Thomas Minten, Sarah Bick, Sophia Adelson, Nils Gehlenborg, Laura M Amendola, François Boemer, Alison J Coffey, Nicolas Encina, Alessandra Ferlini, Janbernd Kirschner, Bianca E Russell, Laurent Servais, Kristen L Sund, Ryan J Taft, Petros Tsipouras, Hana Zouk, Robert C Green, Nina B Gold, David Bick, Mattia Gentile, Paola Orsini, Romina Ficarella, Maria Luisa Valente, Emanuela Ponzi, Athina Ververi, Maria Koutsogianni, Huang Xinwen, Xiao Rui, Zhao Zhengyan, Matthew J Pelo, Jovanka King, Carol Siu, Karin Kassahn, Stefaan Sansen, Enrico Bertini, Aldona Zygmunt, Sophia Adelson, Mattia Gentile, Mette Nyegaard, Emanuele Agolini, Jessica Giordano, Justin O'Sullivan, Aljazi Al-Maraghi, Ulrich Glumer Jensen, Jelili Ojodu, Karla Alex, David Godler, Paola Orsini, Fowzan Alkuraya, Nina Gold, Andrea Oza, Ammira Alshabeeb Akil, Aaron Goldenberg, Katrina Paleologos, Munira Alshehri, Katie GoldenGrant, Richard Parad, Derek Ansel, Cassie Goldman, Holly Peay, Niki Armstrong, José Manuel González de Aledo-Castillo, Matthew Pelo, Matthew Aujla, Daniel Gottlieb, Carolyn Philstrom, Don Bailey, Robert Green, Dominique Pichard, Mei Baker, Christopher Greene, Amanda Pichini, Jorune Balciuniene, Brooke Greenstein, Holly Pickering, Andrew Barry, Scott Grosse, Michelle Pirreca, Bruce Bennetts, Annette Grueters, Malgorzata Ponikowska, Melissa Berenger, Gulcin Gumus, Amy Ponte, Jonathan Berg, Kelly Hagman, Andreas Posch, Donna Bernstein, Kevin Hall, Cynthia Powell, Arindam Bhatatcharjee, Aymeric Harmant, Liana Protopsaltis, Sucheta Bhatt, Sally Hartmanis, Yeyson Quevedo, David Bick, Robin Hayeems, Marianna Raia, Tracey Bishop, Rose Heald, Rebecca Reimers, Asaf Bitton, Madhuri Hegde, Andy Rohrwasser, François Boemer, Rebecca Heiner-Fokkema, Paul Rollier, Natasha Bonhomme, Lidewij Henneman, Lene Rottensten, George Bowley, Becca Hernan, Irakli Rtskhiladze, Brenna Boyd, Charlotte Hobbs, Nabihah Sachedina, Heiko Brennenstuhl, Ingrid Holm, George Sahyoun, Steven Brenner, Layla Horwitz, Aditi Satija, Mairead Bresnahan, Zhanzhi Hu, Christian Schaaf, Thomas Brewster, Maria Iascone, Jennifer Schleit, P J Brooks, Ken Irvine, Richard Scott, Katya Broomberg, Guanjun Jin, Lauren Scully, Amy Brower, Kelsey Kalbfleisch, Stacey Seeloff, Gemma Brown, Ines Kander, Laurent Servais, James Buchanan, Lucy Kaplun, Nidhi Shah, Caleb Bupp, Dalia Kasperaviciute, Maija Siitonen, Candance Cameron, Karin Kassahn, Sikha Singh, Lauren Capacchione, Leni Kauko, Carol Siu, Diana Carli, Riina Kaukonen, Hadley Smith, Onassis Castillo Ceballo, Nicole Kelly, Lisa Sniderman King, Kee Chan, Dhayo Khangsar, Neal Sondheimer, Jillian Chance, Jovanka King, Lourdes St George, Georgia Charalambidou, Clare Kingsley, Zornitza Stark, Winnie Chen, Stephen Kingsmore, Robert Steiner, Yun-Ru Chen, Brian Kirmse, Ulrik Stoltze, Wendy Chung, Rachel Klein, Asbjørg Stray-Pedersen, Brian Chung, Stefan Koelker, Kristen Sund, Megan Clarke, Youssef Kousa, Paris Tafas, Susan Clasper, Elizaveta