Genetic instrumental variable studies of maternal risk behaviors for oral clefts

口裂母亲危险行为的遗传工具变量研究

• 批准号: 8116523
• 负责人: George L Wehby
• 金额: $ 53.61万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8116523
• 关键词: Accounting; Affect; Alcohol consumption; Alcohols; Behavior; Behavior Therapy; Behavioral; Behavioral Genetics; Birth; Characteristics; Child; Cleft Lip; Complex; Congenital Abnormality; Counseling; Data; Data Sources; Denmark; Economics; Endowment; Environmental Health; Etiology; Evaluation; Family; Family health status; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Health; Health behavior; Individual; Infant Health; International; Maternal Health; Measures; Methods; Modeling; Mothers; Norway; Obesity; Operative Surgical Procedures; Outcome; Palate; Perception; Perinatal; Play; Policies; Population; Pregnancy; Prevention; Prevention program; Proxy; Quality of life; Research; Risk; Risk Behaviors; Risk Factors; Role; Sampling; Selection Bias; Smoking; Speech; Theoretical model; Variant; Woman; base; cost effective; design; drinking; effective intervention; fetal; genetic risk factor; genetic variant; instrument; maternal cigarette smoking; mortality; novel; nutrition; oral cleft; preference; prevent; public health relevance; risk perception; suicidal risk

DESCRIPTION (provided by applicant): Cleft lip and/or palate (CL/P) are common and burdensome birth defects with a complex etiology of genetic, behavioral and environmental contributors. CL/P impose significant burden on the health, quality of life and economics of affected individuals individual and families. Several studies have suggested that maternal risk behaviors during pregnancy such as smoking, alcohol use, and obesity play a role in the etiology of CL/P. However, these studies that do not account for unobserved or unmeasured factors that may influence maternal self-selection into risk behaviors but are related to CL/P risks, such as maternal preferences for health and risk tolerance and maternal perceptions of health risks. These factors induce correlations between several maternal risk and health behaviors and are themselves correlated with biologic, environmental and maternal health risk factors. It is virtually impossible to observe all relevant behaviors and risk factors in available data samples. Ignoring these unobserved yet relevant factors may confound the estimates of the effects of maternal risk behaviors on CL/P, including estimates of average effects and interactive effects with genetic risk factors. Accurate estimation of the effects of maternal risk behaviors is needed for developing effective counseling and prevention programs for CL/P. The objective of this study is to estimate the effects of maternal risk behaviors during pregnancy including smoking, alcohol, and obesity on CL/P risks using a genetic instrumental variable (IV) model that accounts for unobserved confounders. The IV model will estimate these effects using variation in the risk behaviors that is predicted by genetic variants (instruments) that are significantly correlated with these risk behaviors but are otherwise unrelated to CL/P through unobserved confounders. Using appropriate instruments, the IV model will provide consistent (asymptotically unbiased) estimates of the "causal" effects of these risk behaviors on CL/P. The study will include a unique and large international consortium of population-level samples of about 8917 mothers of children with CL/P and mothers of unaffected children. The study will select and genotype genetic variants that are strong candidates for use as instruments for the study maternal risk behaviors, evaluate the utility of these variants as instruments, and estimate the effects of the maternal risk behaviors on CL/P using an IV model with the genetic instruments that fit the IV conditions. The employed IV model will estimate the average effects of these risk behaviors on CL/P as well as their interactive effects with genetic risk factors for CL/P. The study will provide consistent estimates of the "causal" effects of major maternal risk behaviors on CL/P which are highly needed for developing effective and cost-effective programs for prevention of CL/P and counseling at risk women. Further, the study utilizes a novel analytical approach that can be applied to study the effects of maternal risk behaviors on other birth defects and perinatal outcomes and has the potential for advancing this research field significantly. PUBLIC HEALTH RELEVANCE: This project will help to identify the effects of several maternal risk behaviors during pregnancy including smoking, alcohol and obesity on the risks of cleft lip and/or palate, which are common and burdensome birth defects. Accurate estimates of the effects of these risk behaviors are needed for developing effective interventions and policies to prevent cleft lip and/or palate.

描述（由申请人提供）：唇裂和/或pa裂（Cl/p）是常见的，繁重的先天缺陷，具有复杂的遗传，行为和环境贡献者的病因。 CL/P对受影响个人的个人和家庭的健康，生活质量以及经济学施加重大负担。几项研究表明，孕妇在妊娠期间的风险行为，例如吸烟，饮酒和肥胖症在Cl/p的病因中起作用。但是，这些研究不考虑可能影响孕产妇自我选择为风险行为的未观察到的因素，但与CL/P风险有关，例如对健康和风险承受能力的母性偏好以及对健康风险的看法。这些因素引起了几种产妇风险和健康行为之间的相关性，并且与生物，环境和孕产妇的健康危险因素相关。几乎不可能在现有数据样本中观察所有相关行为和风险因素。忽略这些未观察到的相关因素可能会使孕产妇风险行为对Cl/p的影响的估计，包括对平均效应的估计以及与遗传风险因素的交互作用的估计。为了制定有效的CL/P的有效咨询和预防计划，需要准确估算孕产妇风险行为的影响。这项研究的目的是估计怀孕期间孕产妇风险行为的影响，包括吸烟，酒精和肥胖对CL/P风险使用遗传仪器变量（IV）模型，该模型解释了未观察到的混杂因素。 IV模型将使用风险行为的变化来估计这些效果，这些变化由遗传变异（仪器）预测，这些变异与这些风险行为显着相关，但通过未观察到的混杂因素与CL/P无关。使用适当的仪器，IV模型将对这些风险行为对Cl/p的“因果”影响提供一致的（渐近无偏见的）估计。这项研究将包括一个独特的大型国际人口级样本联盟，约8917个有Cl/p儿童的母亲和未受影响的儿童的母亲。该研究将选择和基因型遗传变异体，这些变异物是用于研究母体风险行为的工具，评估这些变体作为工具的实用性，并使用适合IV条件的遗传仪器的IV模型来评估这些变体作为工具的实用性。使用的IV模型将估计这些风险行为对CL/P的平均影响，以及它们与CL/P的遗传风险因素的互动效应。该研究将对主要孕产妇风险行为对CL/P的“因果”影响提供一致的估计，这对于制定有效且具有成本效益的计划以预防CL/P和风险女性咨询。此外，该研究采用了一种新型的分析方法，可以应用来研究孕产妇风险行为对其他出生缺陷和围产期结局的影响，并有可能大大推进这一研究领域。 公共卫生相关性：该项目将有助于确定怀孕期间几种产妇风险行为的影响，包括吸烟，酒精和肥胖症对唇lip裂和/或口感的风险，这是常见且繁重的先天性出生缺陷。需要对这些风险行为的影响进行准确估计，以制定有效的干预措施和政策，以防止唇裂和/或pape。