Genetic and environmental pathways to complex diseases

<p>Abstract</p> <p>Background</p> <p>Pathogenesis of complex diseases involves the integration of genetic and environmental factors over time, making it particularly difficult to tease apart relationships between phenotype, genotype, and environmental factors using traditional experimental approaches.</p> <p>Results</p> <p>Using gene-centered databases, we have developed a network of complex diseases and environmental factors through the identification of key molecular pathways associated with both genetic and environmental contributions. Comparison with known chemical disease relationships and analysis of transcriptional regulation from gene expression datasets for several environmental factors and phenotypes clustered in a metabolic syndrome and neuropsychiatric subnetwork supports our network hypotheses. This analysis identifies natural and synthetic retinoids, antipsychotic medications, Omega 3 fatty acids, and pyrethroid pesticides as potential environmental modulators of metabolic syndrome phenotypes through PPAR and adipocytokine signaling and organophosphate pesticides as potential environmental modulators of neuropsychiatric phenotypes.</p> <p>Conclusion</p> <p>Identification of key regulatory pathways that integrate genetic and environmental modulators define disease associated targets that will allow for efficient screening of large numbers of environmental factors, screening that could set priorities for further research and guide public health decisions.</p

The World Federation of ADHD International Consensus Statement:208 Evidence-based conclusions about the disorder

Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.</p

DRS effectively ranks articles for productivity.

<p>(A) The number of total interactions (both novel and repeated) for each quartile is divided by (B) the time spent on curating them to produce (C) an averaged interaction yield rate (interactions per minute) for each quartile.</p

Test set of previously reviewed articles validates assigned DRS.

<p>A total of 1,020 articles are distributed by their text-mining assigned DRS (binned in 20-unit increments, <i>x</i>-axis) and are indicated as to whether they were found to have been either curated (green) or rejected (gray) by a CTD biocurator (as percent of articles in bin) at a previous time. The number of articles in each DRS bin (n) appears at the top of each column. There were no articles for the bins 280–299, 340–359, or 360–379.</p

Curation of heavy metal corpus validates assigned DRS.

<p>Of the original 14,904 articles (boxes in top row, N), a representative set of 3,583 documents (second row, n) were assigned to CTD biocurators for curatorial review, including all articles (1,981) with a high DRS ≥100, all articles (723) with a low DRS ≤20, and the complete subset of the articles (879) with a medium DRS 21–99 for the heavy metal mercury. (The 1,020 previously reviewed articles were not included in the assigned set.) The articles are distributed by their text-mining assigned DRS (binned in 20-unit increments, <i>x</i>-axis) and are indicated as to whether they were either curated (green) or rejected (gray) by a CTD biocurator (as percent of articles in bin). There is a progressive decrease in the percentage of curated articles with DRS <100. In total, 1,685 of the 1,981 articles (85%) with a high DRS ≥100 were curatable, while only 111 of the 723 articles (15%) with a low DRS ≤20 could be curated.</p

Document workflow.

<p>(1) Independent CTD-specific queries were made of PubMed to retrieve 14,904 articles for the seven heavy metals cadmium, cobalt, copper, lead, manganese, mercury, and nickel. (2) These articles were text mined and assigned a document relevancy score (DRS). (3) Of this preliminary corpus, 1,020 articles were found to have been previously reviewed in CTD and were used as a test set to evaluate the DRS and determine suitable cut-offs. (4) Articles with DRS ≥100 (high), DRS ≤20 (low), and a subset with DRS between 21–99 (medium) were combined to provide a final corpus of 3,583 documents which was then (5) sent to five CTD biocurators (who were kept blind to the DRS of each article) for review. (6) Biocurators timed themselves while reviewing all articles and ultimately rejected 1,381 (as non-curatable for CTD) and curated 2,202 of them (7) from whence 41,208 chemical-gene-disease interactions were extracted.</p