Krupoderova, Polakit Teekakirikul, F Sessions Cole, Paul Kruszka, Dimitrios Thanos, Heidi Cope, Katherine Langley, Audrey Thurm, Stephanie Coury, Ciara Leckie, Meekai To, Tony Cox, Emmanuelle Lecommandeur, Petros Tsipouras, Tamara Dangouloff, David Ledbetter, Alice Tuff-Lacey, Earnest James Paul Daniel, Pamela Lee, Heather Turner, Katrin Eivindardottir Danielsen, Beomhee Lee, Philip Twiss, Emeline Davoine, Camille Level, Fiona Ulph, Tom Defay, Celine Lewis, Daniel Uribe, Geethanjali Devadoss Gandhi, Anna Lewis, Tiina Urv, Joseph Dewulf, Ruby Liu, Cora Vacher, Lisa Diller, Mauro Longoni, Kris Van Den Bogaert, Pakhi Dixit, Alberte Lundquist, Mirjam van der Burg, Martijn Dolle, Sebastian Lunke, Eva Van Steijvoort, Lilian Downie, Kate MacDuffie, Yiota Veloudi, Erin Drake, Ankit Malhotra, Elizabeth Vengoechea, Suzanne Drury, Lionel Marcelis, Els Voorhoeve, Annelotte Duintjer, Maria Martinez-Fresno, Martin Vu, Bugrahan Duz, Gert Matthijs, Melissa Wasserstein, David Eckstein, Roberts Melbardis, Michael Watson, Matthew Ellinwood, Jessica Merritt, Bryn Webb, Katarzyna Ellsworth, Radja Messai Badji, Anna Wedell, Sarah Elsea, Lou Metherell, Thomas Westover, Nicolas Encina, Nanna Balle Mikkelsen, Alexandra Wiedemann, Harriet Etheredge, Laura Milko, Meredith Wright, Laurence Faivre, Nicole Miller, Cindy Wu, Alessandra Ferlini, Thomas Minten, Julie Yeo, Monica Ferrie, Sian Morgan, Nancy Yin-Hsiu Chien, Terri Finkel, Katarzyna Mosiewicz, Shamila Yusuff, Petra Furu, Ulrike Mütze, Tomasz Zemojtel, Jamie Galarza-Cornejo, Sukhvinder Nicklen, Bethany Zettler, Ya Gao, Minna Niemela, Zhengyan Zhao, Judit Garcia-Villoria, Dau-Ming Niu, Joanna Ziff, Liz Gardner, Sarah Norris, Rebekah Zimmerman, Amy Gaviglio, Antonio Novelli, Michela Zuccolo, Michael Gelb, Arwa Nusair
{"title":"数据驱动的考虑遗传疾病的全球基因组新生儿筛查计划。","authors":"Thomas Minten, Sarah Bick, Sophia Adelson, Nils Gehlenborg, Laura M Amendola, François Boemer, Alison J Coffey, Nicolas Encina, Alessandra Ferlini, Janbernd Kirschner, Bianca E Russell, Laurent Servais, Kristen L Sund, Ryan J Taft, Petros Tsipouras, Hana Zouk, Robert C Green, Nina B Gold, David Bick, Mattia Gentile, Paola Orsini, Romina Ficarella, Maria Luisa Valente, Emanuela Ponzi, Athina Ververi, Maria Koutsogianni, Huang Xinwen, Xiao Rui, Zhao Zhengyan, Matthew J Pelo, Jovanka King, Carol Siu, Karin Kassahn, Stefaan Sansen, Enrico Bertini, Aldona Zygmunt, Sophia Adelson, Mattia Gentile, Mette Nyegaard, Emanuele Agolini, Jessica Giordano, Justin O'Sullivan, Aljazi Al-Maraghi, Ulrich Glumer Jensen, Jelili Ojodu, Karla Alex, David Godler, Paola Orsini, Fowzan Alkuraya, Nina Gold, Andrea Oza, Ammira Alshabeeb Akil, Aaron Goldenberg, Katrina Paleologos, Munira Alshehri, Katie GoldenGrant, Richard Parad, Derek Ansel, Cassie Goldman, Holly Peay, Niki Armstrong, José Manuel González de Aledo-Castillo, Matthew Pelo, Matthew Aujla, Daniel Gottlieb, Carolyn Philstrom, Don Bailey, Robert Green, Dominique Pichard, Mei Baker, Christopher