Quasi-experimental studies of early risk factors for severe psychopathology

描述（由申请人提供）： 意义：犯罪、药物滥用问题、自杀和严重精神疾病，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相关。确定这些问题的原因，尤其是在生命早期，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相关的假定环境因素，包括母亲在怀孕期间吸烟、母亲在怀孕期间的压力、母亲的生育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否是严重形式的精神病理学的偶然风险因素，或者仅仅是家庭混乱的指标。我们对潜在因果机制的了解有限，部分原因是大多数现有的这些风险研究未能使用可以测试替代假设的研究设计，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和自然实验来分解同时发生的风险机制并解释无法测量的遗传和环境过程，以探索几种假定的早期风险因素的影响。特别是，我们将比较不同程度暴露的同辈兄弟姐妹，这种方法排除了所有可以解释早期假定风险和后期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。我们还将比较差异暴露的同父异母兄弟姐妹、全兄弟姐妹的后代（堂兄弟姐妹）、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使我们进一步确定早期风险因素与严重精神病理学相关的机制。方法：我们建议分析一个大型数据集，其中包括 1940 年至 1995 年在瑞典出生或生活的每个人 (NH7,500,000) 的信息，其中包括早期环境风险的衡量标准、相关的家庭和社区风险，以及来自瑞典国家登记处的严重犯罪、药物滥用、自杀和心理健康问题的经过充分验证的指数。由于数据集还包含每个人与其所有家庭成员的生物学相关性的信息，因此我们能够通过比较环境和遗传风险不同的个体，对这些关联进行大量的准实验研究。环境和研究人员：我们经验丰富的团队包括与早期产前和围产期因素相关的风险方面的国际专家；严重精神病理学的评估和病因学；使用大型国家登记册；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大的环境和相关资源。 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巨大负担已有充分记录。研究人员已经确定了预测这些主要社会问题的早期风险因素，但是，目前尚不清楚假定的早期风险是否真正具有因果关系，或者与这些风险的部分或大部分关联是否是由于背景家族因素造成的。为了改进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来分析一个独特的资源，一个包含瑞典大约五年来每个人的大型数据集，依靠自然实验来严格检验因果假设。

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.