title: Environmental risk factors and Parkinson's disease: An umbrella review of meta-analyses.
abstract: BACKGROUND
  Parkinson's disease is a neurological disorder with complex pathogenesis implicating both environmental and genetic factors. We aimed to summarise the environmental risk factors that have been studied for potential association with Parkinson's disease, assess the presence of diverse biases, and identify the risk factors with the strongest support.
  
  
  METHODS
  We searched PubMed from inception to September 18, 2015, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and Parkinson's disease. For each meta-analysis we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I(2), evidence of small-study effects and evidence of excess significance bias.
  
  
  RESULTS
  Overall, 75 unique meta-analyses on different risk factors for Parkinson's disease were examined, covering diverse biomarkers, dietary factors, drugs, medical history or comorbid diseases, exposure to toxic environmental agents and habits. 21 of 75 meta-analyses had results that were significant at p < 0.001 by random-effects. Evidence for an association was convincing (more than 1000 cases, p < 10(-6) by random-effects, not large heterogeneity, 95% prediction interval excluding the null value and absence of hints for small-study effects and excess significance bias) for constipation, and physical activity.
  
  
  CONCLUSIONS
  Many environmental factors have substantial evidence of association with Parkinson's disease, but several, perhaps most, of them may reflect reverse causation, residual confounding, information bias, sponsor conflicts or other caveats.
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bellou
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
authors.forename: Lazaros
authors.initials: L
authors.lastname: Belbasis
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece; Department of Biostatistics and Epidemiology, Imperial College London, London, UK; MRC-PHE Centre for Environment and Health, Imperial College London, London, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tzoulaki
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece; Department of Biostatistics and Epidemiology, Imperial College London, London, UK.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Evangelou
authors.affiliation: Department of Medicine, Stanford Prevention Research Center, Stanford, CA, USA; Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA; Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA, USA; Department of Statistics, Stanford University School of Humanities and Sciences, Stanford, CA, USA. Electronic address: jioannid@stanford.edu.
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D004781:Environmental Exposure; D006801:Humans; D015201:Meta-Analysis as Topic; D010300:Parkinson Disease / Q000453:epidemiology* / Q000209:etiology*; D012307:Risk Factors
keywords: Environment; Epidemiology; Meta-analysis; Parkinson's disease; Risk factors