Simple methods for assessing haplotype-environment interactions in case-only and case-control studies.

For investigating haplotype-environment interactions in case-control studies, one can implement statistical methods based either on a retrospective likelihood (modeling the probability of haplotype and environment conditional on disease status) or a prospective likelihood (modeling the probability of disease status conditional on haplotype and environment). Retrospective approaches are generally more powerful than prospective approaches, but require an explicit model of the joint distribution of haplotype and environmental factors in the sample with the latter being particularly unattractive to specify. To resolve this issue, we propose a number of simple retrospective procedures for haplotype-environment interaction analysis that do not require explicit modeling of environmental covariates in the sample. We first consider a cases-only procedure, followed by a simple likelihood for case-control data that is proportional to the full-retrospective likelihood. Finally, we consider a retrospective procedure for inference on haplotype-environment interaction effects in matched or finely-stratified case-control studies. Our methods are based on the assumptions that haplotypes and environmental covariates are independent in the target population and that disease is rare. We illustrate our approaches using case-control data from the Finland-United States Investigation of Non-Insulin Dependent Diabetes Mellitus (FUSION) genetic study and simulated data.

Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings.

OBJECTIVE: This study investigated whether cancer patients with and without major depression exhibit immune system abnormalities similar to those reported in medically healthy, depressed subjects without cancer. METHOD: The study subjects consisted of patients diagnosed with pancreatic, esophageal, or breast cancer. Other groups consisted of subjects with major depression (without cancer) and healthy comparison subjects. Subjects' diagnoses were made with the Structured Clinical Interview for DSM-III-R. Severity of depression was measured with the Hamilton Depression Rating Scale. Plasma concentrations of interleukin-6 (IL-6) and postdexamethasone cortisol were measured. RESULTS: Cancer patients with depression had markedly higher plasma concentrations of IL-6 than healthy comparison subjects and cancer patients without depression. Although significant correlations were found between Hamilton depression scale scores and plasma concentrations of postdexamethasone cortisol, no significant correlations were found between plasma IL-6 and postdexamethasone cortisol concentrations. CONCLUSIONS: Higher than normal plasma IL-6 concentrations were associated with a diagnosis of major depression in cancer patients. IL-6 may contribute to sickness behavior that has overlapping symptoms with major depression.

Diagnostic plots for assessing the frailty distribution in multivariate survival data.

In biomedical studies, frailty models are commonly used in analyzing multivariate survival data, where the objective of the study is to estimate both the covariate effect and the dependence between the multivariate survival times. However, inference based on these models are dependent on the distributional assumption of frailty. We propose a diagnostic plot for assessing the frailty assumption. The proposed method is based on the cross-ratio function and the diagnostic plot suggested by Oakes (1989). We use kernel regression smoothing with bandwidth choice by cross-validation, to obtain the proposed plot. The resulting plot is capable of differentiating between the gamma and positive stable frailty models when strong association is present. We illustrate the feasibility of our method using simulation studies under known frailty distributions. The approach is applied to data on blindness for each eye of diabetic patients with adult onset diabetes and a reasonable fit to the gamma frailty model is found.

Modelling survival data with a cured fraction using frailty models.

Cure models have historically been utilized to analyse time-to-event data with a cured fraction. We consider the use of frailty models as an alternative approach to modelling such data. An attractive feature of the models is the allowance for heterogeneity in risk among those individuals experiencing the event of interest in addition to the incorporation of a cured component. Utilizing maximum likelihood techniques, we fit models to data concerning the recurrence of leukaemia among patients receiving autologous transplantation treatment. The analysis suggests that the gamma frailty mixture model and the compound Poisson improve on the fit of the leukaemia data as compared to the standard cure model.

Paroxetine for the prevention of depression induced by high-dose interferon alfa.

BACKGROUND: Depression commonly complicates treatment with the cytokine interferon alfa-2b. Laboratory animals pretreated with antidepressants have less severe depression-like symptoms after the administration of a cytokine. We sought to determine whether a similar strategy would be effective in humans. METHODS: In a double-blind study of 40 patients with malignant melanoma who were eligible for high-dose interferon alfa therapy, we randomly assigned 20 patients to receive the antidepressant paroxetine and 20 to receive placebo. The treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of interferon alfa therapy. RESULTS: During the first 12 weeks of interferon alfa therapy, symptoms consistent with a diagnosis of major depression developed in 2 of 18 patients in the paroxetine group (11 percent) and 9 of 20 patients in the placebo group (45 percent) (relative risk, 0.24; 95 percent confidence interval, 0.08 to 0.93). Severe depression necessitated the discontinuation of interferon alfa before 12 weeks in 1 of the 20 patients in the paroxetine group (5 percent), as compared with 7 patients in the placebo group (35 percent) (relative risk, 0.14; 95 percent confidence interval, 0.05 to 0.85). The incidence of adverse events was similar in the two groups. CONCLUSIONS: In patients with malignant melanoma, pretreatment with paroxetine appears to be an effective strategy for minimizing depression induced by interferon alfa.

