title: A structured approach to hypotheses involving continuous exposures over the life course.
abstract: Epidemiologists are often interested in examining different hypotheses for how exposures measured repeatedly over the life course relate to later-life outcomes. A structured approach for selecting the hypotheses most supported by theory and observed data has been developed for binary exposures. The aim of this paper is to extend this to include continuous exposures and allow for confounding and missing data.
  
  
  
  We studied two examples, the association between: (i) maternal weight during pregnancy and birthweight; and (ii) stressful family events throughout childhood and depression in adolescence. In each example we considered several plausible hypotheses including accumulation, critical periods, sensitive periods, change and effect modification. We used least angle regression to select the hypothesis that explained the most variation in the outcome, demonstrating appropriate methods for adjusting for confounders and dealing with missing data.
  
  
  
  The structured approach identified a combination of sensitive periods: pre-pregnancy weight, and gestational weight gain 0-20 weeks and 20-40 weeks, as the best explanation for variation in birthweight after adjusting for maternal height. A sensitive period hypothesis best explained variation in adolescent depression, with the association strengthening with the proximity of stressful family events. For each example, these models have theoretical support at least as strong as any competing hypothesis.
  
  
  
  We have extended the structured approach to incorporate continuous exposures, confounding and missing data. This approach can be used in either an exploratory or a confirmatory setting. The interpretation, plausibility and consistency with causal assumptions should all be considered when proposing and choosing life course hypotheses.
authors.affiliation: School of Social and Community Medicine Andrew.D.Smith@bristol.ac.uk.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK and.
authors.forename: Andrew Dac
authors.initials: AD
authors.lastname: Smith
authors.affiliation: MRC Unit for Lifelong Health and Ageing, University College London, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hardy
authors.affiliation: School of Social and Community Medicine.
authors.forename: Jon
authors.initials: J
authors.lastname: Heron
authors.affiliation: School of Social and Community Medicine.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Joinson
authors.affiliation: School of Social and Community Medicine.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK and.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: School of Social and Community Medicine.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK and.
authors.forename: Corrie
authors.initials: C
authors.lastname: Macdonald-Wallis
authors.affiliation: School of Social and Community Medicine.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK and.
authors.forename: Kate
authors.initials: K
authors.lastname: Tilling
mesh_terms: D000293:Adolescent; D041923:Adolescent Development; D000328:Adult; D001724:Birth Weight; D001835:Body Weight; D015984:Causality; D015986:Confounding Factors, Epidemiologic; D003627:Data Interpretation, Statistical; D003863:Depression / Q000453:epidemiology*; D005190:Family / Q000523:psychology*; D005260:Female; D006801:Humans; D008016:Life Change Events; D011247:Pregnancy; D012044:Regression Analysis; D012959:Socioeconomic Factors; D013315:Stress, Psychological; D015430:Weight Gain
keywords: ALSPAC; Life course; least angle regression (LARS); structured approach