Predicting venous thromboembolism risk from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges

Abstract

Genetics play a key role in venous thromboembolism (VTE) risk, however established risk factors in European populations do not translate to individuals of African descent because of the differences in allele frequencies between populations. As part of the fifth iteration of the Critical Assessment of Genome Interpretation, participants were asked to predict VTE status in exome data from African American subjects. Participants were provided with 103 unlabeled exomes from patients treated with warfarin for non‐VTE causes or VTE and asked to predict which disease each subject had been treated for. Given the lack of training data, many participants opted to use unsupervised machine learning methods, clustering the exomes by variation in genes known to be associated with VTE. The best performing method using only VTE related genes achieved an area under the ROC curve of 0.65. Here, we discuss the range of methods used in the prediction of VTE from sequence data and explore some of the difficulties of conducting a challenge with known confounders. In addition, we show that an existing genetic risk score for VTE that was developed in European subjects works well in African Americans.

Reports from the fifth edition of CAGI: The Critical Assessment of Genome Interpretation

“…CAGI5 continued the emphasis on the interpretation of clinically relevant large‐scale sequence data, with a challenge on the risk of thrombosis in African‐American cohort given whole exome sequence (McInnes et al, ; Wang & Bromberg, ); the identification of variants contributing to intellectual disability phenotypes given gene panel sequence (Aspromonte et al, ; Carraro et al, ; Chen, ); and a challenge of matching whole genome sequences to clinical profiles for patients at Toronto's Hospital for Sick Children (SickKids) and identifying causal variants (Kasak, Hunter et al, ; Pal, Kundu, Yin, & Moult, ). The latter challenge is related to the CAGI4 SickKids challenge, also described in the assessment paper here.…”

The effects of anticoagulant therapy re‐initiation after gastrointestinal bleeding: A systematic review and meta‐analysis

“…The management of thromboembolism is challenging for clinicians across the world because of its atypical pathophysiological mechanisms, which include co-existing morbidities, diverse manifestations and high-mortality. [41][42][43] The rising prevalence of thromboembolism is one of the fastest growing global health problems and is probably due to modifications in lifestyle settings. 44,45 Antithrombotic agents have been widely recommended to manage thromboembolism and even limit its onset.…”

Genome interpretation using in silico predictors of variant impact

“…Three CAGI challenges were related to predicting the risk of Crohn`s disease, with two of them resulting in unreliable performance evaluations due to sample stratification issues and the third one showing AUCs of up to 0.7 (Giollo et al 2017 ). The performance was slightly worse for predicting the risk for venous thromboembolism, with AUCs up to 0.65 and accuracies up to 0.63 (McInnes et al 2019 ). In a more complex challenge, two methods performed significantly better than chance for matching the clinical descriptions of undiagnosed patients (Kasak et al 2019b ).…”