balanced accuracy and 67.4% F1-score on the entirety of the Child Affective Facial Expression (CAFE) as well as a 79.1% balanced accuracy and 78% F1-score on CAFE Subset A, a subset containing at least 60% human agreement on emotions labels. This performance is at least 10% higher than all previously developed classifiers evaluated against CAFE, the best of which reached a 56% balanced accuracy even when combining "anger" and "disgust" into a single class.This work validates that mobile games designed for pediatric therapies can generate high volumes of domain-relevant data sets to train state-of-the-art classifiers to perform tasks helpful to precision health efforts.

  View details for DOI 10.2196/26760

  View details for PubMedID 35394438

• Identification of Social Engagement Indicators Associated With Autism Spectrum Disorder Using a Game-Based Mobile App: Comparative Study of Gaze Fixation and Visual Scanning Methods. Journal of medical Internet research Varma, M., Washington, P., Chrisman, B., Kline, A., Leblanc, E., Paskov, K., Stockham, N., Jung, J., Sun, M. W., Wall, D. P. 2022; 24 (2): e31830

  Abstract

  BACKGROUND: Autism spectrum disorder (ASD) is a widespread neurodevelopmental condition with a range of potential causes and symptoms. Standard diagnostic mechanisms for ASD, which involve lengthy parent questionnaires and clinical observation, often result in long waiting times for results. Recent advances in computer vision and mobile technology hold potential for speeding up the diagnostic process by enabling computational analysis of behavioral and social impairments from home videos. Such techniques can improve objectivity and contribute quantitatively to the diagnostic process.OBJECTIVE: In this work, we evaluate whether home videos collected from a game-based mobile app can be used to provide diagnostic insights into ASD. To the best of our knowledge, this is the first study attempting to identify potential social indicators of ASD from mobile phone videos without the use of eye-tracking hardware, manual annotations, and structured scenarios or clinical environments.METHODS: Here, we used a mobile health app to collect over 11 hours of video footage depicting 95 children engaged in gameplay in a natural home environment. We used automated data set annotations to analyze two social indicators that have previously been shown to differ between children with ASD and their neurotypical (NT) peers: (1) gaze fixation patterns, which represent regions of an individual's visual focus and (2) visual scanning methods, which refer to the ways in which individuals scan their surrounding environment. We compared the gaze fixation and visual scanning methods used by children during a 90-second gameplay video to identify statistically significant differences between the 2 cohorts; we then trained a long short-term memory (LSTM) neural network to determine if gaze indicators could be predictive of ASD.RESULTS: Our results show that gaze fixation patterns differ between the 2 cohorts; specifically, we could identify 1 statistically significant region of fixation (P<.001). In addition, we also demonstrate that there are unique visual scanning patterns that exist for individuals with ASD when compared to NT children (P<.001). A deep learning model trained on coarse gaze fixation annotations demonstrates mild predictive power in identifying ASD.CONCLUSIONS: Ultimately, our study demonstrates that heterogeneous video data sets collected from mobile devices hold potential for quantifying visual patterns and providing insights into ASD. We show the importance of automated labeling techniques in generating large-scale data sets while simultaneously preserving the privacy of participants, and we demonstrate that specific social engagement indicators associated with ASD can be identified and characterized using such data.

  View details for DOI 10.2196/31830

  View details for PubMedID 35166683

• A Method for Localizing Non-Reference Sequences to the Human Genome. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Chrisman, B. S., Paskov, K. M., He, C., Jung, J., Stockham, N., Washington, P. Y., Wall, D. P. 2022; 27: 313-324

