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Biomedical subjects

John M Williamson

Publications and source records attributed to John M Williamson.

15 recordsLinked to original sources

A practical approach to computing power for generalized linear models with nominal, count, or ordinal responses.

Data analysts facing study design questions on a regular basis could derive substantial benefit from a straightforward and unified approach to power calculations for generalized linear models. Many current proposals for dealing with binary, ordinal, or count outcomes are conceptually or computationally demanding, limited in terms of accommodating covariates, and/or have not been extensively assessed for accuracy assuming moderate sample sizes. Here, we present a simple method for estimating conditional power that requires only standard software for fitting the desired generalized linear model for a non-continuous outcome. The model is fit to an appropriate expanded data set using easily calculated weights that represent response probabilities given the assumed values of the parameters. The variance-covariance matrix resulting from this fit is then used in conjunction with an established non-central chi square approximation to the distribution of the Wald statistic. Alternatively, the model can be re-fit under the null hypothesis to approximate power based on the likelihood ratio statistic. We provide guidelines for constructing a representative expanded data set to allow close approximation of unconditional power based on the assumed joint distribution of the covariates. Relative to prior proposals, the approach proves particularly flexible for handling one or more continuous covariates without any need for discretizing. We illustrate the method for a variety of outcome types and covariate patterns, using simulations to demonstrate its accuracy for realistic sample sizes.

Computer Simulation↗

Sample-size calculations for studies with correlated ordinal outcomes.

Correlated ordinal response data often arise in public health studies. Sample-size (power) calculations are a crucial step in designing such studies to ensure an adequate sample to detect a significant effect. Here we extend Rochon's method of sample-size estimation with a repeated binary response to the ordinal case. The proposed sample-size calculations are based on an analysis with generalized estimating equations (GEE) and inference with the Wald test. Simulation results demonstrate the merit of the proposed power calculations. Analysis of an arthritis clinical trial is used for illustration.

Antirheumatic Agents↗

Estimation of the intervention effect in a non-randomized study with pre- and post-mismeasured binary responses.

In non-randomized clinical studies, the regression phenomenon can confound interpretation of the effectiveness of an intervention. The regression effect arises due to daily variation and/or misclassification of the biologic marker used in selection as well as in the assessment of the intervention effect. We consider a scenario in which the selection criterion for a subject's participation in the study is such that he/she must have a positive diagnostic test at screening. The disease status is then reassessed at the end of intervention. Thus, two repeated measurements of a binary disease outcome are available, with only selected subjects having a second measurement upon follow-up. We propose methods for estimating the change in event probability resulting from implementing the intervention while adjusting for the misclassification that produces the regression effect. We extend this approach to estimation of both the placebo and intervention effects in placebo-controlled studies designed with a misclassified binary outcome. Analyses of two biomedical studies are used for illustration.

Acoustic Impedance Tests↗

Extending McNemar's test: estimation and inference when paired binary outcome data are misclassified.

McNemar's test is popular for assessing the difference between proportions when two observations are taken on each experimental unit. It is useful under a variety of epidemiological study designs that produce correlated binary outcomes. In studies involving outcome ascertainment, cost or feasibility concerns often lead researchers to employ error-prone surrogate diagnostic tests. Assuming an available gold standard diagnostic method, we address point and confidence interval estimation of the true difference in proportions and the paired-data odds ratio by incorporating external or internal validation data. We distinguish two special cases, depending on whether it is reasonable to assume that the diagnostic test properties remain the same for both assessments (e.g., at baseline and at follow-up). Likelihood-based analysis yields closed-form estimates when validation data are external and requires numeric optimization when they are internal. The latter approach offers important advantages in terms of robustness and efficient odds ratio estimation. We consider internal validation study designs geared toward optimizing efficiency given a fixed cost allocated for measurements. Two motivating examples are presented, using gold standard and surrogate bivariate binary diagnoses of bacterial vaginosis (BV) on women participating in the HIV Epidemiology Research Study (HERS).

