Genetics in Medicine最新文献

Mainstreaming of clinical genetic testing: a conceptual framework. 临床基因检测的主流化：一个概念框架。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-22 DOI: 10.1016/j.gim.2025.101465

Michael P Mackley, Julie Richer, Andrea Guerin, Oana Caluseriu, Linlea Armstrong, Katherine A Blood, Francois Bernier, Christie Boswell-Patterson, Marisa Chard, Gregory Costain, David Dyment, Alison Eaton, Hanna Faghfoury, Patrick Frosk, Meredith K Gillespie, Elaine S Goh, Robin Z Hayeems, Bita Hashemi, A Micheil Innes, Molly Jackson, Anne-Marie Laberge, Jacqueline Limoges, Christian Marshall, Hugh McMillan, Tanya N Nelson, Matthew Osmond, Jillian Parboosingh, Lynette Penney, Bradley Prince, Sarah L Sawyer, Victoria Mok Siu, Mary Ann Thomas, Lesley Turner, Noémie Villeneuve-Cloutier, Taila Hartley, Kym M Boycott

{"title":"Mainstreaming of clinical genetic testing: a conceptual framework.","authors":"Michael P Mackley, Julie Richer, Andrea Guerin, Oana Caluseriu, Linlea Armstrong, Katherine A Blood, Francois Bernier, Christie Boswell-Patterson, Marisa Chard, Gregory Costain, David Dyment, Alison Eaton, Hanna Faghfoury, Patrick Frosk, Meredith K Gillespie, Elaine S Goh, Robin Z Hayeems, Bita Hashemi, A Micheil Innes, Molly Jackson, Anne-Marie Laberge, Jacqueline Limoges, Christian Marshall, Hugh McMillan, Tanya N Nelson, Matthew Osmond, Jillian Parboosingh, Lynette Penney, Bradley Prince, Sarah L Sawyer, Victoria Mok Siu, Mary Ann Thomas, Lesley Turner, Noémie Villeneuve-Cloutier, Taila Hartley, Kym M Boycott","doi":"10.1016/j.gim.2025.101465","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101465","url":null,"abstract":"Purpose: Demand for genetic testing is increasing across medicine while the genetics workforce remains stable. In response, mainstreaming models, where non-geneticist clinicians are involved in the genetic testing pathway, are being introduced. As a standardized approach would facilitate evaluation and optimal patient care, a unified framework is warranted.Methods: Through a focus group with clinical genetics experts, a conceptual framework for the mainstreaming of clinical genetic testing is proposed. Through a consensus process, experts elucidated the steps in the diagnostic care pathway and defined a set of variables that influence which mainstreaming model is best suited to specific patient care scenarios.Results: 35 individuals representing 20 distinct clinical genetics services and all Canadian provinces participated in the development of the framework. The framework describes four generalizable mainstreaming models of care, each with varying levels of involvement of the clinical genetics service in the diagnostic care pathway.Conclusion: This framework will help guide clinical teams in the design and evaluation of mainstreaming efforts. It is critical that these programs are evaluated and shared in a standardized way so that we can implement strategies that allow optimal utilization of genetics resources and improve patient care.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101465"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of Laboratory-Driven Proactive Reanalysis: Reclassification to Positive in 5% of Initially Negative or Uncertain Exome Sequencing Cases. 实验室驱动的前瞻性再分析的影响：在5%的最初阴性或不确定的外显子组测序病例中重新分类为阳性。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-22 DOI: 10.1016/j.gim.2025.101464

Meghan C Towne, Jennifer Huang, Sheila Saliganan, Brooklynn Gasser, Melissa Holman, Kendra Webb, Bess Wayburn, Kelly Radtke, Kelly D Farwell Hagman