  Abstract

  As the last decade of human genomics research begins to bear the fruit of advancements in precision medicine, it is important to ensure that genomics' improvements in human health are distributed globally and equitably. An important step to ensuring health equity is to improve the human reference genome to capture global diversity by including a wide variety of alternative haplotypes, sequences that are not currently captured on the reference genome.We present a method that localizes 100 basepair (bp) long sequences extracted from short-read sequencing that can ultimately be used to identify what regions of the human genome non-reference sequences belong to.We extract reads that don't align to the reference genome, and compute the population's distribution of 100-mers found within the unmapped reads. We use genetic data from families to identify shared genetic material between siblings and match the distribution of unmapped k-mers to these inheritance patterns to determine the the most likely genomic region of a k-mer. We perform this localization with two highly interpretable methods of artificial intelligence: a computationally tractable Hidden Markov Model coupled to a Maximum Likelihood Estimator. Using a set of alternative haplotypes with known locations on the genome, we show that our algorithm is able to localize 96% of k-mers with over 90% accuracy and less than 1Mb median resolution. As the collection of sequenced human genomes grows larger and more diverse, we hope that this method can be used to improve the human reference genome, a critical step in addressing precision medicine's diversity crisis.

  View details for PubMedID 34890159

• An Informatics Analysis to Identify Sex Disparities and Healthcare Needs for Autism across the United States. AMIA ... Annual Symposium proceedings. AMIA Symposium Stockham, N. T., Paskov, K. M., Tabatabaei, K., Sutaria, S., Liu, B., Kent, J., Wall, D. P. 2022; 2022: 456-465

  Abstract

  Autism is among the most common neurodevelopmental conditions. Timely diagnosis and access to therapeutic resources are essential for positive prognoses, yet long queues and unevenly dispersed resources leave many untreated. Without granular estimates of autism prevalence by geographic area, it is difficult to identify unmet needs and mechanisms to address them. Mining a dataset of 53M children using meaningful geographic regions, we computed autism prevalence across the country. We then performed comparative analysis against 50,000 resources to identify the type and extent of gaps in access to autism services. We find a steady increase in autism diagnoses from K-5, supporting delayed diagnosis of autism, and consistent under-diagnosis of females. We find a significant inverse relationship between prevalence and availability of resources (p < 0.001). While more work is needed to characterize additional trends including racial and ethnicity-based disparities, the identification of resource gaps can direct and prioritize new innovations.

  View details for PubMedID 35854759

• Crowd annotations can approximate clinical autism impressions from short home videos with privacy protections. Intelligence-based medicine Washington, P., Chrisman, B., Leblanc, E., Dunlap, K., Kline, A., Mutlu, C., Stockham, N., Paskov, K., Wall, D. P. 2022; 6

  Abstract

  Artificial Intelligence (A.I.) solutions are increasingly considered for telemedicine. For these methods to serve children and their families in home settings, it is crucial to ensure the privacy of the child and parent or caregiver. To address this challenge, we explore the potential for global image transformations to provide privacy while preserving the quality of behavioral annotations. Crowd workers have previously been shown to reliably annotate behavioral features in unstructured home videos, allowing machine learning classifiers to detect autism using the annotations as input. We evaluate this method with videos altered via pixelation, dense optical flow, and Gaussian blurring. On a balanced test set of 30 videos of children with autism and 30 neurotypical controls, we find that the visual privacy alterations do not drastically alter any individual behavioral annotation at the item level. The AUROC on the evaluation set was 90.0% ±7.5% for unaltered videos, 85.0% ±9.0% for pixelation, 85.0% ±9.0% for optical flow, and 83.3% ±9.3% for blurring, demonstrating that an aggregation of small changes across behavioral questions can collectively result in increased misdiagnosis rates. We also compare crowd answers against clinicians who provided the same annotations for the same videos as crowd workers, and we find that clinicians have higher sensitivity in their recognition of autism-related symptoms. We also find that there is a linear correlation (r = 0.75, p < 0.0001) between the mean Clinical Global Impression (CGI) score provided by professional clinicians and the corresponding score emitted by a previously validated autism classifier with crowd inputs, indicating that the classifier's output probability is a reliable estimate of the clinical impression of autism. A significant correlation is maintained with privacy alterations, indicating that crowd annotations can approximate clinician-provided autism impression from home videos in a privacy-preserved manner.

