VarSight: Prioritizing clinically reported variants with binary classification algorithms

James M. Holt, Brandon Wilk, Camille L. Birch, Donna M. Brown, Manavalan Gajapathy, Alexander C. Moss, Nadiya Sosonkina, Melissa A. Wilk, Julie A. Anderson, Jeremy M. Harris, Jacob M. Kelly, Fariba Shaterferdosian, Angelina E. Uno-Antonison, Arthur Weborg, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Patrick AllardJustin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong Hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly Leblanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee Kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, Stephan Zuchner, Elizabeth A. Worthey

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. Methods: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. Results: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. Conclusions: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

Original languageEnglish (US)
Article number496
JournalBMC bioinformatics
Volume20
Issue number1
DOIs
StatePublished - Oct 15 2019

Fingerprint

Binary Classification
Classification Algorithm
Prioritization
Classifiers
Classifier
Phenotype
Rare Diseases
Genomics
Annotation
Medicine
Ranking
Filtering
Retrospective Studies

Keywords

  • Binary classification
  • Clinical genome sequencing
  • Variant prioritization

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Computer Science Applications
  • Applied Mathematics

Cite this

Holt, J. M., Wilk, B., Birch, C. L., Brown, D. M., Gajapathy, M., Moss, A. C., ... Worthey, E. A. (2019). VarSight: Prioritizing clinically reported variants with binary classification algorithms. BMC bioinformatics, 20(1), [496]. https://doi.org/10.1186/s12859-019-3026-8