Smooth estimation of the reliability function.

Problems with censored data arise quite frequently in reliability applications. Estimation of the reliability function is usually of concern. Reliability function estimators proposed by Kaplan and Meier (1958), Breslow (1972), are generally used when dealing with censored data. These estimators have the known properties of being asymptotically unbiased, uniformly strongly consistent, and weakly convergent to the same Gaussian process, when properly normalized. We study the properties of the smoothed Kaplan-Meier estimator with a suitable kernel function in this paper. The smooth estimator is compared with the Kaplan-Meier and Breslow estimators for large sample sizes giving an exact expression for an appropriately normalized difference of the mean square error (MSE) of the two estimators. This quantifies the deficiency of the Kaplan-Meier estimator in comparison to the smoothed version. We also obtain a non-asymptotic bound on an expected L1-type error under weak conditions. Some simulations are carried out to examine the performance of the suggested method.

Risk factors for premature ovarian failure in females with galactosemia.

UNLABELLED: The risk for premature ovarian failure (POF) in females with galactosemia can be predicted by analyzing 3 areas of risk pathology: the patient's molecular genotype for galactose-1-phosphate uridyltransferase (GALT), alternate pathways for galactose metabolism, and the patient's environment at diagnosis and during treatment. STUDY DESIGN: Retrospective cross-sectional information was collected on 53 females with classic galactosemia, and their ovarian function was analyzed by determination of serum follicle-stimulating hormone and luteinizing hormone levels and by clinical observation. The associations were analyzed between POF and the mutations in GALT, the highest erythrocyte galactose-1-phosphate (Gal-1-P) level at diagnosis, the age at which dietary treatment was initiated, mean erythrocyte Gal-1-P level during treatment, and whole-body carbon 13-labeled galactose oxidation to (13)CO(2). RESULTS: The most prevalent mutation, Q188R, had a significant effect of genotype category (Q188R/Q188R, Q188R/Other, Other/Other) on POF (P =.04, Fisher exact test and an odds ratio of 8.3). Mean erythrocyte Gal-1-P level during treatment was a significant risk factor for POF (P =.04). Also, all patients studied with less than 5% total body oxidation of galactose to (13)CO(2) had POF, whereas those with more than 5% did not have POF (P =.008, Fisher exact test). CONCLUSION: The development of POF in females with galactosemia is more likely if the patient's genotype is Q188R/Q188R, if the mean erythrocyte Gal-1-P is >3.5 mg/dL during therapy, and if the recovery of (13)CO(2) from whole-body (13)C-galactose oxidation is reduced below 5% of administered (13)C-galactose.

Platelet reactivity in depressed patients treated with paroxetine: preliminary findings.

BACKGROUND: Alterations in platelet reactivity have been previously posited to underlie the increased vulnerability of patients with depression to ischemic heart disease (IHD). The present study sought to determine whether the increased platelet reactivity associated with major depression is reduced after antidepressant treatment. METHODS: Patients diagnosed as having DSM-IV major depression (n = 15) (mean age, 37 +/- 7 years; range, 23-48 years) and 12 normal comparison subjects (mean age, 36 +/- 7; range, 23-48 years) were recruited. None of the controls or depressed group had evidence of IHD; 10 of 15 patients who were depressed had 1 or more traditional IHD risk factors. In vivo platelet activation, secretion, and dose-response aggregation of the controls and patients was measured after overnight bedrest under basal conditions, and after a mild exercise challenge. After 6 weeks of open-label treatment with the selective serotonin reuptake inhibitor paroxetine (20 mg/d), the patients with depression were readmitted and procedures of the first General Clinical Research Center admission repeated. RESULTS: In comparison with the control group, the depressed group exhibited greater procoagulant activity as detected by increased platelet binding of the monoclonal antibodies anti-ligand-induced binding site and GA6, and increased plasma concentrations of platelet factor 4 under basal conditions. After paroxetine treatment, the patients with depression exhibited significant reductions in all 3 parameters. CONCLUSIONS: Normalization of platelet activation is associated with paroxetine treatment of patients with depression. Because this study design did not allow for the determination of whether this effect of paroxetine on platelet function is caused by a direct effect of the drug or placebo or, alternatively, because of recovery from depression, studies containing a placebo and/or psychotherapy treatment arm may resolve this issue.