{"title":"Impact of Laboratory-Driven Proactive Reanalysis: Reclassification to Positive in 5% of Initially Negative or Uncertain Exome Sequencing Cases.","authors":"Meghan C Towne, Jennifer Huang, Sheila Saliganan, Brooklynn Gasser, Melissa Holman, Kendra Webb, Bess Wayburn, Kelly Radtke, Kelly D Farwell Hagman","doi":"10.1016/j.gim.2025.101464","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101464","url":null,"abstract":"Purpose: Reanalysis of exome sequencing (ES) data increases diagnostic utility; however, there is no consensus on when and under what circumstances reanalysis should occur. Requesting and performing ES reanalysis burdens both clinical and laboratory workflows. Maximizing the potential for reclassification is essential. Here, we describe the impact of a laboratory-driven proactive reanalysis process that triggers reanalysis when new evidence is identified.Methods: We reviewed reanalysis outcomes of an ES cohort. Reanalysis events were categorized based on initiating factors (laboratory-driven proactive, family studies, and clinician-initiated). Laboratory-driven proactive reclassifications are prompted by systematic review of new scientific data. Outcomes were evaluated by initiating factors, reclassification types, evidence used, and time since original report.Results: Overall, 23% of cases underwent at least one reanalysis, with 35% of reanalyses resulting in reclassification. There was a 4% increase in diagnostic yield, including 5% of initially unsolved ES receiving diagnostic reports. Diagnostic reclassifications rates were significantly higher for laboratory-driven proactive reanalyses (54%; p<0.0001) than family studies (18%) and clinician-initiated reanalyses (4%). New gene-disease relationships were the most efficacious evidence source. Laboratory-driven proactive reclassifications occurred steadily over time.Conclusion: Laboratory-driven proactive reanalysis effectively provides more diagnostic reclassifications compared to clinician-initiated reanalysis. Laboratories should curate and integrate emerging evidence into ES reanalysis.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101464"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort. 在未诊断疾病网络队列中发现新的重复扩展疾病的全基因组方法。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-22 DOI: 10.1016/j.gim.2025.101462

Sarah Fazal, Harriet Dashnow, Maike F Dohrn, Jacquelyn Raposo, Laurel Hiatt, Matt C Danzi, Isaac R L Xu, Camilo Toro, David R Adams, Karen Usdin, Bruce Hayward, Shilpa Nadimpalli Kobren, Shamil R Sunyaev, Rebecca C Spillmann, Vandana Shashi, Adriana Rebelo, Guney Bademci, Mustafa Tekin, Aaron R Quinlan, Stephan Züchner

{"title":"A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort.","authors":"Sarah Fazal, Harriet Dashnow, Maike F Dohrn, Jacquelyn Raposo, Laurel Hiatt, Matt C Danzi, Isaac R L Xu, Camilo Toro, David R Adams, Karen Usdin, Bruce Hayward, Shilpa Nadimpalli Kobren, Shamil R Sunyaev, Rebecca C Spillmann, Vandana Shashi, Adriana Rebelo, Guney Bademci, Mustafa Tekin, Aaron R Quinlan, Stephan Züchner","doi":"10.1016/j.gim.2025.101462","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101462","url":null,"abstract":"Purpose The Undiagnosed Diseases Network (UDN) is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multi-omics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating. REDs comprise ∼60 characterized disorders, which exhibit a broad spectrum of phenotypes. Thus, a largely unbiased genome-wide approach in a phenotypically diverse sample will add to the diagnostic depth, explore the limits of short-read genome analysis, and establish novel candidate RED loci. Methods Here, we present a genome-wide analysis of repeat expansions conducted on 1,018 genomes from the UDN. By leveraging two distinct bioinformatics tools, ExpansionHunter Denovo and STRling, we show that repeat expansions can be accurately detected in short-read genomes. Results We demonstrate that a genotype-first approach can diagnose atypical cases of known REDs and provide valuable clinical insights. We present clinical details on participants with expansions in ATXN7, DMPK, FMR1, GLS, HTT, RFC1, AFF3, and MARCH6. Importantly, we highlight two cases of juvenile Huntington disease that were discovered through our analysis. Finally, we present a list of novel candidate TRs that could potentially be pathogenic if expanded. Conclusion Importantly, our approach showcases the bioinformatic advancements in genome analysis for RED detection and highlights its practical applications.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101462"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The cost-utility of targeted germline BRCA testing in localised prostate cancer followed by cascade testing first-degree relatives with pathogenic variants. 靶向生殖系BRCA检测在局部前列腺癌中的成本效用，随后进行一级亲属致病变异级联检测。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-22 DOI: 10.1016/j.gim.2025.101463

