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Linear mixed model for heritability estimation that explicitly addresses environmental variation.

ABSTRACT: The linear mixed model (LMM) is now routinely used to estimate heritability. Unfortunately, as we demonstrate, LMM estimates of heritability can be inflated when using a standard model. To help reduce this inflation, we used a more general LMM with two random effects-one based on genomic variants and one based on easily measured spatial location as a proxy for environmental effects. We investigated this approach with simulated data and with data from a Uganda cohort of 4,778 individuals for 34 phenotypes including anthropometric indices, blood factors, glycemic control, blood pressure, lipid tests, and liver function tests. For the genomic random effect, we used identity-by-descent estimates from accurately phased genome-wide data. For the environmental random effect, we constructed a covariance matrix based on a Gaussian radial basis function. Across the simulated and Ugandan data, narrow-sense heritability estimates were lower using the more general model. Thus, our approach addresses, in part, the issue of "missing heritability" in the sense that much of the heritability previously thought to be missing was fictional. Software is available at https://github.com/MicrosoftGenomics/FaST-LMM.

SUBMITTER: Heckerman D

PROVIDER: S-EPMC4941438 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Linear mixed model for heritability estimation that explicitly addresses environmental variation.

Heckerman David D Gurdasani Deepti D Kadie Carl C Pomilla Cristina C Carstensen Tommy T Martin Hilary H Ekoru Kenneth K Nsubuga Rebecca N RN Ssenyomo Gerald G Kamali Anatoli A Kaleebu Pontiano P Widmer Christian C Sandhu Manjinder S MS

Proceedings of the National Academy of Sciences of the United States of America 20160701 27

The linear mixed model (LMM) is now routinely used to estimate heritability. Unfortunately, as we demonstrate, LMM estimates of heritability can be inflated when using a standard model. To help reduce this inflation, we used a more general LMM with two random effects-one based on genomic variants and one based on easily measured spatial location as a proxy for environmental effects. We investigated this approach with simulated data and with data from a Uganda cohort of 4,778 individuals for 34 p ...[more]

PMID: 27382152

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Project description:IntroductionEstimation of accurate time-integrated activity coefficients (TIACs) and radiation absorbed doses (ADs) is desirable for treatment planning in peptide-receptor radionuclide therapy (PRRT). This study aimed to investigate the accuracy of a simplified dosimetry using a physiologically-based pharmacokinetic (PBPK) model, a nonlinear mixed effect (NLME) model, and single-time-point imaging to calculate the TIACs and ADs of 90Y-DOTATATE in various organs of dosimetric interest and tumors.Materials & methodsBiokinetic data of 111In-DOTATATE in tumors, kidneys, liver, spleen, and whole body were obtained from eight patients using planar scintigraphic imaging at T1 = (2.9 ± 0.6), T2 = (4.6 ± 0.4), T3 = (22.8 ± 1.6), T4 = (46.7 ± 1.7) and T5 = (70.9 ± 1.0) h post injection. Serum activity concentration was measured at 5 and 15 min; 0.5, 1, 2, and 4 h; and 1, 2, and 3 d p.i.. A published PBPK model for PRRT, NLME, and a single-time-point imaging datum at different time points were used to calculate TIACs in tumors, kidneys, liver, spleen, whole body, and serum. Relative deviations (RDs) (median [min, max]) between the calculated TIACs from single-time-point imaging were compared to the TIACs calculated from the all-time-points fit. The root mean square error (RMSE) of the difference between the computed ADs from the single-time-point imaging and reference ADs from the all-time point fittings were analyzed. A joint root mean square error RMSEjoint of the ADs was calculated with the RSME from both the tumor and kidneys to sort the time points concerning accurate results for the kidneys and tumor dosimetry. The calculations of TIACs and ADs from the single-time-point dosimetry were repeated using the sum of exponentials (SOE) approach introduced in the literature. The RDs and the RSME of the PBPK approach in our study were compared to the SOE approach.ResultsUsing the PBPK and NLME models and the biokinetic measurements resulted in a good fit based on visual inspection of the fitted curves and the coefficient of variation CV of the fitted parameters (<50%). T4 was identified being the time point with a relatively low median and range of TIACs RDs, i.e., 5 [1, 21]% and 2 [-15, 21]% for kidneys and tumors, respectively. T4 was found to be the time point with the lowest joint root mean square error RMSEjoint of the ADs. Based on the RD and RMSE, our results show a similar performance as the SOE and NLME model approach.SummaryIn this study, we introduced a simplified calculation of TIACs/ADs using a PBPK model, an NLME model, and a single-time-point measurement. Our results suggest a single measurement might be used to calculate TIACs/ADs in the kidneys and tumors during PRRT.

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Linear mixed model for heritability estimation that explicitly addresses environmental variation.

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Linear mixed model for heritability estimation that explicitly addresses environmental variation.

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