  View details for DOI 10.1016/j.ibmed.2022.100056

  View details for PubMedID 35634270

• Improved detection of disease-associated gut microbes using 16S sequence-based biomarkers. BMC bioinformatics Chrisman, B. S., Paskov, K. M., Stockham, N., Jung, J., Varma, M., Washington, P. Y., Tataru, C., Iwai, S., DeSantis, T. Z., David, M., Wall, D. P. 2021; 22 (1): 509

  Abstract

  BACKGROUND: Sequencing partial 16S rRNA genes is a cost effective method for quantifying the microbial composition of an environment, such as the human gut. However, downstream analysis relies on binning reads into microbial groups by either considering each unique sequence as a different microbe, querying a database to get taxonomic labels from sequences, or clustering similar sequences together. However, these approaches do not fully capture evolutionary relationships between microbes, limiting the ability to identify differentially abundant groups of microbes between a diseased and control cohort. We present sequence-based biomarkers (SBBs), an aggregation method that groups and aggregates microbes using single variants and combinations of variants within their 16S sequences. We compare SBBs against other existing aggregation methods (OTU clustering and Microphenoor DiTaxa features) in several benchmarking tasks: biomarker discovery via permutation test, biomarker discovery via linear discriminant analysis, and phenotype prediction power. We demonstrate the SBBs perform on-par or better than the state-of-the-art methods in biomarker discovery and phenotype prediction.RESULTS: On two independent datasets, SBBs identify differentially abundant groups of microbes with similar or higher statistical significance than existing methods in both a permutation-test-based analysis and using linear discriminant analysis effect size. . By grouping microbes by SBB, we can identify several differentially abundant microbial groups (FDR <.1) between children with autism and neurotypical controls in a set of 115 discordant siblings. Porphyromonadaceae, Ruminococcaceae, and an unnamed species of Blastocystis were significantly enriched in autism, while Veillonellaceae was significantly depleted. Likewise, aggregating microbes by SBB on a dataset of obese and lean twins, we find several significantly differentially abundant microbial groups (FDR<.1). We observed Megasphaera andSutterellaceae highly enriched in obesity, and Phocaeicola significantly depleted. SBBs also perform on bar with or better than existing aggregation methods as features in a phenotype prediction model, predicting the autism phenotype with an ROC-AUC score of .64 and the obesity phenotype with an ROC-AUC score of .84.CONCLUSIONS: SBBs provide a powerful method for aggregating microbes to perform differential abundance analysis as well as phenotype prediction. Our source code can be freely downloaded from http://github.com/briannachrisman/16s_biomarkers .

  View details for DOI 10.1186/s12859-021-04427-7

  View details for PubMedID 34666677

• Training Affective Computer Vision Models by Crowdsourcing Soft-Target Labels COGNITIVE COMPUTATION Washington, P., Kalantarian, H., Kent, J., Husic, A., Kline, A., Leblanc, E., Hou, C., Mutlu, C., Dunlap, K., Penev, Y., Stockham, N., Chrisman, B., Paskov, K., Jung, J., Voss, C., Haber, N., Wall, D. P. 2021

  View details for DOI 10.1007/s12559-021-09936-4

  View details for Web of Science ID 000700975300001

• Training Affective Computer Vision Models by Crowdsourcing Soft-Target Labels. Cognitive computation Washington, P., Kalantarian, H., Kent, J., Husic, A., Kline, A., Leblanc, E., Hou, C., Mutlu, C., Dunlap, K., Penev, Y., Stockham, N., Chrisman, B., Paskov, K., Jung, J. Y., Voss, C., Haber, N., Wall, D. P. 2021; 13 (5): 1363-1373