Srinivas Teppala, Paul Scuffham, Kim Edmunds, Matthew J Roberts, David P Smith, David Fairbairn, Lisa G Horvath, Haitham Tuffaha

{"title":"The cost-utility of targeted germline BRCA testing in localised prostate cancer followed by cascade testing first-degree relatives with pathogenic variants.","authors":"Srinivas Teppala, Paul Scuffham, Kim Edmunds, Matthew J Roberts, David P Smith, David Fairbairn, Lisa G Horvath, Haitham Tuffaha","doi":"10.1016/j.gim.2025.101463","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101463","url":null,"abstract":"Purpose: Genetic testing is recommended in localised prostate cancer (PCa) with elevated risk and in metastatic PCa (mPCa). The economics of genetic testing in mPCa has been evaluated but not assessed in localised PCa. We examined the cost-utility of germline BRCA testing in localised PCa with high-risk of pathogenic variants.Methods: Cost-utility analysis of germline BRCA testing in localised PCa with 1) high/very high-risk classification; 2) family history of PCa; 3) Ashkenazi-Jewish ancestry. Analyses were performed from an Australian payer perspective using semi-Markov models over lifetime; quality-adjusted life years (QALYs) were the health outcomes. Decision uncertainty was characterized using one-way and probabilistic sensitivity analyses.Results: The incremental cost-effectiveness ratio (ICER) of BRCA testing compared to no testing was AU$591,408/QALY in high/very high-risk patients, AU$3.9 million/QALY with family history of PCa and AU$650,098/QALY in Ashkenazi-Jews. Adding cascade testing of first-degree relatives (FDRs) resulted in ICERs of AU$18,872/QALY, AU$47,294/QALY and AU$14,637/QALY in the aforementioned groups. At a willingness-to-pay of AU$75,000/QALY, BRCA testing was not likely to be cost-effective in PCa patients; however, was cost-effective after cascade testing FDRs.Conclusion: Germline BRCA testing may not be cost-effective when limited to patients with localised PCa but demonstrates value for money when extended to FDRs.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101463"},"PeriodicalIF":6.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: a phase 3, two-part study compared to a historical placebo cohort. idursulase β治疗粘多糖病II的疗效和安全性：一项与历史安慰剂队列比较的3期两部分研究

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-21 DOI: 10.1016/j.gim.2025.101460

Young Bae Sohn, Aram Yang, Min-Sun Kim, Jinsup Kim, Jae Seong Kim, Youngsin Oh, Dong-Kyu Jin

{"title":"Efficacy and safety of idursulfase beta in the treatment of mucopolysaccharidosis II: a phase 3, two-part study compared to a historical placebo cohort.","authors":"Young Bae Sohn, Aram Yang, Min-Sun Kim, Jinsup Kim, Jae Seong Kim, Youngsin Oh, Dong-Kyu Jin","doi":"10.1016/j.gim.2025.101460","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101460","url":null,"abstract":"Purpose: To investigate the efficacy and safety of idursulfase beta (0.5 mg/kg weekly) in the treatment of mucopolysaccharidosis II (MPS II), compared with a historical placebo from a previous idursulfase trial (TKT024).Methods: The study comprised two sequential parts. In Part 1, a randomized, double-blind study, idursulfase or idursulfase beta were given for 52 weeks. In the open, single cohort Part 2 study, additional participants received idursulfase beta for 52 weeks. Data from the idursulfase beta groups from Parts 1 & 2 were pooled for comparisons with the historical placebo group (n=32). The primary endpoint was a change in the 6-minute walk test (6-MWT) at week 53.Results: Participants in the idursulfase beta groups (n=24) were male Asians (mean age, 12.0 years). Idursulfase beta was superior to placebo in 6-MWT improvement (62.2 m vs. 7.3 m, p < 0.0001). Decrease in urine glycosaminoglycan excretion (-71.13% vs. 21.39%, p < 0.0001) and reduction in the liver (-26.67% vs. -0.80%, p < 0.0001) and spleen volumes (-26.46% vs. 7.2%, p < 0.0001) were significant. The safety profile of idursulfase beta was satisfactory.Conclusion: Idursulfase beta is a safe and effective treatment option in MPS II, addressing crucial somatic ailments presented by patients.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101460"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it? 未确诊患者转化基因组学研究的可持续性：什么是可持续性？我们为什么需要它？我们如何做到这一点？

