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Biomedical subjects

R J Carroll

Publications and source records attributed to R J Carroll.

At least 37 records · Page 2Linked to original sources

Implications of a new dietary measurement error model for estimation of relative risk: application to four calibration studies.

Food records or 24-hour recalls are currently used to calibrate food frequency questionnaires (FFQs) and to correct disease risks for measurement error. The standard regression calibration approach requires that these reference measures contain only random within-person errors uncorrelated with errors in FFQs. Increasing evidence suggests that records/recalls are likely to be also flawed with systematic person-specific biases, so that for any individual the average of multiple replicate assessments may not converge to her/his true usual nutrient intake. The authors propose a new measurement error model to accommodate person-specific bias in the reference measure and its correlation with systematic error in the FFQ. Sensitivity analysis using calibration data from four studies demonstrates that failure to account for person-specific bias in the reference measure can often lead to substantial underestimation of the relative risk for a nutrient. These results indicate that in the absence of information on the extent of person-specific biases in reference instruments and their relation to biases in FFQs, the adequacy of the standard methods of correcting relative risks for measurement error is in question, as is the interpretation of negative findings from nutritional epidemiology such as failure to detect an important relation between fat intake and breast cancer.

Bias↗

Flexible parametric measurement error models.

Inferences in measurement error models can be sensitive to modeling assumptions. Specifically, if the model is incorrect, the estimates can be inconsistent. To reduce sensitivity to modeling assumptions and yet still retain the efficiency of parametric inference, we propose using flexible parametric models that can accommodate departures from standard parametric models. We use mixtures of normals for this purpose. We study two cases in detail: a linear errors-in-variables model and a change-point Berkson model.

Biometry↗

SIMEX variance component tests in generalized linear mixed measurement error models.

In the analysis of clustered data with covariates measured with error, a problem of common interest is to test for correlation within clusters and heterogeneity across clusters. We examined this problem in the framework of generalized linear mixed measurement error models. We propose using the simulation extrapolation (SIMEX) method to construct a score test for the null hypothesis that all variance components are zero. A key feature of this SIMEX score test is that no assumptions need to be made regarding the distributions of the random effects and the unobserved covariates. We illustrate this test by analyzing Framingham heart disease data and evaluate its performance by simulation. We also propose individual SIMEX score tests for testing the variance components separately. Both tests can be easily implemented using existing statistical software.

Analysis of Variance↗

Comparison of the 60- and 100-item NCI-block questionnaires with validation data.

Large epidemiological studies often require short food frequency questionnaires (FFQ) to minimize the respondent burden or to control for confounding from dietary factors. In this analysis, we compared the extensively used National Cancer Institute-Block 60- and 100-item FFQs with one another and with usual intake as estimated from 12 days of validation data. The analysis focused on nutrients from different aspects of the diet, including energy, fat, saturated fat, beta-carotene, dietary fiber, and vitamin C. By use of an errors-in-variables analysis, the correlations of usual intake with the two types of FFQs for these nutrients were not different. Attenuation coefficients, a measure of misclassification error, for both FFQs were of similar magnitude and indicated that substantial attenuation of logistic regression coefficients would result from either FFQ. Our results confirm previous analyses describing the validity and utility of the 60-item FFQ (Epidemiology 1, 58-64, 1990) and indicate that it is essentially equivalent to the 100-item FFQ for epidemiological analyses of major nutrients.

Adult↗

Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6.

To explore the role of chronically elevated free fatty acids (FFAs) in the pathogenesis of the hyperproinsulinemia of type 2 diabetes, we have investigated the effect of FFAs on proinsulin processing and prohormone convertases PC2 and PC1/PC3 in MIN6 cells cultured in Dulbecco's modified Eagle's medium with or without 0.5 mmol/l FFA mixture (palmitic acid:oleic acid = 1:2). After 7 days of culture, the percent of proinsulin in FFA-exposed cells was increased (25.9 +/-0.3% intracellular and 75.4 +/- 1.2% in medium vs. 13.5 +/-0.2 and 56.2 +/- 4.1%, respectively, in control cells). The biosynthesis and secretion of proinsulin and insulin were analyzed by comparing the incorporation of [3H]Leu and [35S]Met. In pulse-chase studies, proinsulin-to-insulin conversion was inhibited, and proinsulin in the medium was increased by 50% after 3 h of chase, while insulin secretion was decreased by 50% after FFA exposure. Levels of cellular PC2 and PC3 analyzed by Western blotting were decreased by 23 and 15%, respectively. However, PC2, PC3, proinsulin, and 7B2 mRNA levels were not altered by FFA exposure. To test for an effect on the biosynthesis of PC2, PC3, proinsulin, and 7B2, a protein required for PC2 activation, MIN6 cells were labeled with [35S]Met for 10-15 min, followed by a prolonged chase. Most proPC2 was converted after 6 h of chase in control cells, but conversion was incomplete even after 6 h of chase in FFA-exposed MIN6 cells. Media from chase incubations showed that FFA-exposed cells secreted more proPC2 than controls. Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2. In conclusion, prolonged exposure of beta-cells to FFAs may affect the biosynthesis and posttranslational processing of proinsulin, PC2, PC3, and 7B2, and thereby contribute to the hyperproinsulinemia of type 2 diabetes. The mechanism of inhibition of secretory granule processing by FFAs may be through changes in Ca2+ concentration, the pH in the secretory granules, and/or other factors that may influence the activation and function of the convertases.