Greene, Amanda Pichini, Jorune Balciuniene, Brooke Greenstein, Holly Pickering, Andrew Barry, Scott Grosse, Michelle Pirreca, Bruce Bennetts, Annette Grueters, Malgorzata Ponikowska, Melissa Berenger, Gulcin Gumus, Amy Ponte, Jonathan Berg, Kelly Hagman, Andreas Posch, Donna Bernstein, Kevin Hall, Cynthia Powell, Arindam Bhatatcharjee, Aymeric Harmant, Liana Protopsaltis, Sucheta Bhatt, Sally Hartmanis, Yeyson Quevedo, David Bick, Robin Hayeems, Marianna Raia, Tracey Bishop, Rose Heald, Rebecca Reimers, Asaf Bitton, Madhuri Hegde, Andy Rohrwasser, François Boemer, Rebecca Heiner-Fokkema, Paul Rollier, Natasha Bonhomme, Lidewij Henneman, Lene Rottensten, George Bowley, Becca Hernan, Irakli Rtskhiladze, Brenna Boyd, Charlotte Hobbs, Nabihah Sachedina, Heiko Brennenstuhl, Ingrid Holm, George Sahyoun, Steven Brenner, Layla Horwitz, Aditi Satija, Mairead Bresnahan, Zhanzhi Hu, Christian Schaaf, Thomas Brewster, Maria Iascone, Jennifer Schleit, P J Brooks, Ken Irvine, Richard Scott, Katya Broomberg, Guanjun Jin, Lauren Scully, Amy Brower, Kelsey Kalbfleisch, Stacey Seeloff, Gemma Brown, Ines Kander, Laurent Servais, James Buchanan, Lucy Kaplun, Nidhi Shah, Caleb Bupp, Dalia Kasperaviciute, Maija Siitonen, Candance Cameron, Karin Kassahn, Sikha Singh, Lauren Capacchione, Leni Kauko, Carol Siu, Diana Carli, Riina Kaukonen, Hadley Smith, Onassis Castillo Ceballo, Nicole Kelly, Lisa Sniderman King, Kee Chan, Dhayo Khangsar, Neal Sondheimer, Jillian Chance, Jovanka King, Lourdes St George, Georgia Charalambidou, Clare Kingsley, Zornitza Stark, Winnie Chen, Stephen Kingsmore, Robert Steiner, Yun-Ru Chen, Brian Kirmse, Ulrik Stoltze, Wendy Chung, Rachel Klein, Asbjørg Stray-Pedersen, Brian Chung, Stefan Koelker, Kristen Sund, Megan Clarke, Youssef Kousa, Paris Tafas, Susan Clasper, Elizaveta Krupoderova, Polakit Teekakirikul, F Sessions Cole, Paul Kruszka, Dimitrios Thanos, Heidi Cope, Katherine Langley, Audrey Thurm, Stephanie Coury, Ciara Leckie, Meekai To, Tony Cox, Emmanuelle Lecommandeur, Petros Tsipouras, Tamara Dangouloff, David Ledbetter, Alice Tuff-Lacey, Earnest James Paul Daniel, Pamela Lee, Heather Turner, Katrin Eivindardottir Danielsen, Beomhee Lee, Philip Twiss, Emeline Davoine, Camille Level, Fiona Ulph, Tom Defay, Celine Lewis, Daniel Uribe, Geethanjali Devadoss Gandhi, Anna Lewis, Tiina Urv, Joseph Dewulf, Ruby Liu, Cora Vacher, Lisa Diller, Mauro Longoni, Kris Van Den Bogaert, Pakhi Dixit, Alberte Lundquist, Mirjam van der Burg, Martijn Dolle, Sebastian Lunke, Eva Van Steijvoort, Lilian Downie, Kate MacDuffie, Yiota Veloudi, Erin Drake, Ankit Malhotra, Elizabeth Vengoechea, Suzanne Drury, Lionel Marcelis, Els Voorhoeve, Annelotte Duintjer, Maria Martinez-Fresno, Martin Vu, Bugrahan Duz, Gert Matthijs, Melissa Wasserstein, David Eckstein, Roberts Melbardis, Michael Watson, Matthew Ellinwood, Jessica Merritt, Bryn Webb, Katarzyna Ellsworth, Radja Messai Badji, Anna Wedell, Sarah Elsea, Lou Metherell, Thomas