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-21 DOI: 10.1016/j.gim.2025.101458

Jennifer L Young, Charis Tang, Lily Liang, Euan Ashley, Holly K Tabor, Meghan C Halley

{"title":"Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it?","authors":"Jennifer L Young, Charis Tang, Lily Liang, Euan Ashley, Holly K Tabor, Meghan C Halley","doi":"10.1016/j.gim.2025.101458","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101458","url":null,"abstract":"Purpose: Genomics research enrolling undiagnosed patients can provide answers for one-third of participants and more can be diagnosed through future reanalysis. The long-term value for participants has raised questions of the \"sustainability\" of these studies, but the meaning, goals and best practices for sustainability remain unclear.Methods: We conducted semi-structured interviews with researchers leading studies enrolling undiagnosed patients in the United States and Canada and utilized thematic content analysis to summarize key themes.Results: Researchers lacked consensus regarding what \"sustainability\" was actually intended to sustain, variably referencing study procedures, personnel, data access, and participant recontact. However, the primary driver of sustainability was widely shared as the perceived obligation to continue to search for answers for undiagnosed participants. Proposed sustainability strategies included diversifying funding sources, developing centralized data infrastructure, and building collaborations across disciplines and institutions. Researchers also emphasized the need to address ethical concerns, to integrate research with clinical care, and for leadership from research funders to guide these efforts.Conclusion: While genomics researchers perceived continued obligations to undiagnosed participants, they also lacked a shared understanding of the goals of sustainability and called for coordinated efforts to develop centralized infrastructure that integrated research and clinical care.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101458"},"PeriodicalIF":6.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-term management strategies for pegvaliase use in phenylketonuria: Lessons learned from the phase 3 PRISM open-label extension study. 苯丙酮尿患者使用pegvaliase的长期管理策略：从PRISM开放标签扩展研究中获得的经验教训

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-20 DOI: 10.1016/j.gim.2025.101459

Cary O Harding, Kaleigh Bulloch Whitehall, Joshua Lilienstein, Ogun Sazova, Kristin Lindstrom, Drew G Levy, Barbara K Burton

{"title":"Long-term management strategies for pegvaliase use in phenylketonuria: Lessons learned from the phase 3 PRISM open-label extension study.","authors":"Cary O Harding, Kaleigh Bulloch Whitehall, Joshua Lilienstein, Ogun Sazova, Kristin Lindstrom, Drew G Levy, Barbara K Burton","doi":"10.1016/j.gim.2025.101459","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101459","url":null,"abstract":"Purpose: Pegvaliase is an enzyme substitution therapy for phenylketonuria, an autosomal recessive disorder of amino acid metabolism resulting in phenylalanine (Phe) accumulation, intellectual disability, and behavioral/psychiatric disorders. The phase 3 PRISM trials (NCT01819727, NCT01889862, NCT03694353) established pegvaliase efficacy in reducing blood Phe, but its pharmacokinetics differs between individuals, resulting in varying times to achieve clinically meaningful blood Phe targets.Methods: Using participant-level data from PRISM, we developed a pharmacokinetic/pharmacodynamic model that explains individual-level blood Phe patterns as a function of pegvaliase clearance during the maintenance phase.Results: As pegvaliase exposure induces immune tolerization, drug clearance declines. A period of high sensitivity of blood Phe to dietary Phe intake and pegvaliase exposure is observed at ∼120-200 μmol/L Phe, reflected in increased blood Phe volatility. This model suggests that this volatility represents impending, but incomplete, tolerization, and that reducing pegvaliase dose or liberalizing dietary Phe intake at or before this stage is premature and can result in marked blood Phe increases. With continued exposure, pegvaliase clearance continues to decline, and dietary Phe intake and blood Phe become uncoupled.Conclusion: These analyses establish how tolerization presents clinically and suggest a staged therapeutic approach: (1) tolerance induction; (2) diet liberalization; (3) gradual dose adjustment.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101459"},"PeriodicalIF":6.6,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Covering medical care costs for participants in the eMERGE Network: Challenges for equity and implementation. 支付新兴网络参与者的医疗保健费用：公平和执行方面的挑战。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-16 DOI: 10.1016/j.gim.2025.101457