VarSight : Prioritizing clinically reported variants with binary classification algorithms. / Holt, James M.; Wilk, Brandon; Birch, Camille L.; Brown, Donna M.; Gajapathy, Manavalan; Moss, Alexander C.; Sosonkina, Nadiya; Wilk, Melissa A.; Anderson, Julie A.; Harris, Jeremy M.; Kelly, Jacob M.; Shaterferdosian, Fariba; Uno-Antonison, Angelina E.; Weborg, Arthur; Acosta, Maria T.; Adam, Margaret; Adams, David R.; Agrawal, Pankaj B.; Alejandro, Mercedes E.; Allard, Patrick; Alvey, Justin; Amendola, Laura; Andrews, Ashley; Ashley, Euan A.; Azamian, Mahshid S.; Bacino, Carlos A.; Bademci, Guney; Baker, Eva; Balasubramanyam, Ashok; Baldridge, Dustin; Bale, Jim; Bamshad, Michael; Barbouth, Deborah; Batzli, Gabriel F.; Bayrak-Toydemir, Pinar; Beck, Anita; Beggs, Alan H.; Bejerano, Gill; Bellen, Hugo J.; Bennet, Jimmy; Berg-Rood, Beverly; Bernier, Raphael; Bernstein, Jonathan A.; Berry, Gerard T.; Bican, Anna; Bivona, Stephanie; Blue, Elizabeth; Bohnsack, John; Bonnenmann, Carsten; Bonner, Devon; Botto, Lorenzo; Briere, Lauren C.; Brokamp, Elly; Burke, Elizabeth A.; Burrage, Lindsay C.; Butte, Manish J.; Byers, Peter; Carey, John; Carrasquillo, Olveen; Chang, Ta Chen Peter; Chanprasert, Sirisak; Chao, Hsiao Tuan; Clark, Gary D.; Coakley, Terra R.; Cobban, Laurel A.; Cogan, Joy D.; Cole, F. Sessions; Colley, Heather A.; Cooper, Cynthia M.; Cope, Heidi; Craigen, William J.; Cunningham, Michael; D'Souza, Precilla; Dai, Hongzheng; Dasari, Surendra; Davids, Mariska; Dayal, Jyoti G.; Dell'Angelica, Esteban C.; Dhar, Shweta U.; Dipple, Katrina; Doherty, Daniel; Dorrani, Naghmeh; Douine, Emilie D.; Draper, David D.; Duncan, Laura; Earl, Dawn; Eckstein, David J.; Emrick, Lisa T.; Eng, Christine M.; Esteves, Cecilia; Estwick, Tyra; Fernandez, Liliana; Ferreira, Carlos; Fieg, Elizabeth L.; Fisher, Paul G.; Fogel, Brent L.; Forghani, Irman; Fresard, Laure; Gahl, William A.; Glass, Ian; Godfrey, Rena A.; Golden-Grant, Katie; Goldman, Alica M.; Goldstein, David B.; Grajewski, Alana; Groden, Catherine A.; Gropman, Andrea L.; Hahn, Sihoun; Hamid, Rizwan; Hanchard, Neil A.; Hayes, Nichole; High, Frances; Hing, Anne; Hisama, Fuki M.; Holm, Ingrid A.; Hom, Jason; Horike-Pyne, Martha; Huang, Alden; Huang, Yong; Isasi, Rosario; Jamal, Fariha; Jarvik, Gail P.; Jarvik, Jeffrey; Jayadev, Suman; Jiang, Yong Hui; Johnston, Jean M.; Karaviti, Lefkothea; Kelley, Emily G.; Kiley, Dana; Kohane, Isaac S.; Kohler, Jennefer N.; Krakow, Deborah; Krasnewich, Donna M.; Korrick, Susan; Koziura, Mary; Krier, Joel B.; Lalani, Seema R.; Lam, Byron; Lam, Christina; Lanpher, Brendan C.; Lanza, Ian R.; Lau, C. Christopher; Leblanc, Kimberly; Lee, Brendan H.; Lee, Hane; Levitt, Roy; Lewis, Richard A.; Lincoln, Sharyn A.; Liu, Pengfei; Liu, Xue Zhong; Longo, Nicola; Loo, Sandra K.; Loscalzo, Joseph; Maas, Richard L.; Macnamara, Ellen F.; MacRae, Calum A.; Maduro, Valerie V.; Majcherska, Marta M.; Malicdan, May Christine V.; Mamounas, Laura A.; Manolio, Teri A.; Mao, Rong; Maravilla, Kenneth; Markello, Thomas C.; Marom, Ronit; Marth, Gabor; Martin, Beth A.; Martin, Martin G.; Martínez-Agosto, Julian A.; Marwaha, Shruti; McCauley, Jacob; McConkie-Rosell, Allyn; McCormack, Colleen E.; McCray, Alexa T.; Mefford, Heather; Merritt, J. Lawrence; Might, Matthew; Mirzaa, Ghayda; Morava-Kozicz, Eva; Moretti, Paolo M.; Morimoto, Marie; Mulvihill, John J.; Murdock, David R.; Nath, Avi; Nelson, Stan F.; Newman, John H.; Nicholas, Sarah K.; Nickerson, Deborah; Novacic, Donna; Oglesbee, Devin; Orengo, James P.; Pace, Laura; Pak, Stephen; Pallais, J. Carl; Palmer, Christina G.S.; Papp, Jeanette C.; Parker, Neil H.; Phillips, John A.; Posey, Jennifer E.; Postlethwait, John H.; Potocki, Lorraine; Pusey, Barbara N.; Quinlan, Aaron; Raskind, Wendy; Raja, Archana N.; Renteria, Genecee; Reuter, Chloe M.; Rives, Lynette; Robertson, Amy K.; Rodan, Lance H.; Rosenfeld, Jill A.; Rowley, Robb K.; Ruzhnikov, Maura; Sacco, Ralph; Sampson, Jacinda B.; Samson, Susan L.; Saporta, Mario; Scott, C. Ron; Schaechter, Judy; Schedl, Timothy; Schoch, Kelly; Scott, Daryl A.; Shakachite, Lisa; Sharma, Prashant; Shashi, Vandana; Shin, Jimann; Signer, Rebecca; Sillari, Catherine H.; Silverman, Edwin K.; Sinsheimer, Janet S.; Sisco, Kathy; Smith, Kevin S.; Solnica-Krezel, Lilianna; Spillmann, Rebecca C.; Stoler, Joan M.; Stong, Nicholas; Sullivan, Jennifer A.; Sun, Angela; Sutton, Shirley; Sweetser, David A.; Sybert, Virginia; Tabor, Holly K.; Tamburro, Cecelia P.; Tan, Queenie K.G.; Tekin, Mustafa; Telischi, Fred; Thorson, Willa; Tifft, Cynthia J.; Toro, Camilo; Tran, Alyssa A.; Urv, Tiina K.; Velinder, Matt; Viskochil, Dave; Vogel, Tiphanie P.; Wahl, Colleen E.; Wallace, Stephanie; Walley, Nicole M.; Walsh, Chris A.; Walker, Melissa; Wambach, Jennifer; Wan, Jijun; Wang, Lee Kai; Wangler, Michael F.; Ward, Patricia A.; Wegner, Daniel; Wener, Mark; Westerfield, Monte; Wheeler, Matthew T.; Wise, Anastasia L.; Wolfe, Lynne A.; Woods, Jeremy D.; Yamamoto, Shinya; Yang, John; Yoon, Amanda J.; Yu, Guoyun; Zastrow, Diane B.; Zhao, Chunli; Zuchner, Stephan; Worthey, Elizabeth A.

In: BMC bioinformatics, Vol. 20, No. 1, 496, 15.10.2019.

