Genomic Ascertainment - Clinical and Behavioral Aspects

基因组确定 - 临床和行为方面

• 批准号: 10683830
• 负责人: Leslie Biesecker
• 金额: $ 161.38万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683830
• 关键词: Address; Amendment; Anxiety; Area; Attitude; Behavioral; Blood specimen; Clinical; Clinical Medicine; Collaborations; Data; Development; Disease; Extramural Activities; Foundations; Fright; Functional disorder; Genes; Genetic Counseling; Genets; Genome; Genomic medicine; Genomics; Genotype; Goals; Grant; Health; Health Care Costs; Healthcare; Image; Individual; Internet; Internships; Laboratories; Lead; Malignant hyperpyrexia due to anesthesia; Measurable; Medical; Medicine; Mental Depression; Modeling; Molecular; Motivation; Muscle; Online Systems; Overutilization of Health Services; Paper; Participant; Penetrance; Perception; Persons; Pharmacogenetics; Phenotype; Physicians; Population; Predisposition; Prevalence; Professional counselor; Randomized, Controlled Trials; Recommendation; Recurrence; Research; Research Personnel; Resources; Risk; Site; Standard Model; Study Section; Surveys; Test Result; Testing; Time; Uncertainty; Variant; Vision; Work; adverse outcome; base; biobank; clinical care; clinical practice; clinical sequencing; clinically relevant; exome; exome sequencing; experience; follow-up; genetic counselor; genetic variant; genome sequencing; genome-wide; genomic data; genomic predictors; health care settings; improved; individual patient; interest; member; neurosurgery; new technology; phenotypic data; precision genomic medicine; predictive test; programs; rare variant; reproductive; research clinical testing; screening; tomography; trial comparing

Predictive genomic medicine or precision genomic medicine is of the highest medical importance and is an active area of research. We began piloting the return of genome-wide rare variants with the inception of the ClinSeq program in 2006, well before exome and genome sequencing became widespread (Biesecker et al., Genome Res 2009). We have continually expanded our work in this area by searching the genome for high penetrance variants that could be useful for clinical care, reproductive risks, pharmacogenetics, and other uses. My vision is that the genome is a health care resource, not a test, and that the cost of this health care resource can be amortized over the lifetime of an individual, long after its primary indicated usage is accomplished. Indeed, it was our work on ClinSeq that undergirded the recommendations we made for secondary findings (opportunistic screening) that were released in 2013 (Green et al., Genet Med 2013) These recommendations were initially highly controversial but with some amendments have now settled into accepted clinical practice an example of how we aim to change the practice of medicine. This paper has been cited more than 1,200 times and has also become the basis of a number of clinical testing laboratories health screening gene sets. ClinSeq has also been a leader in demonstrating to the field that genomes and exomes can be analyzed in healthy people and results returned, with minimal adverse consequences, dispelling the widespread fears about anxiety, depression, health care over-utilization, and other hypothetical risks. ClinSeq was also a charter member of the CSER (Clinical Sequencing Exploratory Research) consortium which allied six research centers to pilot genomics in health care settings. I joined CSER after participating in the study section that evaluated the CSER applications, reasoning that it would be beneficial for ClinSeq and for the other centers to pool efforts and experiences. CSER has ended further grants to extramural sites and we are winding down our collaboration with them. Genomic medicine has at its foundation prediction predicting phenotype based on genotype. To address this foundational challenge, we need to develop research modes that can model and test the predictive power of genomic variants. Resources such as gnomAD provide critical data on population prevalence but are seriously limited with respect to phenotype data. The UK BioBank is supporting genotype ascertainment, but its data are limited to pre-hoc phenotypes and blood samples and participants cannot be re-contacted. There is thus a compelling need for the capacity to perform bespoke phenotyping based on genotypes. Another major bottleneck in predictive genomic medicine is the return of results. The standard clinical model is for a physician or genetic counselor to meet with a patient for an individual session to describe the results, review the clinical implications, and provide genetic counseling and/or recurrence risks. This is obviously not scalable, and the field is in urgent need of alternative approaches to this challenge the variants from an exome (much less a genome) cannot be returned to a participant with this model. While most presume that this means that exomes and genomes need to be throttled or filtered down to just a single or few clinically relevant variants that can be returned using the standard model, the question should be asked as to whether alternative means to results return can be devised. Our efforts to increase the throughput of return of results lead us to set up a randomized controlled trial comparing standard genetic counselor-provided in person return of results to return of results with a web-based platform (Biesecker et al., JAMA Intern Med 2018). We have followed this work with additional analyses showing that there was no significant measurable added value of genetic counseling on top of information provision, either by web or counselor (Lewis et al., Am J Hum Genet 2018), we have also followed up with an analysis of perceptions of uncertainty amongst the recipients of these carrier results, (Umstead et al., Transl Behav Med In Press). In addition, we have undertaken a significant effort to better understand secondary variants in the research setting. We have now undertaken a major project to provide phenotyping for individuals suspected to have malignant hyperthermia susceptibility in collaboration with NIHCC neurosurgery and the USUHS ex vivo muscle testing laboratory.