Biometry↗

In situ-produced 7-chlorokynurenate has different effects on evoked responses in rats with limbic epilepsy in comparison to naive controls.

PURPOSE: Uncontrolled epilepsy remains a significant health concern and requires new approaches to therapy. N-methyl-d-aspartate (NMDA) receptor blockade has been considered, but the adverse cognitive and behavioral effects of conventional NMDA-receptor antagonists have prevented the development of clinically useful compounds. An alternative approach may be the blockade of the glycine coagonist ("glycine(B)") site of the NMDA receptor. METHODS: As a first step in the exploration of this approach, we examined the effect of 4-chloro-kynurenine (4-Cl-KYN), which is converted by astrocytes to the potent NMDA glycine-site antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), on the in vivo epileptiform evoked potentials in the CA1 region of rats with chronic limbic epilepsy (CLE). 4-Cl-KYN (100 mg/kg) was administered intraperitoneally to naive and epileptic rats. Evoked potentials were induced in area CA1 of the hippocampus by electrical stimulation of the midline region of the thalamus. Simultaneous microdialysis was performed in the contralateral hippocampus to determine the extracellular levels of 7-Cl-KYNA over the course of the experiment. RESULTS: Administration of 4-Cl-KYN caused a significant reduction in the amplitude of the population spike and in the number of population spikes in epileptic animals (p < 0.01) but had no effect on the evoked response in naive rats. In contrast, 4-Cl-KYN significantly altered the paired response in naive animals (p < 0.01), but had no significant effect on this parameter in epileptic animals. The levels of 7-Cl-KYNA measured achieved known pharmacologically effective concentrations and paralleled the observed physiological effects. CONCLUSIONS: The use of glial cells for the neosynthesis and local delivery of neuroactive compounds may be a viable strategy for the treatment of limbic epilepsy. These results also underscore the unique pharmacology of neurons in epilepsy.

Animals↗

Generalization of the Mantel-Haenszel estimating function for sparse clustered binary data.

We extend the Mantel-Haenszel estimating function to estimate both the intra-cluster pairwise correlation and the main effects for sparse clustered binary data. We propose both a composite likelihood approach and an estimating function approach for the analysis of such data. The proposed estimators are consistent and asymptotically normally distributed. Simulation results demonstrate that the two approaches are comparable in terms of bias and efficiency; however, the estimating equation approach is computationally simpler. Analysis of the Georgia High Blood Pressure survey is used for illustration.

Cluster Analysis↗

Design and analytic considerations for single-armed studies with misclassification of a repeated binary outcome.

Due to logistics or prohibitive costs, clinical studies often rely upon a potentially misclassified binary outcome variable for assessing an intervention effect. We consider noncomparative single-armed studies that are sometimes necessary for ethical reasons, and we focus on the situation in which subjects are selected to receive the intervention contingent upon a positive screening test. Both initial misclassification at screening and a regression phenomenon impacting the error-prone follow-up outcome measure contribute to bias in the typical treatment effect estimate. We propose a study design involving the collection of internal validation data assuming the availability of a more demanding gold standard outcome measure. We pursue likelihood-based analysis and describe efficiency considerations relevant to two different treatment effect definitions. We identify four possible types of validation study observations, and discuss finding the optimal allocation into these four types in order to minimize the variance of the estimated treatment effect. The optimal allocation can be highly dependent upon whether a ratio or a difference measure is adopted to evaluate the intervention. The methods are illustrated numerically, and a real-life example motivating the proposed optimal design is provided.

Clinical Trials as Topic↗

A semiparametric method for analyzing matched case-control family studies with a continuous outcome and proband sampling.

We consider matched case-control familial studies which match a group of patients, called "case probands," with a group of disease-free subjects, called "control probands," using a set of family-level matching variables. Family members of each proband are then recruited into the study. Of interest here is the familial aggregation of the response variable and the effects of subject-specific covariates on the response. We propose an estimating equation approach to jointly estimate the main effects and intrafamilial correlations for matched family studies with a continuous outcome. Only knowledge of the first two joint moments of the response variable is required. The induced estimators for the main effects and intrafamilial correlations are consistent and asymptotically normally distributed. We apply the proposed method to sleep apnea data. A simulation study demonstrates the usefulness of our approach.