Laura J Rasmussen-Torvik, Katherine E Bonini, Margaret H Harr, Mohammad Ali Abbass, Hana Bangash, Harris T Bland, Brenna M Boyd, Wendy K Chung, Ellen W Clayton, Stuart J Cohen, John J Connolly, Catherine Gascoigne, Valentina Hernandez M, Ingrid A Holm, Martha Horike-Pyne, Gail P Jarvik, Elizabeth W Karlson, Iftikhar J Kullo, Nita A Limdi, Mary E Maradik, Elizabeth M McNally, Emma Perez Mgc, Cynthia A Prows, Gabriel Q Shaibi, Chunhua Weng, Robb K Rowley, Josh F Peterson, Jodell E Linder, Maya Sabatello

{"title":"Covering medical care costs for participants in the eMERGE Network: Challenges for equity and implementation.","authors":"Laura J Rasmussen-Torvik, Katherine E Bonini, Margaret H Harr, Mohammad Ali Abbass, Hana Bangash, Harris T Bland, Brenna M Boyd, Wendy K Chung, Ellen W Clayton, Stuart J Cohen, John J Connolly, Catherine Gascoigne, Valentina Hernandez M, Ingrid A Holm, Martha Horike-Pyne, Gail P Jarvik, Elizabeth W Karlson, Iftikhar J Kullo, Nita A Limdi, Mary E Maradik, Elizabeth M McNally, Emma Perez Mgc, Cynthia A Prows, Gabriel Q Shaibi, Chunhua Weng, Robb K Rowley, Josh F Peterson, Jodell E Linder, Maya Sabatello","doi":"10.1016/j.gim.2025.101457","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101457","url":null,"abstract":"Purpose: The complexities of covering study-recommended medical care costs, so individuals are not limited from participating in translational research due to financial reasons, have received little attention.Materials and methods: We explored the deliberations, decisions and challenges faced by the eMERGE Network during implementation of a genomic research project recommending clinical care based on high-risk results defined largely by polygenic risk scores. Two surveys were disseminated to eMERGE sites: to identify preferences about payment for specific care recommendations (Survey-I) and to understand the operational processes of covering medical care costs (Survey-II).Results: Paying for a subset of care recommendations for the funded study duration was identified as the most feasible approach to covering medical care costs for participants who received high-risk genomic results. Each eMERGE site, by necessity, employed diverse approaches to pay for medical care costs.Discussion: eMERGE researchers balanced competing concerns about bias, equity, study design, regulatory compliance, and cost in designing a unified approach to cover some of the recommended medical care costs in the study. Many implementation challenges were encountered.Conclusions: Findings can inform researchers and regulatory bodies about the implications and complications of covering medical care costs in translational research studies focused on prevention.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101457"},"PeriodicalIF":6.6,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE® phase 1/2 randomized trial. 在COMPOSE®1/2期随机试验中，pegtibatinase酶替代治疗成人经典同型半胱氨酸尿的安全性和有效性

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-14 DOI: 10.1016/j.gim.2025.101456

Can Ficicioglu, Janet A Thomas, Jaya Ganesh, David Kudrow, Melissa Lah, Wendy E Smith, Jalé Güner, Sharon McDermott, Sagar A Vaidya, Liz Wilkening, Harvey L Levy