Sample size estimation for survival outcomes in cluster-randomized studies with small cluster sizes.

We present a method for computing sample size for cluster-randomized studies involving a large number of clusters with relatively small numbers of observations within each cluster. For multivariate survival data, only the marginal bivariate distribution is assumed to be known. The validity of this assumption is also discussed.

Modeling kappa for measuring dependent categorical agreement data.

A method for analysing dependent agreement data with categorical responses is proposed. A generalized estimating equation approach is developed with two sets of equations. The first set models the marginal distribution of categorical ratings, and the second set models the pairwise association of ratings with the kappa coefficient (kappa) as a metric. Covariates can be incorporated into both sets of equations. This approach is compared with a latent variable model that assumes an underlying multivariate normal distribution in which the intraclass correlation coefficient is used as a measure of association. Examples are from a cervical ectopy study and the National Heart, Lung, and Blood Institute Veteran Twin Study.

Parametric analysis for matched pair survival data.

Hougaard's (1986) bivariate Weibull distribution with positive stable frailties is applied to matched pairs survival data when either or both components of the pair may be censored and covariate vectors may be of arbitrary fixed length. When there is no censoring, we quantify the corresponding gain in Fisher information over a fixed-effects analysis. With the appropriate parameterization, the results take a simple algebraic form. An alternative marginal ("independence working model") approach to estimation is also considered. This method ignores the correlation between the two survival times in the derivation of the estimator, but provides a valid estimate of standard error. It is shown that when both the correlation between the two survival times is high, and the ratio of the within-pair variability to the between-pair variability of the covariates is high, the fixed-effects analysis captures most of the information about the regression coefficient but the independence working model does badly. When the correlation is low, and/or most of the variability of the covariates occurs between pairs, the reverse is true. The random effects model is applied to data on skin grafts, and on loss of visual acuity among diabetics. In conclusion some extensions of the methods are indicated and they are placed in a wider context of Generalized Estimation Equation methodology.

Testing for contributions of mitochondrial DNA mutations to complex diseases.

Several complex disorders are suspected of being associated with mitochondrial DNA (mtDNA) mutations. We studied the statistical properties of a test based on proband-relative pairs to identify potential mtDNA mutation involvement in a complex disorder. The test compares the recurrence risk of relatives of probands along the mitochondrial lineage with that of relatives along the nonmitochondrial lineage. If mtDNA mutations are involved, the recurrence risk will be higher among relatives in the mitochondrial lineage. The form of the test is independent of the assumed models of inheritance and interaction of the nuclear autosomal mutations with mtDNA mutations. The power of the test, however, differs among the different models and by the type of proband-relative pairs used in the test. We considered heterogeneity models with and without phenocopies, a three-state heteroplasmic mtDNA transmission model, and a multiplicative epistasis model. Under the heterogeneity model, the power of the test increases as the relationship between the proband and the relative becomes more distant. Under the multiplicative epistasis model, the power of the test decreases as the relationship between the proband and the relative becomes more distant.

Heritability estimates from human twin data by incorporating historical prior information.

Bayesian methods are commonly used in some analyses of human genetic data, such as segregation and linkage analyses, but they are not typically used for analyses of human twin data. In this paper we develop a scheme for a Bayesian analysis of human twin data. We develop prior elicitation schemes to incorporate historical information. We consider three prior schemes: fully informative, semi-informative and noninformative. We use Markov chain Monte Carlo sampling algorithms to facilitate Bayesian computation and provide detailed implementation schemes. We also develop model diagnostics for assessing the goodness of fit of twin models. Using a simulation study, we show that if the purpose of the study is to estimate the intraclass correlations or heritability in twin studies, then the semi-informative prior is as informative as the fully informative prior. Finally, a real data example is used to illustrate the proposed methodologies.

Effect of administered potassium on the renin-aldosterone axis in young blacks compared with whites.

