Filtering Metrics. The criteria used to initially classify a variant in the training set for the quadratic discriminant model. (DOCX 14Â kb

Ana Claasen (4526038)

Baffour Awuah (4526032)

Daniel Enriquez (4526041)

David Craig (117059)

Evelyn Jaigge (4526023)

Irene Cherni (130548)

Jessica Aldrich (128110)

John Carpten (117061)

Jonathan Keats (191714)

Joseph Oppong (757902)

Lisa Newman (2094511)

Max Wicha (4526035)

Megan Russell (4526029)

Rebecca Halperin (4526026)

Sara Byron (4526044)

Seungchan Kim (292997)

Winnie Liang (399313)

Zarko Manojlovic (585158)

BMC Medical Genomics

Abstract Background Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers. However, matched germline samples are frequently not available such as with archival tissues, which makes it difficult to distinguish somatic from germline variants. While population databases may be used to filter out known germline variants, recent studies have shown private germline variants result in an inflated false positive rate in unmatched tumor samples, and the number germline false positives in an individual may be related to ancestry. Methods First, we examined the relationship between the germline false positives and ancestry. Then we developed and implemented a tumor only caller (LumosVar) that leverages differences in allelic frequency between somatic and germline variants in impure tumors. We used simulated data to systematically examine how copy number alterations, tumor purity, and sequencing depth should affect the sensitivity of our caller. Finally, we evaluated the caller on real data. Results We find the germline false-positive rate is significantly higher for individuals of non-European Ancestry largely due to the limited diversity in public polymorphism databases and due to population-specific characteristics such as admixture or recent expansions. Our Bayesian tumor only caller (LumosVar) is able to greatly reduce false positives from private germline variants, and our sensitivity is similar to predictions based on simulated data. Conclusions Taken together, our results suggest that studies of individuals of non-European ancestry would most benefit from our approach. However, high sensitivity requires sufficiently impure tumors and adequate sequencing depth. Even in impure tumors, there are copy number alterations that result in germline and somatic variants having similar allele frequencies, limiting the sensitivity of the approach. We believe our approach could greatly improve the analysis of archival samples in a research setting where the normal is not available

Rebecca F. Halperin

John D. Carpten

Zarko Manojlovic

Jessica Aldrich

Jonathan Keats

Sara Byron

Winnie S. Liang

Megan Russell

Daniel Enriquez

Ana Claasen

Irene Cherni

Baffour Awuah

Joseph Oppong

Max S. Wicha

Lisa A. Newman

Evelyn Jaigge

Seungchan Kim

David W. Craig

Directory of Open Access Journals

A method to reduce ancestry related germline false positives in tumor only somatic variant calling

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Additional file 4: Table S2. of A method to reduce ancestry related germline false positives in tumor only somatic variant calling

BACKGROUND: Significant clinical and research applications are driving large scale adoption of individualized tumor sequencing in cancer in order to identify tumors-specific mutations. When a matched germline sample is available, somatic mutations may be identified using comparative callers. However, matched germline samples are frequently not available such as with archival tissues, which makes it difficult to distinguish somatic from germline variants. While population databases may be used to filter out known germline variants, recent studies have shown private germline variants result in an inflated false positive rate in unmatched tumor samples, and the number germline false positives in an individual may be related to ancestry.
METHODS: First, we examined the relationship between the germline false positives and ancestry. Then we developed and implemented a tumor only caller (LumosVar) that leverages differences in allelic frequency between somatic and germline variants in impure tumors. We used simulated data to systematically examine how copy number alterations, tumor purity, and sequencing depth should affect the sensitivity of our caller. Finally, we evaluated the caller on real data.
RESULTS: We find the germline false-positive rate is significantly higher for individuals of non-European Ancestry largely due to the limited diversity in public polymorphism databases and due to population-specific characteristics such as admixture or recent expansions. Our Bayesian tumor only caller (LumosVar) is able to greatly reduce false positives from private germline variants, and our sensitivity is similar to predictions based on simulated data.
CONCLUSIONS: Taken together, our results suggest that studies of individuals of non-European ancestry would most benefit from our approach. However, high sensitivity requires sufficiently impure tumors and adequate sequencing depth. Even in impure tumors, there are copy number alterations that result in germline and somatic variants having similar allele frequencies, limiting the sensitivity of the approach. We believe our approach could greatly improve the analysis of archival samples in a research setting where the normal is not available

Halperin, Rebecca F

Carpten, John D

Manojlovic, Zarko

Aldrich, Jessica

Keats, Jonathan

Byron, Sara

Liang, Winnie S

Russell, Megan

Enriquez, Daniel

Claasen, Ana

Cherni, Irene

Awuah, Baffour

Oppong, Joseph

Wicha, Max S

Newman, Lisa A

Jaigge, Evelyn

Kim, Seungchan

Craig, David W

Henry Ford Health System Scholarly Commons

https://figshare.com/articles/Additional_file_4_Table_S2_of_A_method_to_reduce_ancestry_related_germline_false_positives_in_tumor_only_somatic_variant_calling/5519443

Additional file 4: Table S2. of A method to reduce ancestry related germline false positives in tumor only somatic variant calling

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