Research output: Contribution to journalArticle

Holt, JM, Wilk, B, Birch, CL, Brown, DM, Gajapathy, M, Moss, AC, Sosonkina, N, Wilk, MA, Anderson, JA, Harris, JM, Kelly, JM, Shaterferdosian, F, Uno-Antonison, AE, Weborg, A, Acosta, MT, Adam, M, Adams, DR, Agrawal, PB, Alejandro, ME, Allard, P, Alvey, J, Amendola, L, Andrews, A, Ashley, EA, Azamian, MS, Bacino, CA, Bademci, G, Baker, E, Balasubramanyam, A, Baldridge, D, Bale, J, Bamshad, M, Barbouth, D, Batzli, GF, Bayrak-Toydemir, P, Beck, A, Beggs, AH, Bejerano, G, Bellen, HJ, Bennet, J, Berg-Rood, B, Bernier, R, Bernstein, JA, Berry, GT, Bican, A, Bivona, S, Blue, E, Bohnsack, J, Bonnenmann, C, Bonner, D, Botto, L, Briere, LC, Brokamp, E, Burke, EA, Burrage, LC, Butte, MJ, Byers, P, Carey, J, Carrasquillo, O, Chang, TCP, Chanprasert, S, Chao, HT, Clark, GD, Coakley, TR, Cobban, LA, Cogan, JD, Cole, FS, Colley, HA, Cooper, CM, Cope, H, Craigen, WJ, Cunningham, M, D'Souza, P, Dai, H, Dasari, S, Davids, M, Dayal, JG, Dell'Angelica, EC, Dhar, SU, Dipple, K, Doherty, D, Dorrani, N, Douine, ED, Draper, DD, Duncan, L, Earl, D, Eckstein, DJ, Emrick, LT, Eng, CM, Esteves, C, Estwick, T, Fernandez, L, Ferreira, C, Fieg, EL, Fisher, PG, Fogel, BL, Forghani, I, Fresard, L, Gahl, WA, Glass, I, Godfrey, RA, Golden-Grant, K, Goldman, AM, Goldstein, DB, Grajewski, A, Groden, CA, Gropman, AL, Hahn, S, Hamid, R, Hanchard, NA, Hayes, N, High, F, Hing, A, Hisama, FM, Holm, IA, Hom, J, Horike-Pyne, M, Huang, A, Huang, Y, Isasi, R, Jamal, F, Jarvik, GP, Jarvik, J, Jayadev, S, Jiang, YH, Johnston, JM, Karaviti, L, Kelley, EG, Kiley, D, Kohane, IS, Kohler, JN, Krakow, D, Krasnewich, DM, Korrick, S, Koziura, M, Krier, JB, Lalani, SR, Lam, B, Lam, C, Lanpher, BC, Lanza, IR, Lau, CC, Leblanc, K, Lee, BH, Lee, H, Levitt, R, Lewis, RA, Lincoln, SA, Liu, P, Liu, XZ, Longo, N, Loo, SK, Loscalzo, J, Maas, RL, Macnamara, EF, MacRae, CA, Maduro, VV, Majcherska, MM, Malicdan, MCV, Mamounas, LA, Manolio, TA, Mao, R, Maravilla, K, Markello, TC, Marom, R, Marth, G, Martin, BA, Martin, MG, Martínez-Agosto, JA, Marwaha, S, McCauley, J, McConkie-Rosell, A, McCormack, CE, McCray, AT, Mefford, H, Merritt, JL, Might, M, Mirzaa, G, Morava-Kozicz, E, Moretti, PM, Morimoto, M, Mulvihill, JJ, Murdock, DR, Nath, A, Nelson, SF, Newman, JH, Nicholas, SK, Nickerson, D, Novacic, D, Oglesbee, D, Orengo, JP, Pace, L, Pak, S, Pallais, JC, Palmer, CGS, Papp, JC, Parker, NH, Phillips, JA, Posey, JE, Postlethwait, JH, Potocki, L, Pusey, BN, Quinlan, A, Raskind, W, Raja, AN, Renteria, G, Reuter, CM, Rives, L, Robertson, AK, Rodan, LH, Rosenfeld, JA, Rowley, RK, Ruzhnikov, M, Sacco, R, Sampson, JB, Samson, SL, Saporta, M, Scott, CR, Schaechter, J, Schedl, T, Schoch, K, Scott, DA, Shakachite, L, Sharma, P, Shashi, V, Shin, J, Signer, R, Sillari, CH, Silverman, EK, Sinsheimer, JS, Sisco, K, Smith, KS, Solnica-Krezel, L, Spillmann, RC, Stoler, JM, Stong, N, Sullivan, JA, Sun, A, Sutton, S, Sweetser, DA, Sybert, V, Tabor, HK, Tamburro, CP, Tan, QKG, Tekin, M, Telischi, F, Thorson, W, Tifft, CJ, Toro, C, Tran, AA, Urv, TK, Velinder, M, Viskochil, D, Vogel, TP, Wahl, CE, Wallace, S, Walley, NM, Walsh, CA, Walker, M, Wambach, J, Wan, J, Wang, LK, Wangler, MF, Ward, PA, Wegner, D, Wener, M, Westerfield, M, Wheeler, MT, Wise, AL, Wolfe, LA, Woods, JD, Yamamoto, S, Yang, J, Yoon, AJ, Yu, G, Zastrow, DB, Zhao, C, Zuchner, S & Worthey, EA 2019, 'VarSight: Prioritizing clinically reported variants with binary classification algorithms', BMC bioinformatics, vol. 20, no. 1, 496. https://doi.org/10.1186/s12859-019-3026-8
