Multi-objective prioritization of genes for high-throughput functional assays towards improved clinical variant classification.

The accurate interpretation of genetic variants is essential for clinical actionability. However, a majority of variants remain of uncertain significance. Multiplexed assays of variant effects (MAVEs), can help provide functional evidence for variants of uncertain significance (VUS) at the scale of entire genes. Although the systematic prioritization of genes for such assays has been of great interest from the clinical perspective, existing strategies have rarely emphasized this motivation. Here, we propose three objectives for quantifying the importance of genes each satisfying a specific clinical goal: (1) Movability scores to prioritize genes with the most VUS moving to non-VUS categories, (2) Correction scores to prioritize genes with the most pathogenic and/or benign variants that could be reclassified, and (3) Uncertainty scores to prioritize genes with VUS for which variant pathogenicity predictors used in clinical classification exhibit the greatest uncertainty. We demonstrate that existing approaches are sub-optimal when considering these explicit clinical objectives. We also propose a combined weighted score that optimizes the three objectives simultaneously and finds optimal weights to improve over existing approaches. Our strategy generally results in better performance than existing knowledge-driven and data-driven strategies and yields gene sets that are clinically relevant. Our work has implications for systematic efforts that aim to iterate between predictor development, experimentation and translation to the clinic.

Classification in biological networks with hypergraphlet kernels.

MOTIVATION: Biological and cellular systems are often modeled as graphs in which vertices represent objects of interest (genes, proteins and drugs) and edges represent relational ties between these objects (binds-to, interacts-with and regulates). This approach has been highly successful owing to the theory, methodology and software that support analysis and learning on graphs. Graphs, however, suffer from information loss when modeling physical systems due to their inability to accurately represent multiobject relationships. Hypergraphs, a generalization of graphs, provide a framework to mitigate information loss and unify disparate graph-based methodologies. RESULTS: We present a hypergraph-based approach for modeling biological systems and formulate vertex classification, edge classification and link prediction problems on (hyper)graphs as instances of vertex classification on (extended, dual) hypergraphs. We then introduce a novel kernel method on vertex- and edge-labeled (colored) hypergraphs for analysis and learning. The method is based on exact and inexact (via hypergraph edit distances) enumeration of hypergraphlets; i.e. small hypergraphs rooted at a vertex of interest. We empirically evaluate this method on fifteen biological networks and show its potential use in a positive-unlabeled setting to estimate the interactome sizes in various species. AVAILABILITY AND IMPLEMENTATION: https://github.com/jlugomar/hypergraphlet-kernels. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Machine learning for patient risk stratification for acute respiratory distress syndrome.

BACKGROUND: Existing prediction models for acute respiratory distress syndrome (ARDS) require manual chart abstraction and have only fair performance-limiting their suitability for driving clinical interventions. We sought to develop a machine learning approach for the prediction of ARDS that (a) leverages electronic health record (EHR) data, (b) is fully automated, and (c) can be applied at clinically relevant time points throughout a patient's stay. METHODS AND FINDINGS: We trained a risk stratification model for ARDS using a cohort of 1,621 patients with moderate hypoxia from a single center in 2016, of which 51 patients developed ARDS. We tested the model in a temporally distinct cohort of 1,122 patients from 2017, of which 27 patients developed ARDS. Gold standard diagnosis of ARDS was made by intensive care trained physicians during retrospective chart review. We considered both linear and non-linear approaches to learning the model. The best model used L2-logistic regression with 984 features extracted from the EHR. For patients observed in the hospital at least six hours who then developed moderate hypoxia, the model achieved an area under the receiver operating characteristics curve (AUROC) of 0.81 (95% CI: 0.73-0.88). Selecting a threshold based on the 85th percentile of risk, the model had a sensitivity of 56% (95% CI: 35%, 74%), specificity of 86% (95% CI: 85%, 87%) and positive predictive value of 9% (95% CI: 5%, 14%), identifying a population at four times higher risk for ARDS than other patients with moderate hypoxia and 17 times the risk of hospitalized adults. CONCLUSIONS: We developed an ARDS prediction model based on EHR data with good discriminative performance. Our results demonstrate the feasibility of a machine learning approach to risk stratifying patients for ARDS solely from data extracted automatically from the EHR.