Regis A. James, PhD

Tarrytown, New York, United States
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I build autonomous AI systems that we teach to recommend/make complex, data-driven…

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  • Regeneron

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  • A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

    Genome Medicine

    Keywords: Exome; Semantic similarity; Variant prioritization

    Background
    Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We developed…

    Keywords: Exome; Semantic similarity; Variant prioritization

    Background
    Genome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and prioritization of filtered rare variants. We developed visually interactive, analytically transparent analysis software that leverages existing disease catalogs to integrate patient phenotype and variant data into ranked diagnostic alternatives.

    Methods
    Our tool, “OMIM Explorer” (http://www.omimexplorer.com), extends the biomedical application of semantic similarity methods beyond those previously reported. The visual approach uses semantic similarity with multidimensional scaling to collapse high-dimensional phenotype and genotype data from an individual into a graphical format that contextualizes the patient within a low-dimensional disease map. The map proposes a differential diagnosis and algorithmically suggests potential alternatives for phenotype queries—in essence, generating a computationally assisted differential diagnosis informed by the individual’s personal genome. Visual interactivity allows the user to filter and update variant rankings by interacting with intermediate results. The tool also implements an adaptive approach for disease gene discovery based on patient phenotypes.

    Results
    Our tool assigned to clinically reported variants a median rank of 2, placing causal variants in the top 1 % of filtered candidates across the 47 cohort cases with reported molecular diagnoses of exome variants in OMIM Morbidmap genes.

    Conclusions
    Our integrative paradigm can improve efficiency and, potentially, the quality of genomic medicine by more effectively utilizing available phenotype information, catalog data, and genomic knowledge.

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  • parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

    american journal of human genetics

    most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. interestingly, new mutations in x-linked recessive disease show elevated familial recurrence rates. in male offspring, these mutations must be inherited from mothers. we previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. in this paper, we extend and formalize the model to provide analytical results and…

    most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. interestingly, new mutations in x-linked recessive disease show elevated familial recurrence rates. in male offspring, these mutations must be inherited from mothers. we previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. in this paper, we extend and formalize the model to provide analytical results and flexible formulas. the results implicate parent of origin and parental mosaicism as central variables in recurrence risk. consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. parental somatic mosaicism considerably elevates risk for both parents. these findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. we provide a convenient online tool and source code implementing our analytical results. these tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures.

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