{"title":"Safety and efficacy of pegtibatinase enzyme replacement therapy in adults with classical homocystinuria in the COMPOSE® phase 1/2 randomized trial.","authors":"Can Ficicioglu, Janet A Thomas, Jaya Ganesh, David Kudrow, Melissa Lah, Wendy E Smith, Jalé Güner, Sharon McDermott, Sagar A Vaidya, Liz Wilkening, Harvey L Levy","doi":"10.1016/j.gim.2025.101456","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101456","url":null,"abstract":"Purpose: As classical homocystinuria (HCU) standard-of-care treatment often cannot achieve adequate metabolic control, the phase 1/2 COMPOSE® trial (NCT03406611) evaluated pegtibatinase enzyme replacement therapy.Methods: Participants with HCU aged 12-65 years with elevated total plasma homocysteine (tHcy) receiving standard-of-care treatment were randomized 3:1 into six increasing dose cohorts (each n≈4) of subcutaneous pegtibatinase (≤2.5 mg/kg twice weekly [BIW]) or placebo. Primary end points included adverse event incidence and immunogenicity. Secondary end points included tHcy change from baseline to post-treatment (geometric mean of weeks 6-12).Results: Overall, 24 participants were enrolled. Pegtibatinase was generally well tolerated at all doses with no anaphylaxis or severe immune reactions; 15 participants (62.5%) experienced ≥1 treatment-related treatment-emergent adverse event (most commonly injection-site reactions; one serious [acute urticaria]). At the two highest doses, substantial tHcy reductions were observed post-treatment (relative reduction: 57% for 1.5 mg/kg BIW; 67% for 2.5 mg/kg BIW) and all participants maintained tHcy <100 μM. One participant receiving 2.5 mg/kg BIW achieved tHcy <15 μM (normal) and methionine <14 μM (below normal), enabling increased dietary intact protein intake. Changes in other metabolites aligned with tHcy.Conclusion: Pegtibatinase was generally well tolerated and substantially reduced tHcy levels, demonstrating potential as a treatment for HCU.","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101456"},"PeriodicalIF":6.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rethinking Agency for Genetic Testing Intention among Latinos: Determining Predictors of Intention for Carrier Screening and Cancer Predisposition Testing. 拉丁美洲人基因检测意向的反思机构：确定携带者筛查和癌症易感性检测意向的预测因素。

IF 6.6 1区医学

Genetics in Medicine Pub Date : 2025-05-14 DOI: 10.1016/j.gim.2025.101455

Daniel Chavez-Yenter, Kimberly A Kaphingst

{"title":"Rethinking Agency for Genetic Testing Intention among Latinos: Determining Predictors of Intention for Carrier Screening and Cancer Predisposition Testing.","authors":"Daniel Chavez-Yenter, Kimberly A Kaphingst","doi":"10.1016/j.gim.2025.101455","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101455","url":null,"abstract":"Purpose: Attitudes and clinical processes have been well studied in genetic testing contexts; however, studies tend to underutilize theoretical frameworks, especially among Latino groups. Behavioral intention is a consistent predictor of uptake of behavior and has many theoretical roots. Using the Integrated Behavioral Model (IBM), we modeled the relationships between attitudes, norms, and perceived agency with behavioral intention for both carrier screening (CS) and cancer predisposition testing (CPT) for a Latino-only cohort.Methods: Using Structural Equation Modeling, we ran both measurement and structural models. An initial measurement model used confirmatory factor analysis for each latent variable (attitude, norms, and agency) and their indicators of the IBM. Factor loadings less than .500 were removed, and we subsequently ran a structural model with the outcome of intention to use CS and CPT.Results: Agency was the most consistent predictor for both testing types (β=.381, p<.01 - CS; β=.559, p<.01 - CPT), with attitudes being negatively associated with CS (β=-.313, p<.05) while norms were positively associated (β=.350, p<.01).Conclusion: Many interventions among Latino groups tend to focus on education and attitude change. Our findings suggest that more effort should be made to address agency to empower patients for improved genetic testing access. (197).","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101455"},"PeriodicalIF":6.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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