Animals↗

Relationship between DNA adduct levels, repair enzyme, and apoptosis as a function of DNA methylation by azoxymethane.

DNA alkylating agent exposure results in the formation of a number of DNA adducts, with O6-methyl-deoxyguanosine (O6-medG) being the major mutagenic and cytotoxic DNA lesion. Critical to the prevention of colon cancer is the removal of O6-medG DNA adducts, either through repair, for example, by O6-alkylguanine-DNA alkyltransferase (ATase) or targeted apoptosis. We report how rat colonocytes respond to administration of azoxymethane (a well-characterized experimental colon carcinogen and DNA-methylating agent) in terms of O6-medG DNA adduct formation and adduct removal by ATase and apoptosis. Our results are: (a) DNA damage is greater in actively proliferating cells than in the differentiated cell compartment; (b) expression of the DNA repair enzyme ATase was not targeted to the proliferating cells or stem cells but rather is confined primarily to the upper portion of the crypt; (c) apoptosis is primarily targeted to the stem cell and proliferative compartments; and (d) the increase in DNA repair enzyme expression over time in the bottom one-third of the crypt corresponds with the decrease in apoptosis in this same crypt region.

Alkyl and Aryl Transferases↗

Measurement error and dietary intake.

This chapter reviews work of Carroll, Freedman, Kipnis, and Li (1998) on the statistical analysis of the relationship between dietary intake and health outcomes. In the area of nutritional epidemiology, there is some evidence from biomarker studies that the usual statistical model for dietary measurements may break down due to two causes: (a) systematic biases depending on a person's body mass index; and (b) an additional random component of bias, so that the error structure is the same as a one-way random effects model. We investigate this problem, in the context of (1) the estimation of the distribution of usual nutrient intake; (2) estimating the correlation between a nutrient instrument and usual nutrient intake; and (3) estimating the true relative risk from an estimated relative risk using the error-prone covariate. While systematic bias due to body mass index appears to have little effect, the additional random effect in the variance structure is shown to have a potentially important impact on overall results, both on corrections for relative risk estimates and in estimating the distribution usual of nutrient intake. Our results point to a need for new experiments aimed at estimation of a crucial parameter.

Bias↗

Measurement error, biases, and the validation of complex models for blood lead levels in children.

Measurement error causes biases in regression fits. If one could accurately measure exposure to environmental lead media, the line obtained would differ in important ways from the line obtained when one measures exposure with error. The effects of measurement error vary from study to study. It is dangerous to take measurement error corrections derived from one study and apply them to data from entirely different studies or populations. Measurement error can falsely invalidate a correct (complex mechanistic) model. If one builds a model such as the integrated exposure uptake biokinetic model carefully, using essentially error-free lead exposure data, and applies this model in a different data set with error-prone exposures, the complex mechanistic model will almost certainly do a poor job of prediction, especially of extremes. Although mean blood lead levels from such a process may be accurately predicted, in most cases one would expect serious underestimates or overestimates of the proportion of the population whose blood lead level exceeds certain standards.

Algorithms↗

Statistical design of calibration studies.

We investigated some design aspects of calibration studies. The specific situation addressed was one in which a large group is evaluated with a food-frequency questionnaire and a smaller calibration study is conducted through use of repeated food records or recalls, with the subjects in the calibration study constituting a random sample of those in the large group. In designing a calibration study, one may use large sample sizes and few food records per individual or smaller samples and more records per subject. Neither strategy is always preferable. Instead, the optimal method for a given study depends on the survey instrument used (24-h recalls or multiple-day food records) and the variables of interest.

Computer Simulation↗

Categorical regression analysis of acute exposure to tetrachloroethylene.