  Abstract

  Emotion detection classifiers traditionally predict discrete emotions. However, emotion expressions are often subjective, thus requiring a method to handle compound and ambiguous labels. We explore the feasibility of using crowdsourcing to acquire reliable soft-target labels and evaluate an emotion detection classifier trained with these labels. We hypothesize that training with labels that are representative of the diversity of human interpretation of an image will result in predictions that are similarly representative on a disjoint test set. We also hypothesize that crowdsourcing can generate distributions which mirror those generated in a lab setting.We center our study on the Child Affective Facial Expression (CAFE) dataset, a gold standard collection of images depicting pediatric facial expressions along with 100 human labels per image. To test the feasibility of crowdsourcing to generate these labels, we used Microworkers to acquire labels for 207 CAFE images. We evaluate both unfiltered workers as well as workers selected through a short crowd filtration process. We then train two versions of a ResNet-152 neural network on soft-target CAFE labels using the original 100 annotations provided with the dataset: (1) a classifier trained with traditional one-hot encoded labels, and (2) a classifier trained with vector labels representing the distribution of CAFE annotator responses. We compare the resulting softmax output distributions of the two classifiers with a 2-sample independent t-test of L1 distances between the classifier's output probability distribution and the distribution of human labels.While agreement with CAFE is weak for unfiltered crowd workers, the filtered crowd agree with the CAFE labels 100% of the time for happy, neutral, sad and "fear + surprise", and 88.8% for "anger + disgust". While the F1-score for a one-hot encoded classifier is much higher (94.33% vs. 78.68%) with respect to the ground truth CAFE labels, the output probability vector of the crowd-trained classifier more closely resembles the distribution of human labels (t=3.2827, p=0.0014).For many applications of affective computing, reporting an emotion probability distribution that accounts for the subjectivity of human interpretation can be more useful than an absolute label. Crowdsourcing, including a sufficient filtering mechanism for selecting reliable crowd workers, is a feasible solution for acquiring soft-target labels.

  View details for DOI 10.1007/s12559-021-09936-4

  View details for PubMedID 35669554

  View details for PubMedCentralID PMC9165031

• A maximum flow-based network approach for identification of stable noncoding biomarkers associated with the multigenic neurological condition, autism. BioData mining Varma, M., Paskov, K. M., Chrisman, B. S., Sun, M. W., Jung, J., Stockham, N. T., Washington, P. Y., Wall, D. P. 2021; 14 (1): 28

  Abstract

  BACKGROUND: Machine learning approaches for predicting disease risk from high-dimensional whole genome sequence (WGS) data often result in unstable models that can be difficult to interpret, limiting the identification of putative sets of biomarkers. Here, we design and validate a graph-based methodology based on maximum flow, which leverages the presence of linkage disequilibrium (LD) to identify stable sets of variants associated with complex multigenic disorders.RESULTS: We apply our method to a previously published logistic regression model trained to identify variants in simple repeat sequences associated with autism spectrum disorder (ASD); this L1-regularized model exhibits high predictive accuracy yet demonstrates great variability in the features selected from over 230,000 possible variants. In order to improve model stability, we extract the variants assigned non-zero weights in each of 5 cross-validation folds and then assemble the five sets of features into a flow network subject to LD constraints. The maximum flow formulation allowed us to identify 55 variants, which we show to be more stable than the features identified by the original classifier.CONCLUSION: Our method allows for the creation of machine learning models that can identify predictive variants. Our results help pave the way towards biomarker-based diagnosis methods for complex genetic disorders.

  View details for DOI 10.1186/s13040-021-00262-x

  View details for PubMedID 33941233

• Estimating sequencing error rates using families. BioData mining Paskov, K., Jung, J., Chrisman, B., Stockham, N. T., Washington, P., Varma, M., Sun, M. W., Wall, D. P. 2021; 14 (1): 27

  Abstract

  BACKGROUND: As next-generation sequencing technologies make their way into the clinic, knowledge of their error rates is essential if they are to be used to guide patient care. However, sequencing platforms and variant-calling pipelines are continuously evolving, making it difficult to accurately quantify error rates for the particular combination of assay and software parameters used on each sample. Family data provide a unique opportunity for estimating sequencing error rates since it allows us to observe a fraction of sequencing errors as Mendelian errors in the family, which we can then use to produce genome-wide error estimates for each sample.RESULTS: We introduce a method that uses Mendelian errors in sequencing data to make highly granular per-sample estimates of precision and recall for any set of variant calls, regardless of sequencing platform or calling methodology. We validate the accuracy of our estimates using monozygotic twins, and we use a set of monozygotic quadruplets to show that our predictions closely match the consensus method. We demonstrate our method's versatility by estimating sequencing error rates for whole genome sequencing, whole exome sequencing, and microarray datasets, and we highlight its sensitivity by quantifying performance increases between different versions of the GATK variant-calling pipeline. We then use our method to demonstrate that: 1) Sequencing error rates between samples in the same dataset can vary by over an order of magnitude. 2) Variant calling performance decreases substantially in low-complexity regions of the genome. 3) Variant calling performance in whole exome sequencing data decreases with distance from the nearest target region. 4) Variant calls from lymphoblastoid cell lines can be as accurate as those from whole blood. 5) Whole-genome sequencing can attain microarray-level precision and recall at disease-associated SNV sites.CONCLUSION: Genotype datasets from families are powerful resources that can be used to make fine-grained estimates of sequencing error for any sequencing platform and variant-calling methodology.