Holt, James M. ; Wilk, Brandon ; Birch, Camille L. ; Brown, Donna M. ; Gajapathy, Manavalan ; Moss, Alexander C. ; Sosonkina, Nadiya ; Wilk, Melissa A. ; Anderson, Julie A. ; Harris, Jeremy M. ; Kelly, Jacob M. ; Shaterferdosian, Fariba ; Uno-Antonison, Angelina E. ; Weborg, Arthur ; Acosta, Maria T. ; Adam, Margaret ; Adams, David R. ; Agrawal, Pankaj B. ; Alejandro, Mercedes E. ; Allard, Patrick ; Alvey, Justin ; Amendola, Laura ; Andrews, Ashley ; Ashley, Euan A. ; Azamian, Mahshid S. ; Bacino, Carlos A. ; Bademci, Guney ; Baker, Eva ; Balasubramanyam, Ashok ; Baldridge, Dustin ; Bale, Jim ; Bamshad, Michael ; Barbouth, Deborah ; Batzli, Gabriel F. ; Bayrak-Toydemir, Pinar ; Beck, Anita ; Beggs, Alan H. ; Bejerano, Gill ; Bellen, Hugo J. ; Bennet, Jimmy ; Berg-Rood, Beverly ; Bernier, Raphael ; Bernstein, Jonathan A. ; Berry, Gerard T. ; Bican, Anna ; Bivona, Stephanie ; Blue, Elizabeth ; Bohnsack, John ; Bonnenmann, Carsten ; Bonner, Devon ; Botto, Lorenzo ; Briere, Lauren C. ; Brokamp, Elly ; Burke, Elizabeth A. ; Burrage, Lindsay C. ; Butte, Manish J. ; Byers, Peter ; Carey, John ; Carrasquillo, Olveen ; Chang, Ta Chen Peter ; Chanprasert, Sirisak ; Chao, Hsiao Tuan ; Clark, Gary D. ; Coakley, Terra R. ; Cobban, Laurel A. ; Cogan, Joy D. ; Cole, F. Sessions ; Colley, Heather A. ; Cooper, Cynthia M. ; Cope, Heidi ; Craigen, William J. ; Cunningham, Michael ; D'Souza, Precilla ; Dai, Hongzheng ; Dasari, Surendra ; Davids, Mariska ; Dayal, Jyoti G. ; Dell'Angelica, Esteban C. ; Dhar, Shweta U. ; Dipple, Katrina ; Doherty, Daniel ; Dorrani, Naghmeh ; Douine, Emilie D. ; Draper, David D. ; Duncan, Laura ; Earl, Dawn ; Eckstein, David J. ; Emrick, Lisa T. ; Eng, Christine M. ; Esteves, Cecilia ; Estwick, Tyra ; Fernandez, Liliana ; Ferreira, Carlos ; Fieg, Elizabeth L. ; Fisher, Paul G. ; Fogel, Brent L. ; Forghani, Irman ; Fresard, Laure ; Gahl, William A. ; Glass, Ian ; Godfrey, Rena A. ; Golden-Grant, Katie ; Goldman, Alica M. ; Goldstein, David B. ; Grajewski, Alana ; Groden, Catherine A. ; Gropman, Andrea L. ; Hahn, Sihoun ; Hamid, Rizwan ; Hanchard, Neil A. ; Hayes, Nichole ; High, Frances ; Hing, Anne ; Hisama, Fuki M. ; Holm, Ingrid A. ; Hom, Jason ; Horike-Pyne, Martha ; Huang, Alden ; Huang, Yong ; Isasi, Rosario ; Jamal, Fariha ; Jarvik, Gail P. ; Jarvik, Jeffrey ; Jayadev, Suman ; Jiang, Yong Hui ; Johnston, Jean M. ; Karaviti, Lefkothea ; Kelley, Emily G. ; Kiley, Dana ; Kohane, Isaac S. ; Kohler, Jennefer N. ; Krakow, Deborah ; Krasnewich, Donna M. ; Korrick, Susan ; Koziura, Mary ; Krier, Joel B. ; Lalani, Seema R. ; Lam, Byron ; Lam, Christina ; Lanpher, Brendan C. ; Lanza, Ian R. ; Lau, C. Christopher ; Leblanc, Kimberly ; Lee, Brendan H. ; Lee, Hane ; Levitt, Roy ; Lewis, Richard A. ; Lincoln, Sharyn A. ; Liu, Pengfei ; Liu, Xue Zhong ; Longo, Nicola ; Loo, Sandra K. ; Loscalzo, Joseph ; Maas, Richard L. ; Macnamara, Ellen F. ; MacRae, Calum A. ; Maduro, Valerie V. ; Majcherska, Marta M. ; Malicdan, May Christine V. ; Mamounas, Laura A. ; Manolio, Teri A. ; Mao, Rong ; Maravilla, Kenneth ; Markello, Thomas C. ; Marom, Ronit ; Marth, Gabor ; Martin, Beth A. ; Martin, Martin G. ; Martínez-Agosto, Julian A. ; Marwaha, Shruti ; McCauley, Jacob ; McConkie-Rosell, Allyn ; McCormack, Colleen E. ; McCray, Alexa T. ; Mefford, Heather ; Merritt, J. Lawrence ; Might, Matthew ; Mirzaa, Ghayda ; Morava-Kozicz, Eva ; Moretti, Paolo M. ; Morimoto, Marie ; Mulvihill, John J. ; Murdock, David R. ; Nath, Avi ; Nelson, Stan F. ; Newman, John H. ; Nicholas, Sarah K. ; Nickerson, Deborah ; Novacic, Donna ; Oglesbee, Devin ; Orengo, James P. ; Pace, Laura ; Pak, Stephen ; Pallais, J. Carl ; Palmer, Christina G.S. ; Papp, Jeanette C. ; Parker, Neil H. ; Phillips, John A. ; Posey, Jennifer E. ; Postlethwait, John H. ; Potocki, Lorraine ; Pusey, Barbara N. ; Quinlan, Aaron ; Raskind, Wendy ; Raja, Archana N. ; Renteria, Genecee ; Reuter, Chloe M. ; Rives, Lynette ; Robertson, Amy K. ; Rodan, Lance H. ; Rosenfeld, Jill A. ; Rowley, Robb K. ; Ruzhnikov, Maura ; Sacco, Ralph ; Sampson, Jacinda B. ; Samson, Susan L. ; Saporta, Mario ; Scott, C. Ron ; Schaechter, Judy ; Schedl, Timothy ; Schoch, Kelly ; Scott, Daryl A. ; Shakachite, Lisa ; Sharma, Prashant ; Shashi, Vandana ; Shin, Jimann ; Signer, Rebecca ; Sillari, Catherine