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Hum Mutat. 2019 Sep;40(9):1321-1329. doi: 10.1002/humu.23824. Epub 2019 Jul 3.

Identifying mutation-driven changes in gene functionality that lead to venous thromboembolism.

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Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, New Jersey.
Department of Genetics, Rutgers University, New Brunswick, New Jersey.


Venous thromboembolism (VTE) is a common hematological disorder. VTE affects millions of people around the world each year and can be fatal. Earlier studies have revealed the possible VTE genetic risk factors in Europeans. The 2018 Critical Assessment of Genome Interpretation (CAGI) challenge had asked participants to distinguish between 66 VTE and 37 non-VTE African American (AA) individuals based on their exome sequencing data. We used variants from AA VTE association studies and VTE genes from DisGeNET database to evaluate VTE risk via four different approaches; two of these methods were most successful at the task. Our best performing method represented each exome as a vector of predicted functional effect scores of variants within the known genes. These exome vectors were then clustered with k-means. This approach achieved 70.8% precision and 69.7% recall in identifying VTE patients. Our second-best ranked method had collapsed the variant effect scores into gene-level function changes, using the same vector clustering approach for patient/control identification. These results show predictability of VTE risk in AA population and highlight the importance of variant-driven gene functional changes in judging disease status. Of course, more in-depth understanding of AA VTE pathogenicity is still needed for more precise predictions.


CAGI; function; prediction; venous thromboembolism; warfarin

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