Figure 1.

The directed acyclic graph (DAG) for the main variables included in the analyses for parental preterm birth or low birthweight and autism spectrum disorder (ASD) risk in children.

The directed acyclic graph represents proposed causal relationships between the variables of interest. A crude (unadjusted) model includes all possible pathways between maternal or paternal birth outcomes and autism spectrum disorder (ASD) in children. First, the direct causal effect (indicated by the long dash line) summarizes possible epigenetic reprogramming of the germ cells that leads to multigenerational transmission of ASD risk. Second, several indirect or mediating paths from parental birth characteristics and ASD in children were evaluated (indicated by dash-dot lines). Maternal chronic diseases and pregnancy complications are not expected to mediate paternal exposures (indicated with dotted line). Finally, factors that could influence the intrauterine growth of the parents constitute possible backdoor paths (solid lines). We blocked these backdoor paths by controlling for several measured factors in the adjusted models. Possible influences of other unmeasured genetic and environmental factors shared across generations (denoted with a bracket) could not be directly evaluated in this project and warrant future investigation.