H. ; Silverman, Edwin K. ; Sinsheimer, Janet S. ; Sisco, Kathy ; Smith, Kevin S. ; Solnica-Krezel, Lilianna ; Spillmann, Rebecca C. ; Stoler, Joan M. ; Stong, Nicholas ; Sullivan, Jennifer A. ; Sun, Angela ; Sutton, Shirley ; Sweetser, David A. ; Sybert, Virginia ; Tabor, Holly K. ; Tamburro, Cecelia P. ; Tan, Queenie K.G. ; Tekin, Mustafa ; Telischi, Fred ; Thorson, Willa ; Tifft, Cynthia J. ; Toro, Camilo ; Tran, Alyssa A. ; Urv, Tiina K. ; Velinder, Matt ; Viskochil, Dave ; Vogel, Tiphanie P. ; Wahl, Colleen E. ; Wallace, Stephanie ; Walley, Nicole M. ; Walsh, Chris A. ; Walker, Melissa ; Wambach, Jennifer ; Wan, Jijun ; Wang, Lee Kai ; Wangler, Michael F. ; Ward, Patricia A. ; Wegner, Daniel ; Wener, Mark ; Westerfield, Monte ; Wheeler, Matthew T. ; Wise, Anastasia L. ; Wolfe, Lynne A. ; Woods, Jeremy D. ; Yamamoto, Shinya ; Yang, John ; Yoon, Amanda J. ; Yu, Guoyun ; Zastrow, Diane B. ; Zhao, Chunli ; Zuchner, Stephan ; Worthey, Elizabeth A. / VarSight : Prioritizing clinically reported variants with binary classification algorithms. In: BMC bioinformatics. 2019 ; Vol. 20, No. 1.
@article{bf578914f9a140f4b6fba04cb5f05101,
title = "VarSight: Prioritizing clinically reported variants with binary classification algorithms",
abstract = "Background: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. Methods: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. Results: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72{\%} of all reported variants and 94{\%} of reported pathogenic variants in the top 20. Conclusions: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.",
keywords = "Binary classification, Clinical genome sequencing, Variant prioritization",
author = "Holt, {James M.} and Brandon Wilk and Birch, {Camille L.} and Brown, {Donna M.} and Manavalan Gajapathy and Moss, {Alexander C.} and Nadiya Sosonkina and Wilk, {Melissa A.} and Anderson, {Julie A.} and Harris, {Jeremy M.} and Kelly, {Jacob M.} and Fariba Shaterferdosian and Uno-Antonison, {Angelina E.} and Arthur Weborg and Acosta, {Maria T.} and Margaret Adam and Adams, {David R.} and Agrawal, {Pankaj B.} and Alejandro, {Mercedes E.} and Patrick Allard and Justin Alvey and Laura Amendola and Ashley Andrews and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Guney Bademci and Eva Baker and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Michael Bamshad and Deborah Barbouth and Batzli, {Gabriel F.} and Pinar Bayrak-Toydemir and Anita Beck and Beggs, {Alan H.} and Gill Bejerano and Bellen, {Hugo J.} and Jimmy Bennet and Beverly Berg-Rood and Raphael Bernier and Bernstein, {Jonathan A.} and Berry, {Gerard T.} and Anna Bican and Stephanie Bivona and Elizabeth Blue and John Bohnsack and Carsten Bonnenmann and Devon Bonner and Lorenzo Botto and Briere, {Lauren C.} and Elly Brokamp and Burke, {Elizabeth A.} and Burrage, {Lindsay C.} and Butte, {Manish J.} and Peter Byers and John Carey and Olveen Carrasquillo and Chang, {Ta Chen Peter} and Sirisak Chanprasert and Chao, {Hsiao Tuan} and Clark, {Gary D.} and Coakley, {Terra R.} and Cobban, {Laurel A.} and Cogan, {Joy D.} and Cole, {F. Sessions} and Colley, {Heather A.} and Cooper, {Cynthia M.} and Heidi Cope and Craigen, {William J.} and Michael Cunningham and Precilla D'Souza and Hongzheng Dai and Surendra Dasari and Mariska Davids and Dayal, {Jyoti G.} and Dell'Angelica, {Esteban C.} and Dhar, {Shweta U.} and Katrina Dipple and Daniel Doherty and Naghmeh Dorrani and Douine, {Emilie D.} and Draper, {David D.} and Laura Duncan and Dawn Earl and Eckstein, {David J.} and Emrick, {Lisa T.} and Eng, {Christine M.} and Cecilia Esteves and Tyra Estwick and Liliana Fernandez and Carlos Ferreira and Fieg, {Elizabeth L.} and Fisher, {Paul G.} and Fogel, {Brent L.} and Irman Forghani and Laure Fresard and Gahl, {William A.} and Ian Glass and Godfrey, {Rena A.} and Katie Golden-Grant and Goldman, {Alica M.} and Goldstein, {David B.} and Alana Grajewski and Groden, {Catherine A.