Westover, Nicolas Encina, Nanna Balle Mikkelsen, Alexandra Wiedemann, Harriet Etheredge, Laura Milko, Meredith Wright, Laurence Faivre, Nicole Miller, Cindy Wu, Alessandra Ferlini, Thomas Minten, Julie Yeo, Monica Ferrie, Sian Morgan, Nancy Yin-Hsiu Chien, Terri Finkel, Katarzyna Mosiewicz, Shamila Yusuff, Petra Furu, Ulrike Mütze, Tomasz Zemojtel, Jamie Galarza-Cornejo, Sukhvinder Nicklen, Bethany Zettler, Ya Gao, Minna Niemela, Zhengyan Zhao, Judit Garcia-Villoria, Dau-Ming Niu, Joanna Ziff, Liz Gardner, Sarah Norris, Rebekah Zimmerman, Amy Gaviglio, Antonio Novelli, Michela Zuccolo, Michael Gelb, Arwa Nusair","doi":"10.1016/j.gim.2025.101443","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes.</p><p><strong>Methods: </strong>We assembled a dataset comprising 25 characteristics about each of the 4,390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion, and developed a machine learning model to rank genes for public health consideration.</p><p><strong>Results: </strong>Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4,299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%) and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (AUC = 0.915, R<sup>2</sup> = 84%).</p><p><strong>Conclusion: </strong>The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101443"},"PeriodicalIF":6.6000,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Data-driven consideration of genetic disorders for global genomic newborn screening programs.\",\"authors\":\"Thomas Minten, Sarah Bick, Sophia Adelson, Nils Gehlenborg, Laura M Amendola, François Boemer, Alison J Coffey, Nicolas Encina, Alessandra Ferlini, Janbernd Kirschner, Bianca E Russell, Laurent Servais, Kristen L Sund, Ryan J Taft, Petros Tsipouras, Hana Zouk, Robert C Green, Nina B Gold, David Bick, Mattia Gentile, Paola Orsini, Romina Ficarella, Maria Luisa Valente, Emanuela Ponzi, Athina Ververi, Maria Koutsogianni, Huang Xinwen, Xiao Rui, Zhao Zhengyan, Matthew J Pelo, Jovanka King, Carol Siu, Karin Kassahn, Stefaan Sansen, Enrico Bertini, Aldona Zygmunt, Sophia Adelson, Mattia Gentile, Mette Nyegaard, Emanuele Agolini, Jessica Giordano, Justin O'Sullivan, Aljazi Al-Maraghi, Ulrich Glumer Jensen, Jelili Ojodu, Karla Alex, David Godler, Paola Orsini, Fowzan Alkuraya, Nina Gold, Andrea Oza, Ammira Alshabeeb Akil, Aaron Goldenberg, Katrina Paleologos, Munira Alshehri, Katie GoldenGrant, Richard Parad, Derek Ansel, Cassie Goldman, Holly Peay, Niki Armstrong, José Manuel González de Aledo-Castillo, Matthew Pelo, Matthew Aujla, Daniel Gottlieb, Carolyn Philstrom, Don Bailey, Robert Green, Dominique Pichard, Mei Baker, Christopher Greene, Amanda Pichini, Jorune Balciuniene, Brooke Greenstein, Holly Pickering, Andrew Barry, Scott Grosse, Michelle Pirreca, Bruce Bennetts, Annette Grueters, Malgorzata Ponikowska, Melissa Berenger, Gulcin Gumus, Amy Ponte, Jonathan Berg, Kelly Hagman, Andreas Posch, Donna Bernstein, Kevin Hall, Cynthia Powell, Arindam Bhatatcharjee, Aymeric