Exposure-response analysis of acute noncancer risks should consider both concentration (C) and duration (T) of exposure, as well as severity of response. Stratified categorical regression is a form of meta-analysis that addresses these needs by combining studies and analyzing response data expressed as ordinal severity categories. A generalized linear model for ordinal data was used to estimate the probability of response associated with exposure and severity category. Stratification of the regression model addresses systematic differences among studies by allowing one or more model parameters to vary across strata defined, for example, by species and sex. The ability to treat partial information addresses the difficulties in assigning consistent severity scores. Studies containing information on acute effects of tetrachloroethylene in rats, mice, and humans were analyzed. The mouse data were highly uncertain due to lack of data on effects of low concentrations and were excluded from the analysis. A model with species-specific concentration intercept terms for rat and human central nervous system data improved fit to the data compared with the base model (combined species). More complex models with strata defined by sex and species did not improve the fit. The stratified regression model allows human effect levels to be identified more confidently by basing the intercept on human data and the slope parameters on the combined data (on a C x T plot). This analysis provides an exposure-response function for acute exposures to tetrachloroethylene using categorical regression analysis.

Administration, Inhalation↗

Transformations to additivity in measurement error models.

In many problems, one wants to model the relationship between a response Y and a covariate X. Sometimes it is difficult, expensive, or even impossible to observe X directly, but one can instead observe a substitute variable W that is easier to obtain. By far, the most common model for the relationship between the actual covariate of interest X and the substitute W is W = X + U, where the variable U represents measurement error. This assumption of additive measurement error may be unreasonable for certain data sets. We propose a new model, namely h(W) = h(X) + U, where h(.) is a monotone transformation function selected from some family H of monotone functions. The idea of the new model is that, in the correct scale, measurement error is additive. We propose two possible transformation families H. One is based on selecting a transformation that makes the within-sample mean and standard deviation of replicated W's uncorrelated. The second is based on selecting the transformation so that the errors (U's) fit a prespecified distribution. Transformation families used are the parametric power transformations and a cubic spline family. Several data examples are presented to illustrate the methods.

Adult↗

Analyzing bivariate continuous data grouped into categories defined by empirical quantiles of marginal distributions.

Epidemiologists sometimes study the association between two measurements of exposure on the same subjects by grouping the original bivariate continuous data into categories that are defined by the empirical quantiles of the two marginal distributions. Although such grouped data are presented in a two-way contingency table, the cell counts in this table do not have a multinomial distribution. We describe the joint distribution of counts in such a table by the term empirical bivariate quantile-partitioned (EBQP) distribution. Blomqvist (1950, Annals of Mathematical Statistics 21, 539-600) gave an asymptotic EBQP theory for bivariate data partitioned by the sample medians. We demonstrate that his asymptotic theory is not correct, however, except in special cases. We present a general asymptotic theory for tables of arbitrary dimensions and apply this theory to construct confidence intervals for the kappa statistic. We show by simulations that the confidence interval procedures we propose have near nominal coverage for sample sizes exceeding 60 for both 2 x 2 and 3 x 3 tables. These simulations also illustrate that the asymptotic theory of Blomqvist (1950) and the methods that Fleiss, Cohen, and Everitt (1969, Psychological Bulletin 72, 323-327) give for multinomial tables can yield subnominal coverage for kappa calculated from EBQP tables, although in some cases the coverage for these procedures is near nominal levels.

Analysis of Variance↗

Design aspects of calibration studies in nutrition, with analysis of missing data in linear measurement error models.

Motivated by an example in nutritional epidemiology, we investigate some design and analysis aspects of linear measurement error models with missing surrogate data. The specific problem investigated consists of an initial large sample in which the response (a food frequency questionnaire, FFQ) is observed and then a smaller calibration study in which replicates of the error prone predictor are observed (food records or recalls, FR). The difference between our analysis and most of the measurement error model literature is that, in our study, the selection into the calibration study can depend on the value of the response. Rationale for this type of design is given. Two major problems are investigated. In the design of a calibration study, one has the option of larger sample sizes and fewer replicates or smaller sample sizes and more replicates. Somewhat surprisingly, neither strategy is uniformly preferable in cases of practical interest. The answers depend on the instrument used (recalls or records) and the parameters of interest. The second problem investigated is one of analysis. In the usual linear model with no missing data, method of moments estimates and normal-theory maximum likelihood estimates are approximately equivalent, with the former method in most use because it can be calculated easily and explicitly. Both estimates are valid without any distributional assumptions. In contrast, in the missing data problem under consideration, only the moments estimate is distribution-free, but the maximum likelihood estimate has at least 50% greater precision in practical situations when normality obtains. Implications for the design of nutritional calibration studies are discussed.

Aged↗

On design considerations and randomization-based inference for community intervention trials.