} and Gropman, {Andrea L.} and Sihoun Hahn and Rizwan Hamid and Hanchard, {Neil A.} and Nichole Hayes and Frances High and Anne Hing and Hisama, {Fuki M.} and Holm, {Ingrid A.} and Jason Hom and Martha Horike-Pyne and Alden Huang and Yong Huang and Rosario Isasi and Fariha Jamal and Jarvik, {Gail P.} and Jeffrey Jarvik and Suman Jayadev and Jiang, {Yong Hui} and Johnston, {Jean M.} and Lefkothea Karaviti and Kelley, {Emily G.} and Dana Kiley and Kohane, {Isaac S.} and Kohler, {Jennefer N.} and Deborah Krakow and Krasnewich, {Donna M.} and Susan Korrick and Mary Koziura and Krier, {Joel B.} and Lalani, {Seema R.} and Byron Lam and Christina Lam and Lanpher, {Brendan C.} and Lanza, {Ian R.} and Lau, {C. Christopher} and Kimberly Leblanc and Lee, {Brendan H.} and Hane Lee and Roy Levitt and Lewis, {Richard A.} and Lincoln, {Sharyn A.} and Pengfei Liu and Liu, {Xue Zhong} and Nicola Longo and Loo, {Sandra K.} and Joseph Loscalzo and Maas, {Richard L.} and Macnamara, {Ellen F.} and MacRae, {Calum A.} and Maduro, {Valerie V.} and Majcherska, {Marta M.} and Malicdan, {May Christine V.} and Mamounas, {Laura A.} and Manolio, {Teri A.} and Rong Mao and Kenneth Maravilla and Markello, {Thomas C.} and Ronit Marom and Gabor Marth and Martin, {Beth A.} and Martin, {Martin G.} and Mart{\'i}nez-Agosto, {Julian A.} and Shruti Marwaha and Jacob McCauley and Allyn McConkie-Rosell and McCormack, {Colleen E.} and McCray, {Alexa T.} and Heather Mefford and Merritt, {J. Lawrence} and Matthew Might and Ghayda Mirzaa and Eva Morava-Kozicz and Moretti, {Paolo M.} and Marie Morimoto and Mulvihill, {John J.} and Murdock, {David R.} and Avi Nath and Nelson, {Stan F.} and Newman, {John H.} and Nicholas, {Sarah K.} and Deborah Nickerson and Donna Novacic and Devin Oglesbee and Orengo, {James P.} and Laura Pace and Stephen Pak and Pallais, {J. Carl} and Palmer, {Christina G.S.} and Papp, {Jeanette C.} and Parker, {Neil H.} and Phillips, {John A.} and Posey, {Jennifer E.} and Postlethwait, {John H.} and Lorraine Potocki and Pusey, {Barbara N.} and Aaron Quinlan and Wendy Raskind and Raja, {Archana N.} and Genecee Renteria and Reuter, {Chloe M.} and Lynette Rives and Robertson, {Amy K.} and Rodan, {Lance H.} and Rosenfeld, {Jill A.} and Rowley, {Robb K.} and Maura Ruzhnikov and Ralph Sacco and Sampson, {Jacinda B.} and Samson, {Susan L.} and Mario Saporta and Scott, {C. Ron} and Judy Schaechter and Timothy Schedl and Kelly Schoch and Scott, {Daryl A.} and Lisa Shakachite and Prashant Sharma and Vandana Shashi and Jimann Shin and Rebecca Signer and Sillari, {Catherine H.} and Silverman, {Edwin K.} and Sinsheimer, {Janet S.} and Kathy Sisco and Smith, {Kevin S.} and Lilianna Solnica-Krezel and Spillmann, {Rebecca C.} and Stoler, {Joan M.} and Nicholas Stong and Sullivan, {Jennifer A.} and Angela Sun and Shirley Sutton and Sweetser, {David A.} and Virginia Sybert and Tabor, {Holly K.} and Tamburro, {Cecelia P.} and Tan, {Queenie K.G.} and Mustafa Tekin and Fred Telischi and Willa Thorson and Tifft, {Cynthia J.} and Camilo Toro and Tran, {Alyssa A.} and Urv, {Tiina K.} and Matt Velinder and Dave Viskochil and Vogel, {Tiphanie P.} and Wahl, {Colleen E.} and Stephanie Wallace and Walley, {Nicole M.} and Walsh, {Chris A.} and Melissa Walker and Jennifer Wambach and Jijun Wan and Wang, {Lee Kai} and Wangler, {Michael F.} and Ward, {Patricia A.} and Daniel Wegner and Mark Wener and Monte Westerfield and Wheeler, {Matthew T.} and Wise, {Anastasia L.} and Wolfe, {Lynne A.} and Woods, {Jeremy D.} and Shinya Yamamoto and John Yang and Yoon, {Amanda J.} and Guoyun Yu and Zastrow, {Diane B.} and Chunli Zhao and Stephan Zuchner and Worthey, {Elizabeth A.}",
year = "2019",
month = "10",
day = "15",
doi = "10.1186/s12859-019-3026-8",
language = "English (US)",
volume = "20",
journal = "BMC Bioinformatics",
issn = "1471-2105",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - VarSight

