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Effect of regulatory architecture on broad versus narrow sense heritability.

ABSTRACT: Additive genetic variance (VA ) and total genetic variance (VG ) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA /VG ratios from line-cross experiments is not well understood. Here we report how the VA /VG ratio, and thus the ratio between narrow and broad sense heritability (h(2) /H(2) ), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models (of the cAMP pathway, the glycolysis, the circadian rhythms, the cell cycle, and heart cell dynamics). We assumed genetic variation to be reflected in model parameters and extracted phenotypes summarizing the system dynamics. Even when imposing purely linear genotype to parameter maps and no environmental variation, we observed quite low VA /VG ratios. In particular, systems with positive feedback and cyclic dynamics gave more non-monotone genotype-phenotype maps and much lower VA /VG ratios than those without. The results show that some regulatory architectures consistently maintain a transparent genotype-to-phenotype relationship, whereas other architectures generate more subtle patterns. Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3649986 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Effect of regulatory architecture on broad versus narrow sense heritability.

Wang Yunpeng Y Vik Jon Olav JO Omholt Stig W SW Gjuvsland Arne B AB

PLoS computational biology 20130509 5

Additive genetic variance (VA ) and total genetic variance (VG ) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA /VG ratios from line-cross experiments is not well understood. Here we report how the VA /VG ratio, and thus the ratio between narrow and broad sense heritability (h(2) /H(2) ), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models ...[more]

PMID: 23671414

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Project description:ObjectiveThe aim of this study is to describe the proportion of children hospitalized with urinary tract infections (UTIs) who receive initial narrow- versus broad-spectrum antibiotics across children's hospitals and explore whether the use of initial narrow-spectrum antibiotics is associated with different outcomes.Design, setting and participantsWe performed a retrospective cohort analysis of children aged 2 months to 17 years hospitalized with UTI (inclusive of pyelonephritis) using the Pediatric Health Information System (PHIS) database.Main outcome and measuresWe analyzed the proportions of children initially receiving narrow- versus broad-spectrum antibiotics; additionally, we compiled antibiogram data for common uropathogenic organisms from participating hospitals to compare with the observed antibiotic susceptibility patterns. We examined the association of antibiotic type with adjusted outcomes including length of stay (LOS), costs, and 7- and 30-day emergency department (ED) revisits and hospital readmissions.ResultsWe identified 10,740 hospitalizations for UTI across 39 hospitals. Approximately 5% of encounters demonstrated initial narrow-spectrum antibiotics, with hospital-level narrow-spectrum use ranging from <1% to 25%. Approximately 80% of hospital antibiograms demonstrated >80% Escherichia coli susceptibility to cefazolin. In adjusted models, those who received initial narrow-spectrum antibiotics had shorter LOS (narrow-spectrum: 33.1 [95% confidence interval; CI]: 30.8-35.4] h vs. broad-spectrum: 46.1 [95% CI: 44.1-48.2] h) and reduced costs (narrow-spectrum: $4570 [$3751-5568] versus broad-spectrum: $5699 [$5005-$6491]). There were no differences in ED revisits or hospital readmissions. In summary, children's hospitals have low rates of narrow-spectrum antibiotic use for UTIs despite many reporting high rates of cefazolin-susceptible E. coli. These findings, coupled with the observed decreased LOS and costs among those receiving narrow-spectrum antibiotics, highlight potential antibiotic stewardship opportunities.

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Effect of regulatory architecture on broad versus narrow sense heritability.

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Effect of regulatory architecture on broad versus narrow sense heritability.

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