Quasi-experimental studies of early risk factors for severe psychopathology

说明(申请人提供)：意义：犯罪、药物使用问题、自杀和严重的精神疾病，如精神分裂症和双相情感障碍，与巨大的个人痛苦和社会成本有关。确定这些问题的原因，特别是在生命的早期，是一项至关重要的研究工作。研究人员已经确定了许多与这些严重问题风险增加有关的假定环境因素，包括母亲在怀孕期间吸烟、母亲在怀孕期间的压力、母亲生育时的年龄以及父亲生育年龄的提前。然而，我们不知道这些风险因素是严重精神病的偶然风险因素，还是仅仅是家庭混乱的指标。我们对潜在因果机制的了解有限，部分原因是现有的大多数关于这些风险的研究未能使用能够检验替代假说的研究设计，特别是环境和遗传选择因素的作用。创新：我们建议利用强大的准实验设计，即可以拆分共生风险机制并解释不可测量的遗传和环境过程的自然实验，来探索几个假定的早期风险因素的影响。特别是，我们将比较暴露在不同环境中的完全兄弟姐妹，这种方法排除了所有可能解释早期推定风险和后来结果之间统计关联的遗传因素，以及兄弟姐妹共有的所有环境因素。我们还将比较暴露在不同环境中的同父异母兄弟姐妹、完全兄弟姐妹的后代(完全表亲)、同父异母兄弟姐妹的后代(同父异母的堂兄弟姐妹)和双胞胎的后代。这些额外的比较将使我们能够为我们的发现提供一致的证据，并确定任何家族选择因素(遗传和/或环境)的来源。对后代、父母和社区层面风险的详细评估将进一步使我们能够确定早期风险因素与严重精神病理相关的机制。方法：我们建议分析一个大型数据集，其中包括1940-1995年间在瑞典出生或生活的每个人的信息(NH7,500,000)，其中包括早期环境风险、相关的家庭和社区风险的测量，以及瑞典国家登记处对严重犯罪、药物使用、自杀和精神健康问题的良好验证的指数。由于数据集还包括关于每个人与其所有家庭成员的生物关联性的信息，我们能够通过比较在环境和遗传风险方面不同的个人来对这些联系进行许多准实验研究。环境和研究人员：我们经验丰富的团队包括以下方面的国际专家：与早期产前和围产期因素相关的风险；严重精神病理学的评估和病因学；大型国家登记的使用；以及使用准实验设计来研究假定的环境因素。印第安纳大学和卡罗林斯卡学院提供了强有力的环境和相关资源。 公共卫生相关性：暴力、药物使用问题、自杀和严重精神疾病给个人和社会造成的惊人负担已经得到了很好的记录。研究人员已经确定了预测这些重大社会问题的早期风险因素，但尚不清楚假定的早期风险是否真的是因果关系，或者与这些风险的部分或大部分关联是否源于背景家庭因素。为了改善预防计划和我们对早期风险因素的理解，当前的提案寻求支持，以分析一种独特的资源，即一个包含瑞典大约50年来每个人的大型数据集，依靠自然实验严格测试因果假设。

DESCRIPTION (provided by applicant): Significance: Crime, substance use problems, suicide, and severe mental illness, such as schizophrenia and bipolar disorder, are associated with enormous personal distress and societal costs. Identifying the causes of these problems, especially very early in life, is a crucial research endeavor. Researchers have identified numerous putative environmental factors that are associated with increased risk for these severe problems, including maternal smoking during pregnancy, maternal stress during pregnancy, maternal age at childbearing, and advancing paternal age at childbearing. We do not know, however, whether these risk factors are casual risk factors for severe forms of psychopathology or are merely indices of family confounding. Our limited understanding of the underlying causal mechanisms is due, in part, to the fact that most existent studies of these risks have failed to use research designs that can test alternative hypotheses, especially the role of environmental and genetic selection factors. Innovation: We propose to utilize powerful quasi-experimental designs, natural experiments that can pull-apart co-occurring risk mechanisms and account for unmeasured genetic and environmental processes, to explore the effects of several putative early risk factors. In particular, we will compare differentially exposed full siblings, an approach that rules out all genetic factors that could account for the statistical association between early putative risks and later outcomes, as well as all environmental factors that siblings share. We will also compare differentially exposed half siblings, offspring of full siblings (full cousins), offspring of half siblings (half cousins), and offspring of twins. These additional comparisons will enable us to provide converging evidence for our findings and identify the source any familial selection factors (genetic and/or environmental). Detailed assessments of offspring, parental, and community- level risks will further enable us to identify the mechanisms through which early risk factors are associated with severe psychopathology. Approach: We propose to analyze a large dataset that includes information on every individual who was born or lived in Sweden from 1940-1995 (NH7,500,000), which includes measures of early environmental risks, correlated familial and community risks, and well-validated indices of severe criminal, substance use, suicide, and mental health problems from Swedish national registries. Because the dataset also includes information on the biological relatedness of each individual with all of their family members, we are able to conduct numerous quasi-experimental studies of the associations by comparing individuals who differ in both their environmental and genetic risk. Environment and Investigators: Our experienced team includes international experts in the risks associated with early prenatal and perinatal factors; the assessment and etiology of severe psychopathology; the use of large, national registries; and the use of quasi-experimental designs to study putative environmental factors. Indiana University and the Karolinska Institutet provide strong environments and relevant resources. PUBLIC HEALTH RELEVANCE: The staggering burden on individuals and society caused by violence, substance use problems, suicide, and severe mental illness has been well documented. Researchers have identified early risk factors that predict these major societal problems, but, it is still unclear whether putative early risks are truly causal or whether part-or most-of the associations with these risks are due to background familial factors. In order to improve prevention programs and our understanding of early risk factors, the current proposal seeks support to analyze a unique resource, a large dataset that includes every individual in Sweden for roughly five decades, relying on natural experiments to rigorously test causal hypotheses.