T2 - Prioritizing clinically reported variants with binary classification algorithms

AU - Holt, James M.

AU - Wilk, Brandon

AU - Birch, Camille L.

AU - Brown, Donna M.

AU - Gajapathy, Manavalan

AU - Moss, Alexander C.

AU - Sosonkina, Nadiya

AU - Wilk, Melissa A.

AU - Anderson, Julie A.

AU - Harris, Jeremy M.

AU - Kelly, Jacob M.

AU - Shaterferdosian, Fariba

AU - Uno-Antonison, Angelina E.

AU - Weborg, Arthur

AU - Acosta, Maria T.

AU - Adam, Margaret

AU - Adams, David R.

AU - Agrawal, Pankaj B.

AU - Alejandro, Mercedes E.

AU - Allard, Patrick

AU - Alvey, Justin

AU - Amendola, Laura

AU - Andrews, Ashley

AU - Ashley, Euan A.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Bademci, Guney

AU - Baker, Eva

AU - Balasubramanyam, Ashok

AU - Baldridge, Dustin

AU - Bale, Jim

AU - Bamshad, Michael

AU - Barbouth, Deborah

AU - Batzli, Gabriel F.

AU - Bayrak-Toydemir, Pinar

AU - Beck, Anita

AU - Beggs, Alan H.

AU - Bejerano, Gill

AU - Bellen, Hugo J.

AU - Bennet, Jimmy

AU - Berg-Rood, Beverly

AU - Bernier, Raphael

AU - Bernstein, Jonathan A.

AU - Berry, Gerard T.

AU - Bican, Anna

AU - Bivona, Stephanie

AU - Blue, Elizabeth

AU - Bohnsack, John

AU - Bonnenmann, Carsten

AU - Bonner, Devon

AU - Botto, Lorenzo

AU - Briere, Lauren C.

AU - Brokamp, Elly

AU - Burke, Elizabeth A.

AU - Burrage, Lindsay C.

AU - Butte, Manish J.

AU - Byers, Peter

AU - Carey, John

AU - Carrasquillo, Olveen

AU - Chang, Ta Chen Peter

AU - Chanprasert, Sirisak

AU - Chao, Hsiao Tuan

AU - Clark, Gary D.

AU - Coakley, Terra R.

AU - Cobban, Laurel A.

AU - Cogan, Joy D.

AU - Cole, F. Sessions

AU - Colley, Heather A.

AU - Cooper, Cynthia M.

AU - Cope, Heidi

AU - Craigen, William J.

AU - Cunningham, Michael

AU - D'Souza, Precilla

AU - Dai, Hongzheng

AU - Dasari, Surendra

AU - Davids, Mariska

AU - Dayal, Jyoti G.

AU - Dell'Angelica, Esteban C.

AU - Dhar, Shweta U.

AU - Dipple, Katrina

AU - Doherty, Daniel

AU - Dorrani, Naghmeh

AU - Douine, Emilie D.

AU - Draper, David D.

AU - Duncan, Laura

AU - Earl, Dawn

AU - Eckstein, David J.

AU - Emrick, Lisa T.

AU - Eng, Christine M.

AU - Esteves, Cecilia

AU - Estwick, Tyra

AU - Fernandez, Liliana

AU - Ferreira, Carlos

AU - Fieg, Elizabeth L.

AU - Fisher, Paul G.

AU - Fogel, Brent L.

AU - Forghani, Irman

AU - Fresard, Laure

AU - Gahl, William A.

AU - Glass, Ian

AU - Godfrey, Rena A.

AU - Golden-Grant, Katie

AU - Goldman, Alica M.

AU - Goldstein, David B.

AU - Grajewski, Alana

AU - Groden, Catherine A.

AU - Gropman, Andrea L.

AU - Hahn, Sihoun

AU - Hamid, Rizwan

AU - Hanchard, Neil A.

AU - Hayes, Nichole

AU - High, Frances

AU - Hing, Anne

AU - Hisama, Fuki M.

AU - Holm, Ingrid A.

AU - Hom, Jason

AU - Horike-Pyne, Martha

AU - Huang, Alden

AU - Huang, Yong

AU - Isasi, Rosario

AU - Jamal, Fariha

AU - Jarvik, Gail P.

AU - Jarvik, Jeffrey

AU - Jayadev, Suman

AU - Jiang, Yong Hui

AU - Johnston, Jean M.

AU - Karaviti, Lefkothea

AU - Kelley, Emily G.

AU - Kiley, Dana

AU - Kohane, Isaac S.

AU - Kohler, Jennefer N.

AU - Krakow, Deborah

AU - Krasnewich, Donna M.

AU - Korrick, Susan

AU - Koziura, Mary

AU - Krier, Joel B.

AU - Lalani, Seema R.

AU - Lam, Byron

AU - Lam, Christina

AU - Lanpher, Brendan C.

AU - Lanza, Ian R.

AU - Lau, C. Christopher

AU - Leblanc, Kimberly

AU - Lee, Brendan H.

AU - Lee, Hane

AU - Levitt, Roy

AU - Lewis, Richard A.

AU - Lincoln, Sharyn A.

