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Modeling measurement error in tumor characterization studies.

ABSTRACT: Etiologic studies of cancer increasingly use molecular features such as gene expression, DNA methylation and sequence mutation to subclassify the cancer type. In large population-based studies, the tumor tissues available for study are archival specimens that provide variable amounts of amplifiable DNA for molecular analysis. As molecular features measured from small amounts of tumor DNA are inherently noisy, we propose a novel approach to improve statistical efficiency when comparing groups of samples. We illustrate the phenomenon using the MethyLight technology, applying our proposed analysis to compare MLH1 DNA methylation levels in males and females studied in the Colon Cancer Family Registry.We introduce two methods for computing empirical weights to model heteroscedasticity that is caused by sampling variable quantities of DNA for molecular analysis. In a simulation study, we show that using these weights in a linear regression model is more powerful for identifying differentially methylated loci than standard regression analysis. The increase in power depends on the underlying relationship between variation in outcome measure and input DNA quantity in the study samples.Tumor characteristics measured from small amounts of tumor DNA are inherently noisy. We propose a statistical analysis that accounts for the measurement error due to sampling variation of the molecular feature and show how it can improve the power to detect differential characteristics between patient groups.

SUBMITTER: Rakovski C

PROVIDER: S-EPMC3213130 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Modeling measurement error in tumor characterization studies.

Rakovski Cyril C Weisenberger Daniel J DJ Marjoram Paul P Laird Peter W PW Siegmund Kimberly D KD

BMC bioinformatics 20110713

<h4>Background</h4>Etiologic studies of cancer increasingly use molecular features such as gene expression, DNA methylation and sequence mutation to subclassify the cancer type. In large population-based studies, the tumor tissues available for study are archival specimens that provide variable amounts of amplifiable DNA for molecular analysis. As molecular features measured from small amounts of tumor DNA are inherently noisy, we propose a novel approach to improve statistical efficiency when c ...[more]

PMID: 21752297

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Project description:Spatiotemporal air pollution models are increasingly being used to estimate health effects in epidemiological studies. Although such exposure prediction models typically result in improved spatial and temporal resolution of air pollution predictions, they remain subject to shared measurement error, a type of measurement error common in spatiotemporal exposure models which occurs when measurement error is not independent of exposures. A fundamental challenge of exposure measurement error in air pollution assessment is the strong correlation and sometimes identical (shared) error of exposure estimates across geographic space and time. When exposure estimates with shared measurement error are used to estimate health risk in epidemiological analyses, complex errors are potentially introduced, resulting in biased epidemiological conclusions. We demonstrate the influence of using a three-stage spatiotemporal exposure prediction model and introduce formal methods of shared, multiplicative measurement error (SMME) correction of epidemiological health risk estimates. Using our three-stage, ensemble learning based nitrogen oxides (NOx) exposure prediction model, we quantified SMME. We conducted an epidemiological analysis of wheeze risk in relation to NOx exposure among school-aged children. To demonstrate the incremental influence of exposure modeling stage, we iteratively estimated the health risk using assigned exposure predictions from each stage of the NOx model. We then determined the impact of SMME on the variance of the health risk estimates under various scenarios. Depending on the stage of the spatiotemporal exposure model used, we found that wheeze odds ratio ranged from 1.16 to 1.28 for an interquartile range increase in NOx. With each additional stage of exposure modeling, the health effect estimate moved further away from the null (OR=1). When corrected for observed SMME, the health effects confidence intervals slightly lengthened, but our epidemiological conclusions were not altered. When the variance estimate was corrected for the potential "worst case scenario" of SMME, the standard error further increased, having a meaningful influence on epidemiological conclusions. Our framework can be expanded and used to understand the implications of using exposure predictions subject to shared measurement error in future health investigations.

Project description:BackgroundTwo distinctly different types of measurement error are Berkson and classical. Impacts of measurement error in epidemiologic studies of ambient air pollution are expected to depend on error type. We characterize measurement error due to instrument imprecision and spatial variability as multiplicative (i.e. additive on the log scale) and model it over a range of error types to assess impacts on risk ratio estimates both on a per measurement unit basis and on a per interquartile range (IQR) basis in a time-series study in Atlanta.MethodsDaily measures of twelve ambient air pollutants were analyzed: NO2, NOx, O3, SO2, CO, PM10 mass, PM2.5 mass, and PM2.5 components sulfate, nitrate, ammonium, elemental carbon and organic carbon. Semivariogram analysis was applied to assess spatial variability. Error due to this spatial variability was added to a reference pollutant time-series on the log scale using Monte Carlo simulations. Each of these time-series was exponentiated and introduced to a Poisson generalized linear model of cardiovascular disease emergency department visits.ResultsMeasurement error resulted in reduced statistical significance for the risk ratio estimates for all amounts (corresponding to different pollutants) and types of error. When modelled as classical-type error, risk ratios were attenuated, particularly for primary air pollutants, with average attenuation in risk ratios on a per unit of measurement basis ranging from 18% to 92% and on an IQR basis ranging from 18% to 86%. When modelled as Berkson-type error, risk ratios per unit of measurement were biased away from the null hypothesis by 2% to 31%, whereas risk ratios per IQR were attenuated (i.e. biased toward the null) by 5% to 34%. For CO modelled error amount, a range of error types were simulated and effects on risk ratio bias and significance were observed.ConclusionsFor multiplicative error, both the amount and type of measurement error impact health effect estimates in air pollution epidemiology. By modelling instrument imprecision and spatial variability as different error types, we estimate direction and magnitude of the effects of error over a range of error types.

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Modeling measurement error in tumor characterization studies.

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Modeling measurement error in tumor characterization studies.

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