BACKGROUND: We had observed previously that the aldosterone excretion rate and plasma aldosterone concentration were lower for black children than they were for white children. We did not know whether this was secondary to a lower intake of potassium or to suppression of the renin-angiotensin system in blacks. OBJECTIVE: To test the hypothesis that the secretion of aldosterone in response to potassium would be different in blacks than in a control group of whites. DESIGN: Black and white subjects were selected on the basis of their having aldosterone excretion rates that were in the lowest quartile for the entire original cohort. Since the blacks typically had lower aldosterone excretion rates than did the whites, the black participants were represented primarily by those with average rates of aldosterone production among blacks, whereas the whites were represented by those with the lowest aldosterone production rates among whites. The protocol consisted of a placebo-controlled, randomized cross-over study design. METHODS: Twelve blacks and 12 whites, aged 14.1 +/- 1.6 (mean +/- SD) and 15.4 +/- 2.1 years, respectively, were allocated randomly to double-blind treatment either with placebo or with 40 mmol/day potassium chloride for 7 days and then the alternate treatment Measurements of the plasma renin activity (PRA), plasma aldosterone concentration, and urinary aldosterone excretion were performed in an inpatient research unit at the end of the treatment. The blood pressure was monitored for 24 h. RESULTS: Treatment with potassium increased the plasma aldosterone concentration (P = 0.0006) and the urinary excretion of aldosterone (P = 0.0002) significantly both for blacks and for whites. There was no significant racial difference in the response to potassium. The PRA was overall 1.605-fold lower in the blacks than it was in the whites (P = 0.0124). The lowest PRA levels, such as those in the blacks when they were supine, tended to be increased with the potassium treatment. The blood pressure did not change significantly with the potassium supplement for either racial group. CONCLUSIONS: After we had supplemented the intake of potassium, aldosterone production increased in the blacks and in the control group of whites to the same extent The potassium treatment appeared to increase lower PRA levels. A lower intake of potassium could at least partially account for the suppression of the renin-aldosterone system in blacks.

Multicenter trial validation of a camera-based method to measure Tc-99m mercaptoacetyltriglycine, or Tc-99m MAG3, clearance.

PURPOSE: To evaluate an improved camera-based method for calculating the clearance of technetium-99m mercaptoacetyltriglycine (MAG3) in a multicenter trial. MATERIALS AND METHODS: Tc-99m MAG3 scintigraphy was performed in 49 patients at three sites in the United States and Canada. The percentage of the injected dose of Tc-99m MAG3 in the kidney at 1-2, 1.0-2.5, and 2-3 minutes after injection was correlated with the plasma-based Tc-99m MAG3 clearances. The data were combined with the results obtained in 20 additional patients in a previously published pilot study. RESULTS: Regression models correlating the plasma-based Tc-99m MAG3 clearance with the percentage uptake in the kidney for each time interval were developed; there was no statistically significant difference among sites in the regression equations. Correction for body surface area statistically significantly (P < .005) improved the correlation coefficient for each time interval. For the 1.0-2.5-minute interval, the body surface area-corrected correlation coefficient for the four combined sites was .87, and it improved to .93 when one outlier was omitted from the analysis. Similar results were obtained with the other time intervals. Independent processing by two observers showed no clinically important differences in the percentage dose in the kidney or in relative function. CONCLUSION: An improved camera-based method to calculate the clearance of Tc-99m MAG3 was validated in a multicenter trial.

Assessing interrater agreement from dependent data.

Estimation of interrater agreement for ordered categorical data is examined when the same sample is being assessed by various raters with different methods. We investigate the use of a latent model proposed by Qu, Piedmonte, and Medendorp (1995, Biomerics 51, 268-275) to estimate the correlation between raters for each method, and test for their equality. For each of the assessment methods, these correlations can be interpreted as the variance components of random effects representing subject and rater. This method is applied to an HIV study, in which the amount of ectopy on a woman's cervix is measured by both direct visual assessment and a computer planimetry method.

Mechanisms permitting nephrotic patients to achieve nitrogen equilibrium with a protein-restricted diet.

UNLABELLED: Clinical experience suggests nephrotic patients are at risk for malnutrition. To determine if nephrotic patients can adapt successfully to a protein-restricted diet, nephrotic (glomerular filtration rate, 52+/-15 ml/min; urinary protein [Uprot.], 7.2+/-2.2 grams/d) and control subjects completed a crossover comparison of diets providing 0.8 or 1.6 grams protein (plus 1 gram protein/gram Uprot.) and 35 kcal per kg per day. Nitrogen balance (BN) was determined and whole body protein turnover measured during fasting and feeding using intravenous -[1-13C]leucine and intragastric -[5,5, 5- 2H3]leucine. BN was positive in both nephrotic and control subjects consuming either diet and rates of whole-body protein synthesis, protein degradation, and leucine oxidation did not differ between groups. In both nephrotic and control subjects anabolism was due to a suppression of whole-body protein degradation and stimulation of protein synthesis during feeding. The principal compensatory response to dietary protein restriction was a decrease in amino acid oxidation and this response was the same in both groups. With the low protein diet leucine oxidation rates during feeding correlated inversely with Uprot. losses (r = -0.83; P < 0. 05). CONCLUSIONS: (a) a diet providing 0.8 gram protein (plus 1 gram protein/gram Uprot.) and 35 kcal per kg per day maintains BN in nephrotic patients; (b) nephrotic patients activate normal anabolic responses to dietary protein restriction (suppression of amino acid oxidation) and feeding (stimulation of protein synthesis and inhibition of protein degradation); (c) the inverse correlation between leucine oxidation and Uprot. losses suggests that proteinuria is a stimulus to conserve dietary essential amino acids.