Biometry↗

AIDS wasting syndrome: trends, influence on opportunistic infections, and survival.

The authors examined data from a large cohort of HIV-infected persons to demonstrate recent trends in wasting syndrome, to examine the influence of wasting syndrome on the incidence of other opportunistic illnesses, and to explore if any of the commonly prescribed treatments for wasting are associated with improved survival. Kaplan-Meier analysis and multivariate left-truncated Cox models were used to estimate time to death after the first diagnosis of wasting syndrome and to quantify the association between the covariate and mortality, respectively. The incidence of wasting declined during 1992 through 1999, with the most marked rate of decline occurring after 1995. The incidence of AIDS- and non-AIDS-defining illnesses was generally high at or after a diagnosis of wasting syndrome. Factors significantly associated with improved survival include having a CD4+ count of > or =200 cells/L during the interval of the wasting syndrome diagnosis and antiretroviral therapy with two or more drugs at or after the diagnosis of wasting syndrome. Prescription of oxandrolone was associated with improved survival, but the results did not quite reach statistical significance. The authors' study provides supportive information that treatment of wasting syndrome may have a favorable impact on survival.

AIDS-Related Opportunistic Infections↗

Development of proteinuria or elevated serum creatinine and mortality in HIV-infected women.

BACKGROUND: Data on the incidence and prognostic significance of renal dysfunction in HIV disease are limited. OBJECTIVE: To determine the incidence of proteinuria and elevated serum creatinine in HIV-positive and HIV-negative women and to determine whether these abnormalities are predictors of mortality or associated with causes of death listed on the death certificate in HIV-positive women. DESIGN: The incidence of proteinuria or elevated serum creatinine and mortality was assessed in a cohort of 885 HIV-positive women and 425 at-risk HIV-negative women. SETTING: Women from the general community or HIV care clinics in four urban locations in the United States. OUTCOME MEASURES: Creatinine of >or=1.4 mg/dL, proteinuria 2 or more, or both. Deaths confirmed by a death certificate (92%) or medical record/community report (8%). RESULTS: At baseline, 64 (7.2%) HIV-positive women and 10 (2.4%) HIV-negative women had proteinuria or elevated creatinine. An additional 128 (14%) HIV-positive women and 18 (4%) HIV-negative women developed these abnormalities over the next (mean) 21 months. Relative hazards of mortality were significantly increased (adjusted relative hazard = 2.5; 95% confidence interval: 1.9-3.3), and there were more renal causes recorded on death certificates (24/92 (26%) vs. 3/127 (2.7%), p<.0001) in HIV-infected women with, compared with those without these renal abnormalities. CONCLUSIONS: Proteinuria, elevated serum creatinine, or both frequently occurred in these HIV-infected women. These renal abnormalities in HIV-infected women are associated with an increased risk of death after controlling for other risk factors and with an increased likelihood of having renal causes listed on the death certificate. The recognition and management of proteinuria and elevated serum creatinine should be a priority for HIV-infected persons.

AIDS-Associated Nephropathy↗

Marginal analyses of clustered data when cluster size is informative.

We propose a new approach to fitting marginal models to clustered data when cluster size is informative. This approach uses a generalized estimating equation (GEE) that is weighted inversely with the cluster size. We show that our approach is asymptotically equivalent to within-cluster resampling (Hoffman, Sen, and Weinberg, 2001, Biometrika 73, 13-22), a computationally intensive approach in which replicate data sets containing a randomly selected observation from each cluster are analyzed, and the resulting estimates averaged. Using simulated data and an example involving dental health, we show the superior performance of our approach compared to unweighted GEE, the equivalence of our approach with WCR for large sample sizes, and the superior performance of our approach compared with WCR when sample sizes are small.