  View details for DOI 10.1186/s13040-021-00259-6

  View details for PubMedID 33892748

• Indels in SARS-CoV-2 occur at template-switching hotspots. BioData mining Chrisman, B. S., Paskov, K., Stockham, N., Tabatabaei, K., Jung, J., Washington, P., Varma, M., Sun, M. W., Maleki, S., Wall, D. P. 2021; 14 (1): 20

  Abstract

  The evolutionary dynamics of SARS-CoV-2 have been carefully monitored since the COVID-19 pandemic began in December 2019. However, analysis has focused primarily on single nucleotide polymorphisms and largely ignored the role of insertions and deletions (indels) as well as recombination in SARS-CoV-2 evolution. Using sequences from the GISAID database, we catalogue over 100 insertions and deletions in the SARS-CoV-2 consensus sequences. We hypothesize that these indels are artifacts of recombination events between SARS-CoV-2 replicates whereby RNA-dependent RNA polymerase (RdRp) re-associates with a homologous template at a different loci ("imperfect homologous recombination"). We provide several independent pieces of evidence that suggest this. (1) The indels from the GISAID consensus sequences are clustered at specific regions of the genome. (2) These regions are also enriched for 5' and 3' breakpoints in the transcription regulatory site (TRS) independent transcriptome, presumably sites of RNA-dependent RNA polymerase (RdRp) template-switching. (3) Within raw reads, these indel hotspots have cases of both high intra-host heterogeneity and intra-host homogeneity, suggesting that these indels are both consequences of de novo recombination events within a host and artifacts of previous recombination. We briefly analyze the indels in the context of RNA secondary structure, noting that indels preferentially occur in "arms" and loop structures of the predicted folded RNA, suggesting that secondary structure may be a mechanism for TRS-independent template-switching in SARS-CoV-2 or other coronaviruses. These insights into the relationship between structural variation and recombination in SARS-CoV-2 can improve our reconstructions of the SARS-CoV-2 evolutionary history as well as our understanding of the process of RdRp template-switching in RNA viruses.

  View details for DOI 10.1186/s13040-021-00251-0

  View details for PubMedID 33743803

• Activity Recognition with Moving Cameras and Few Training Examples: Applications for Detection of Autism-Related Headbanging Washington, P., Kline, A., Mutlu, O., Leblanc, E., Hou, C., Stockham, N., Paskov, K., Chrisman, B., Wall, D., ACM ASSOC COMPUTING MACHINERY. 2021

  View details for DOI 10.1145/3411763.3451701

  View details for Web of Science ID 000759178502011

• Game theoretic centrality: a novel approach to prioritize disease candidate genes by combining biological networks with the Shapley value. BMC bioinformatics Sun, M. W., Moretti, S., Paskov, K. M., Stockham, N. T., Varma, M., Chrisman, B. S., Washington, P. Y., Jung, J., Wall, D. P. 2020; 21 (1): 356

  Abstract

  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

• Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism BIOMEDICAL INFORMATICS INSIGHTS Sun, M., Gupta, A., Varma, M., Paskov, K. M., Jung, J., Stockham, N. T., Wall, D. P. 2019; 11

  View details for DOI 10.1177/1178222619832859

  View details for Web of Science ID 000462005200001

• Outgroup Machine Learning Approach Identifies Single Nucleotide Variants in Noncoding DNA Associated with Autism Spectrum Disorder Varma, M., Paskov, K., Jung, J., Chrisman, B., Stockham, N., Washington, P., Wall, D., Altman, R. B., Dunker, A. K., Hunter, L., Ritchie, M. D., Murray, T., Klein, T. E. WORLD SCIENTIFIC PUBL CO PTE LTD. 2019: 260–71