Background subtraction in technetium-99m-MAG3 renography.

UNLABELLED: Correction represents a potential source of error in estimating split renal function and camera-based clearances. The purpose of this study was to determine which of five background options and four time intervals was associated with the least error for 99mTc-mercaptoacetyltriglycine (MAG3). METHODS: Fifteen single-kidney patients were imaged supine after 111-370 MBq (3-10 mCi) 99mTc-MAG3 injection. A phantom kidney was drawn on the 2-3-min images, approximately equal in size to the solitary kidney and used for all time intervals. Counts in the phantom and native kidneys were calculated using manual inferior and lateral regions of interest (ROIs), automated elliptical and perirenal background ROIs and no background correction at various time intervals (1-2, 1-2.5, 1.5-2.5 and 2-3 min) postinjection. With optimal background correction, counts and the relative function in the phantom kidney should be zero. The error was measuring by estimating both the relative function and absolute function expressed as the percent injected dose in the phantom kidney. RESULTS: The percent injected dose in the phantom kidney as well as the error in measuring relative function were significantly greater than zero for the inferior background correction and the no background correction options at all time intervals, p < 0.05. The percent dose in the kidney and the error associated with the lateral, elliptical and perirenal ROIs were not significantly different from zero. CONCLUSION: Regardless of time interval, the greatest error was associated with no background correction. The inferior ROI consistently underestimated the background correction and probably should not be used for 99mTc-MAG3. There was no significant difference between errors generated using the lateral and automated ROIs, although automated ROIs are probably more reproducible for sequential studies.

Exaggerated platelet reactivity in major depression.

OBJECTIVE: This study investigated whether depressed patients exhibit exaggerated platelet reactivity. METHOD: In vivo platelet activation, secretion, and dose-response aggregation were measured in 12 depressed patients and eight normal comparison subjects after overnight bed rest and following orthostatic challenge. RESULTS: The depressed patients exhibited increased platelet activation at baseline, demonstrated by increased binding of monoclonal antibody (moAb) annexin V protein reacting with prothrombinase complex binding sites. Following orthostatic challenge, the depressed patients exhibited increases in binding of moAbs PAC1 and anti-LIBS1 against activated glycoprotein IIb/IIIa and GE12 against P-selectin expressed upon secretion. The normal comparison subjects exhibited increases in platelet activation only with GE12. CONCLUSIONS: Depressed patients exhibit enhanced baseline platelet activation and responsiveness in comparison with normal subjects. Heightened susceptibility to platelet activation may be a mechanism by which depression is a significant risk factor for ischemic heart and cerebrovascular disease and/or mortality after myocardial infarction.

Racial difference in the relationship of an angiotensin I-converting enzyme gene polymorphism to serum angiotensin I-converting enzyme activity.

An insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) gene that has been associated with certain cardiovascular disorders accounts for nearly half the variation in serum ACE level in white subjects. Whether a similar association of serum ACE with the I/D polymorphism occurs in other racial groups is not known. We studied the I/D polymorphism of ACE in relation to serum ACE activity in 141 white and 62 black healthy, unrelated children and adolescents (mean age, 14.7 years). The mean level of ACE activity in whites homozygous for the D allele was higher than in heterozygotes (P = .002) and in homozygotes for the I allele (P = .0001), consistent with an earlier study. In blacks, on the other hand, no significant difference in serum ACE activity between genotypes was observed. An additional finding was a significantly positive relationship between serum ACE activity and diastolic pressure (P = .009). In children and adolescents, serum ACE activity is related to the ACE gene I/D polymorphism in whites but not in blacks. The results indicate a potentially important ethnic variation in genetic regulation of serum ACE activity and the relationship of the I/D polymorphism to cardiovascular disease.