Cluster Analysis↗

Protease inhibitors and cardiovascular outcomes in patients with HIV-1.

Protease inhibitors for treatment of HIV-1 have been linked with increased risk of hyperlipidaemia and hyperglycaemia. In a cohort of 5672 outpatients with HIV-1 seen at nine US HIV clinics between January, 1993, and January, 2002, the frequency of myocardial infarctions increased after the introduction of protease inhibitors in 1996 (test for trend, p=0.0125). We noted that 19 of 3247 patients taking, but only two of 2425 who did not take, protease inhibitors had a myocardial infarction (odds ratio 7.1, 95% CI 1.6-44.3; Cox proportional hazards model-adjusted for smoking, sex, age, diabetes, hyperlipidaemia, and hypertension-hazard ratio 6.5, 0.9-47.8). Our findings suggest that, although infrequent, use of protease inhibitors is associated with increased risk of myocardial infarction in patients with HIV-1.

Adult↗

Phenobarbital and MK-801, but not phenytoin, improve the long-term outcome of status epilepticus.

To examine the effect of therapy on status epilepticus (SE) acutely and on long-term outcome, we compared three drugs with three different mechanisms. Phenobarbital, MK-801, and phenytoin were administered at 1, 2, and 4 hours after initiation of limbic status epilepticus by "continuous" hippocampal stimulation in rats. We evaluated the effects of these drugs on the course of SE and the subsequent development of chronic epilepsy. Phenobarbital and MK-801 were superior to phenytoin in suppressing SE and in preventing chronic epilepsy. There was no benefit if treatment was given 2 hours after the initiation of SE. Phenobarbital was most effective in suppressing electrographic seizure activity, but MK-801 had a slightly wider window for the prevention of chronic epilepsy. Early treatment, rather than electrographic suppression of SE, correlated with prevention of chronic epilepsy. This study shows that the drugs administered, which have different mechanisms of action, have clear differences in altering the outcomes. The findings suggest that studies of SE treatment should examine the effect of therapy on SE itself, as well as the long-term benefits of each treatment. The use of N-methyl-D-aspartate receptor antagonists should be considered early in the treatment of SE.

Animals↗

Bias in a placebo-controlled study due to mismeasurement of disease status and the regression effect.

We raise the concern of whether the use of a placebo group in a randomized clinical trial is sufficient to eliminate bias in the assessment of the effectiveness of a drug when enrollment into the trial prior to intervention requires diagnosis of a dichotomous disease, and the diagnostic test is subject to uncertainty. Due to misclassification and the regression effect, the observed difference in the proportions of diseased individuals between the treatment and placebo groups at follow-up will be equal to the true difference multiplied by the positive predictive value at screening and the difference between the sensitivity and the false-positive value at follow-up. Thus, measurement error of disease status before and after administering the intervention attenuates the intervention effect. Validation data corresponding to both the screening and follow-up conditions are necessary to provide additional information on the validity of the diagnostic test. Proper statistical analysis should include such data for an accurate portrayal of the effectiveness of the treatment.

Amoxicillin-Potassium Clavulanate Combination↗

Weighted least-squares approach for comparing correlated kappa.

In the medical sciences, studies are often designed to assess the agreement between different raters or different instruments. The kappa coefficient is a popular index of agreement for binary and categorical ratings. Here we focus on testing for the equality of two dependent kappa coefficients. We use the weighted least-squares (WLS) approach of Koch et al. (1977, Biometrics 33, 133-158) to take into account the correlation between the estimated kappa statistics. We demonstrate how the SAS PROC CATMOD can be used to test for the equality of dependent Cohen's kappa coefficients and dependent intraclass kappa coefficients with nominal categorical ratings. We also test for the equality of dependent Cohen's kappa and dependent weighted kappa with ordinal ratings. The major advantage of the WLS approach is that it allows the data analyst a way of testing dependent kappa with popular SAS software. The WLS approach can handle any number of categories. Analyses of three biomedical studies are used for illustration.

Atrophy↗