  View details for Web of Science ID 000461866400024

• Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Cell Ruzzo, E. K., Pérez-Cano, L. n., Jung, J. Y., Wang, L. K., Kashef-Haghighi, D. n., Hartl, C. n., Singh, C. n., Xu, J. n., Hoekstra, J. N., Leventhal, O. n., Leppä, V. M., Gandal, M. J., Paskov, K. n., Stockham, N. n., Polioudakis, D. n., Lowe, J. K., Prober, D. A., Geschwind, D. H., Wall, D. P. 2019; 178 (4): 850–66.e26

  Abstract

  We performed a comprehensive assessment of rare inherited variation in autism spectrum disorder (ASD) by analyzing whole-genome sequences of 2,308 individuals from families with multiple affected children. We implicate 69 genes in ASD risk, including 24 passing genome-wide Bonferroni correction and 16 new ASD risk genes, most supported by rare inherited variants, a substantial extension of previous findings. Biological pathways enriched for genes harboring inherited variants represent cytoskeletal organization and ion transport, which are distinct from pathways implicated in previous studies. Nevertheless, the de novo and inherited genes contribute to a common protein-protein interaction network. We also identified structural variants (SVs) affecting non-coding regions, implicating recurrent deletions in the promoters of DLG2 and NR3C2. Loss of nr3c2 function in zebrafish disrupts sleep and social function, overlapping with human ASD-related phenotypes. These data support the utility of studying multiplex families in ASD and are available through the Hartwell Autism Research and Technology portal.

  View details for DOI 10.1016/j.cell.2019.07.015

  View details for PubMedID 31398340

• Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism. Biomedical informatics insights Sun, M. W., Gupta, A., Varma, M., Paskov, K. M., Jung, J., Stockham, N. T., Wall, D. P. 2019; 11: 1178222619832859

  Abstract

  Studies on autism spectrum disorder (ASD) have amassed substantial evidence for the role of genetics in the disease's phenotypic manifestation. A large number of coding and non-coding variants with low penetrance likely act in a combinatorial manner to explain the variable forms of ASD. However, many of these combined interactions, both additive and epistatic, remain undefined. Coalitional game theory (CGT) is an approach that seeks to identify players (individual genetic variants or genes) who tend to improve the performance-association to a disease phenotype of interest-of any coalition (subset of co-occurring genetic variants) they join. This method has been previously applied to boost biologically informative signal from gene expression data and exome sequencing data but remains to be explored in the context of cooperativity among non-coding genomic regions. We describe our extension of previous work, highlighting non-coding chromosomal regions relevant to ASD using CGT on alteration data of 4595 fully sequenced genomes from 756 multiplex families. Genomes were encoded into binary matrices for three types of non-coding regions previously implicated in ASD and separated into ASD (case) and unaffected (control) samples. A player metric, the Shapley value, enabled determination of individual variant contributions in both sets of cohorts. A total of 30 non-coding positions were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Cross-study analyses revealed that a subset of mutated non-coding regions (all of which are in human accelerated regions (HARs)) and related genes are involved in biological pathways or behavioral outcomes known to be affected in autism, suggesting the importance of single nucleotide polymorphisms (SNPs) within HARs in ASD. These findings support the use of CGT in identifying hidden yet influential non-coding players from large-scale genomic data, to better understand the precise underpinnings of complex neurodevelopmental disorders such as autism.

  View details for PubMedID 30886520

• Analysis of Sex and Recurrence Ratios in Simplex and Multiplex Autism Spectrum Disorder Implicates Sex-Specific Alleles as Inheritance Mechanism Chrisman, B., Varma, M., Washington, P., Paskov, K., Stockham, N., Jung, J., Wall, D. P., Zheng, H., Callejas, Z., Griol, D., Wang, H., Hu, Schmidt, H., Baumbach, J., Dickerson, J., Zhang, L. IEEE. 2018: 1470–77

  View details for Web of Science ID 000458654000258