This paper discusses design considerations and the role of randomization-based inference in randomized community intervention trials. We stress that longitudinal follow-up of cohorts within communities often yields useful information on the effects of intervention on individuals, whereas cross-sectional surveys can usefully assess the impact of intervention on group indices of health. We also discuss briefly special design considerations, such as sampling cohorts from targeted subpopulations (for example, heavy smokers), matching the communities, calculating sample size, and other practical issues. We present randomization tests for matched and unmatched cohort designs. As is well known, these tests necessarily have proper size under the strong null hypothesis that treatment has no effect on any community response. It is less well known, however, that the size of randomization tests can exceed nominal levels under the 'weak' null hypothesis that intervention does not affect the average community response. Because this weak null hypothesis is of interest in community intervention trials, we study the size of randomization tests by simulation under conditions in which the weak null hypothesis holds but the strong null hypothesis does not. In unmatched studies, size may exceed nominal levels under the weak null hypothesis if there are more intervention than control communities and if the variance among community responses is larger among control communities than among intervention communities; size may also exceed nominal levels if there are more control than intervention communities and if the variance among community responses is larger among intervention communities. Otherwise, size is likely near nominal levels. To avoid such problems, we recommend use of the same numbers of control and intervention communities in unmatched designs. Pair-matched designs usually have size near nominal levels, even under the weak null hypothesis. We have identified some extreme cases, unlikely to arise in practice, in which even the size of pair-matched studies can exceed nominal levels. These simulations, however, tend to confirm the robustness of randomization tests for matched and unmatched community intervention trials, particularly if the latter designs have equal numbers of intervention and control communities. We also describe adaptations of randomization tests to allow for covariate adjustment, missing data, and application to cross-sectional surveys. We show that covariate adjustment can increase power, but such power gains diminish as the random component of variation among communities increases, which corresponds to increasing intraclass correlation of responses within communities. We briefly relate our results to model-based methods of inference for community intervention trials that include hierarchical models such as an analysis of variance model with random community effects and fixed intervention effects. Although we have tailored this paper to the design of community intervention trials, many of the ideas apply to other experiments in which one allocates groups or clusters of subjects at random to intervention or control treatments.

Clinical Trials as Topic↗

Use of semiquantitative food frequency questionnaires to estimate the distribution of usual intake.

The authors consider whether semiquantitative food frequency questionnaires can be used to survey a population to estimate the distribution of usual intake. They take as an assumption that, if they were possible to obtain, the mean of many food records or recalls would be an accurate representation of an individual's usual diet. They then assume that nutrient intake as measured by a questionnaire follows a linear regression model when regressed against the usual intake of that nutrient. If the coefficients in this regression relation were known, then the distribution of usual intake could be constructed from the responses to the questionnaire. Since one generally does not know the values of the coefficients, they need to be estimated from a calibration study in which respondents complete the questionnaire together with multiple food records or recalls. This can be done either through an internal subset of the data or through an independent external study. With an internal substudy, the authors find that food frequency questionnaires typically provide little information about the distribution of usual intake in addition to that obtained from the multiple records or recalls in the substudy. When the substudy is external, if it is small then having very large numbers of subjects completing food frequency questionnaires in the survey is no more efficient than having a few subjects completing food records or recalls. However, if the external substudy is large and accurately characterizes the relation between the questionnaire response and usual intake, food frequency questionnaires can provide a cost-efficient way of estimating the distribution of usual intake. These results do not apply to the different problem of correcting relative risks for the effects of measurement error.

Bias↗

Quasilikelihood estimation in measurement error models with correlated replicates.

We consider quasilikelihood models when some of the predictors are measured with error. In many cases, the true but fallible predictor is impossible to measure, and the best one can do is to obtain replicates of the fallible predictor. We consider the case that the replicates are not independent. If one assumes that replicates are independent and they are not, one typically underestimates the extent of the measurement error, leading to an inconsistent errors in variables correction. We devise techniques for estimating the measurement error covariance matrix. In addition, we discuss how one might perform a quasilikelihood analysis by computing the mean and variance functions of the observed data, both using approximations and also exactly through a Monte Carlo method. The methods are illustrated on a data set involving systolic blood pressure and urinary sodium chloride, where the measurement errors appear to be approximately normally distributed but highly correlated, and the distribution of the true predictor is reasonably modeled as a mixture of normals.

Analysis of Variance↗

Estimating the reliability of an exposure variable in the presence of confounders.

In this paper we discuss estimation of the reliability of an exposure variable in the presence of confounders measured without error. We give an explicit formula that shows how the exposure becomes less reliable as the degree of correlation between the exposure and confounders increases. We also discuss biases in the corresponding logistic regression estimates and methods for correction. Data from a matched case-control study of hormone levels and risk of breast cancer are used to illustrate the methods.

Breast Neoplasms↗