AU - Liu, Pengfei

AU - Liu, Xue Zhong

AU - Longo, Nicola

AU - Loo, Sandra K.

AU - Loscalzo, Joseph

AU - Maas, Richard L.

AU - Macnamara, Ellen F.

AU - MacRae, Calum A.

AU - Maduro, Valerie V.

AU - Majcherska, Marta M.

AU - Malicdan, May Christine V.

AU - Mamounas, Laura A.

AU - Manolio, Teri A.

AU - Mao, Rong

AU - Maravilla, Kenneth

AU - Markello, Thomas C.

AU - Marom, Ronit

AU - Marth, Gabor

AU - Martin, Beth A.

AU - Martin, Martin G.

AU - Martínez-Agosto, Julian A.

AU - Marwaha, Shruti

AU - McCauley, Jacob

AU - McConkie-Rosell, Allyn

AU - McCormack, Colleen E.

AU - McCray, Alexa T.

AU - Mefford, Heather

AU - Merritt, J. Lawrence

AU - Might, Matthew

AU - Mirzaa, Ghayda

AU - Morava-Kozicz, Eva

AU - Moretti, Paolo M.

AU - Morimoto, Marie

AU - Mulvihill, John J.

AU - Murdock, David R.

AU - Nath, Avi

AU - Nelson, Stan F.

AU - Newman, John H.

AU - Nicholas, Sarah K.

AU - Nickerson, Deborah

AU - Novacic, Donna

AU - Oglesbee, Devin

AU - Orengo, James P.

AU - Pace, Laura

AU - Pak, Stephen

AU - Pallais, J. Carl

AU - Palmer, Christina G.S.

AU - Papp, Jeanette C.

AU - Parker, Neil H.

AU - Phillips, John A.

AU - Posey, Jennifer E.

AU - Postlethwait, John H.

AU - Potocki, Lorraine

AU - Pusey, Barbara N.

AU - Quinlan, Aaron

AU - Raskind, Wendy

AU - Raja, Archana N.

AU - Renteria, Genecee

AU - Reuter, Chloe M.

AU - Rives, Lynette

AU - Robertson, Amy K.

AU - Rodan, Lance H.

AU - Rosenfeld, Jill A.

AU - Rowley, Robb K.

AU - Ruzhnikov, Maura

AU - Sacco, Ralph

AU - Sampson, Jacinda B.

AU - Samson, Susan L.

AU - Saporta, Mario

AU - Scott, C. Ron

AU - Schaechter, Judy

AU - Schedl, Timothy

AU - Schoch, Kelly

AU - Scott, Daryl A.

AU - Shakachite, Lisa

AU - Sharma, Prashant

AU - Shashi, Vandana

AU - Shin, Jimann

AU - Signer, Rebecca

AU - Sillari, Catherine H.

AU - Silverman, Edwin K.

AU - Sinsheimer, Janet S.

AU - Sisco, Kathy

AU - Smith, Kevin S.

AU - Solnica-Krezel, Lilianna

AU - Spillmann, Rebecca C.

AU - Stoler, Joan M.

AU - Stong, Nicholas

AU - Sullivan, Jennifer A.

AU - Sun, Angela

AU - Sutton, Shirley

AU - Sweetser, David A.

AU - Sybert, Virginia

AU - Tabor, Holly K.

AU - Tamburro, Cecelia P.

AU - Tan, Queenie K.G.

AU - Tekin, Mustafa

AU - Telischi, Fred

AU - Thorson, Willa

AU - Tifft, Cynthia J.

AU - Toro, Camilo

AU - Tran, Alyssa A.

AU - Urv, Tiina K.

AU - Velinder, Matt

AU - Viskochil, Dave

AU - Vogel, Tiphanie P.

AU - Wahl, Colleen E.

AU - Wallace, Stephanie

AU - Walley, Nicole M.

AU - Walsh, Chris A.

AU - Walker, Melissa

AU - Wambach, Jennifer

AU - Wan, Jijun

AU - Wang, Lee Kai

AU - Wangler, Michael F.

AU - Ward, Patricia A.

AU - Wegner, Daniel

AU - Wener, Mark

AU - Westerfield, Monte

AU - Wheeler, Matthew T.

AU - Wise, Anastasia L.

AU - Wolfe, Lynne A.

AU - Woods, Jeremy D.

AU - Yamamoto, Shinya

AU - Yang, John

AU - Yoon, Amanda J.

AU - Yu, Guoyun

AU - Zastrow, Diane B.

AU - Zhao, Chunli

AU - Zuchner, Stephan

AU - Worthey, Elizabeth A.

PY - 2019/10/15

Y1 - 2019/10/15

N2 - Background: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. Methods: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. Results: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. Conclusions: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

AB - Background: When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. Methods: We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. Results: We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. Conclusions: We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.

KW - Binary classification

KW - Clinical genome sequencing

KW - Variant prioritization

UR - http://www.scopus.com/inward/record.url?scp=85073430239&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073430239&partnerID=8YFLogxK

U2 - 10.1186/s12859-019-3026-8

DO - 10.1186/s12859-019-3026-8

M3 - Article

C2 - 31615419

AN - SCOPUS:85073430239

VL - 20

JO - BMC Bioinformatics

JF - BMC Bioinformatics

SN - 1471-2105

IS - 1

M1 - 496

ER -