Harmant, Liana Protopsaltis, Sucheta Bhatt, Sally Hartmanis, Yeyson Quevedo, David Bick, Robin Hayeems, Marianna Raia, Tracey Bishop, Rose Heald, Rebecca Reimers, Asaf Bitton, Madhuri Hegde, Andy Rohrwasser, François Boemer, Rebecca Heiner-Fokkema, Paul Rollier, Natasha Bonhomme, Lidewij Henneman, Lene Rottensten, George Bowley, Becca Hernan, Irakli Rtskhiladze, Brenna Boyd, Charlotte Hobbs, Nabihah Sachedina, Heiko Brennenstuhl, Ingrid Holm, George Sahyoun, Steven Brenner, Layla Horwitz, Aditi Satija, Mairead Bresnahan, Zhanzhi Hu, Christian Schaaf, Thomas Brewster, Maria Iascone, Jennifer Schleit, P J Brooks, Ken Irvine, Richard Scott, Katya Broomberg, Guanjun Jin, Lauren Scully, Amy Brower, Kelsey Kalbfleisch, Stacey Seeloff, Gemma Brown, Ines Kander, Laurent Servais, James Buchanan, Lucy Kaplun, Nidhi Shah, Caleb Bupp, Dalia Kasperaviciute, Maija Siitonen, Candance Cameron, Karin Kassahn, Sikha Singh, Lauren Capacchione, Leni Kauko, Carol Siu, Diana Carli, Riina Kaukonen, Hadley Smith, Onassis Castillo Ceballo, Nicole Kelly, Lisa Sniderman King, Kee Chan, Dhayo Khangsar, Neal Sondheimer, Jillian Chance, Jovanka King, Lourdes St George, Georgia Charalambidou, Clare Kingsley, Zornitza Stark, Winnie Chen, Stephen Kingsmore, Robert Steiner, Yun-Ru Chen, Brian Kirmse, Ulrik Stoltze, Wendy Chung, Rachel Klein, Asbjørg Stray-Pedersen, Brian Chung, Stefan Koelker, Kristen Sund, Megan Clarke, Youssef Kousa, Paris Tafas, Susan Clasper, Elizaveta Krupoderova, Polakit Teekakirikul, F Sessions Cole, Paul Kruszka, Dimitrios Thanos, Heidi Cope, Katherine Langley, Audrey Thurm, Stephanie Coury, Ciara Leckie, Meekai To, Tony Cox, Emmanuelle Lecommandeur, Petros Tsipouras, Tamara Dangouloff, David Ledbetter, Alice Tuff-Lacey, Earnest James Paul Daniel, Pamela Lee, Heather Turner, Katrin Eivindardottir Danielsen, Beomhee Lee, Philip Twiss, Emeline Davoine, Camille Level, Fiona Ulph, Tom Defay, Celine Lewis, Daniel Uribe, Geethanjali Devadoss Gandhi, Anna Lewis, Tiina Urv, Joseph Dewulf, Ruby Liu, Cora Vacher, Lisa Diller, Mauro Longoni, Kris Van Den Bogaert, Pakhi Dixit, Alberte Lundquist, Mirjam van der Burg, Martijn Dolle, Sebastian Lunke, Eva Van Steijvoort, Lilian Downie, Kate MacDuffie, Yiota Veloudi, Erin Drake, Ankit Malhotra, Elizabeth Vengoechea, Suzanne Drury, Lionel Marcelis, Els Voorhoeve, Annelotte Duintjer, Maria Martinez-Fresno, Martin Vu, Bugrahan Duz, Gert Matthijs, Melissa Wasserstein, David Eckstein, Roberts Melbardis, Michael Watson, Matthew Ellinwood, Jessica Merritt, Bryn Webb, Katarzyna Ellsworth, Radja Messai Badji, Anna Wedell, Sarah Elsea, Lou Metherell, Thomas Westover, Nicolas Encina, Nanna Balle Mikkelsen, Alexandra Wiedemann, Harriet Etheredge, Laura Milko, Meredith Wright, Laurence Faivre, Nicole Miller, Cindy Wu, Alessandra Ferlini, Thomas Minten, Julie Yeo, Monica Ferrie, Sian Morgan, Nancy Yin-Hsiu Chien, Terri Finkel, Katarzyna Mosiewicz, Shamila Yusuff, Petra Furu, Ulrike Mütze, Tomasz Zemojtel, Jamie Galarza-Cornejo, Sukhvinder Nicklen, Bethany Zettler, Ya Gao, Minna Niemela, Zhengyan Zhao, Judit Garcia-Villoria, Dau-Ming Niu, Joanna Ziff, Liz Gardner, Sarah Norris, Rebekah Zimmerman, Amy Gaviglio, Antonio Novelli, Michela Zuccolo, Michael Gelb, Arwa Nusair\",\"doi\":\"10.1016/j.gim.2025.101443\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes.</p><p><strong>Methods: </strong>We assembled a dataset comprising 25 characteristics about each of the 4,390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion, and developed a machine learning model to rank genes for public health consideration.</p><p><strong>Results: </strong>Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4,299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%) and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. 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Data-driven consideration of genetic disorders for global genomic newborn screening programs.
Purpose: Over 30 international studies are exploring newborn sequencing (NBSeq) to expand the range of genetic disorders included in newborn screening. Substantial variability in gene selection across programs exists, highlighting the need for a systematic approach to prioritize genes.
Methods: We assembled a dataset comprising 25 characteristics about each of the 4,390 genes included in 27 NBSeq programs. We used regression analysis to identify several predictors of inclusion, and developed a machine learning model to rank genes for public health consideration.
Results: Among 27 NBSeq programs, the number of genes analyzed ranged from 134 to 4,299, with only 74 (1.7%) genes included by over 80% of programs. The most significant associations with gene inclusion across programs were presence on the US Recommended Uniform Screening Panel (inclusion increase of 74.7%, CI: 71.0%-78.4%), robust evidence on the natural history (29.5%, CI: 24.6%-34.4%) and treatment efficacy (17.0%, CI: 12.3%-21.7%) of the associated genetic disease. A boosted trees machine learning model using 13 predictors achieved high accuracy in predicting gene inclusion across programs (AUC = 0.915, R2 = 84%).
Conclusion: The machine learning model developed here provides a ranked list of genes that can adapt to emerging evidence and regional needs, enabling more consistent and informed gene selection in NBSeq initiatives.
期刊介绍：
Genetics in Medicine (GIM) is the official journal of the American College of Medical Genetics and Genomics. The journal''s mission is to enhance the knowledge, understanding, and practice of medical genetics and genomics through publications in clinical and laboratory genetics and genomics, including ethical, legal, and social issues as well as public health.
GIM encourages research that combats racism, includes diverse populations and is written by authors from diverse and underrepresented backgrounds.
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