预测基因组医学或精确基因组医学具有最高的医学重要性，并且是一个活跃的研究领域。在2006年ClinSeq计划开始时，我们开始试验全基因组罕见变体的回归，远远早于外显子组和基因组测序变得普遍（Biesecker et al. Genome Res 2009）。我们不断扩大我们在这一领域的工作，通过搜索基因组中的高突变变异，可能是有用的临床护理，生殖风险，药物遗传学，和其他用途。我的愿景是，基因组是一种医疗资源，而不是一种测试，这种医疗资源的成本可以在个人的一生中摊销，在其主要指定用途完成后很久。事实上，正是我们在ClinSeq上的工作支持了我们对2013年发布的次要发现（机会性筛选）的建议（绿色等人，Genet Med 2013）这些建议最初备受争议，但经过一些修改，现在已经成为公认的临床实践，这是我们如何改变医学实践的一个例子。这篇论文被引用超过1,200次，也成为多家临床检测实验室健康筛查基因集的基础。ClinSeq也一直是该领域的领导者，它证明了可以在健康人群中分析基因组和外显子组，并返回结果，同时将不良后果降至最低，消除了人们对焦虑，抑郁，医疗保健过度使用和其他假设风险的普遍担忧。ClinSeq也是CSER（临床测序探索性研究）联盟的创始成员，该联盟将六个研究中心联合起来，在医疗保健环境中进行基因组学试验。我在参加了评估CSER应用的研究部分后加入了CSER，理由是这将有利于ClinSeq和其他中心汇集努力和经验。CSER已经结束了对校外网站的进一步赠款，我们正在逐步结束与他们的合作。 基因组医学的基础是基于基因型的表型预测。为了应对这一基础性挑战，我们需要开发能够建模和测试基因组变异预测能力的研究模式。gnomAD等资源提供了关于人口流行率的关键数据，但在表型数据方面严重有限。英国生物银行支持基因型确定，但其数据仅限于事前表型和血液样本，并且无法重新联系参与者。因此，迫切需要基于基因型进行定制表型分析的能力。 预测基因组医学的另一个主要瓶颈是结果的返回。标准的临床模式是由医生或遗传咨询师与患者进行单独会谈，以描述结果，审查临床意义，并提供遗传咨询和/或复发风险。这显然是不可扩展的，并且该领域迫切需要替代方法来应对这一挑战-来自外显子组（更不用说基因组）的变体不能返回到具有该模型的参与者。虽然大多数人认为这意味着外显子组和基因组需要被节流或过滤到只有一个或几个临床相关的变异，可以使用标准模型返回，但问题应该是是否可以设计出结果返回的替代方法。 我们增加结果返回的通量的努力导致我们建立了一项随机对照试验，将标准遗传咨询师亲自提供的结果返回与基于网络的平台的结果返回进行比较（Biesecker等人，JAMA Intern Med 2018）。我们已经跟踪了这项工作，并进行了额外的分析，结果表明，无论是通过网络还是咨询师，在信息提供的基础上，遗传咨询都没有显著的可测量的附加值（刘易斯等人，Am J Genet 2018），我们还对这些载体结果的接受者对不确定性的看法进行了分析（Umstead等人，翻译Behav医学出版社）。此外，我们还做出了重大努力，以更好地了解研究环境中的次要变异。 我们现在已经开展了一个重大项目，与NIHCC神经外科和USUHS体外肌肉测试实验室合作，为疑似恶性高热易感性的个体提供表型分析。