Search

The prediction of random effects corresponding to subject-specific characteristics (e.g. means or rates of change) can be very useful in medical and epidemiologic research. At times, one may be most interested in obtaining accurate and/or precise predictions for subjects whose characteristic places them in a tail of the distribution. While the typical posterior mean predictor dominates others in terms of overall mean squared error of prediction (MSEP), its tendency to 'overshrink' has motivated research into alternatives emphasizing other criteria. Here, we specifically target MSEP within a certain region (e.g. above a known cut-off for high risk or a specified percentile of the random effect distribution), and we consider minimizing this quantity with and without constraints on overall MSEP efficiency. We use the normal-theory random intercept model to derive prediction methods with potential to yield markedly better performance for subjects in the specified region, given a well-controlled and (if desired) modest concession of overall MSEP. Criteria geared toward classification as well as overall and regional prediction unbiasedness are also provided. We evaluate the proposed techniques and illustrate them using repeated measures data on fasting blood glucose from type 2 diabetes patients. A simulation study verifies that theoretical properties and relative performances of the proposed predictors are essentially maintained when calculating them in practice based on estimated mixed linear model parameters. Straightforward extensions to incorporate covariates and additional random effects are briefly outlined.

Objective To identify factors associated with cancer treatment–induced amenorrhea and time to return of menses. Design Population-based cohort study. Setting Not applicable. Patient(s) Female cancer survivors who were diagnosed with cancer between the ages of 20 and 35 and were at least 2 years postdiagnosis at the time of recruitment (median = 7 years; interquartile range, 5–11). Intervention(s) None. Main Outcome Measure(s) Amenorrhea (≥6 months without menses) and resumption of menses. Result(s) After excluding women with hysterectomies before cancer diagnosis, 1,043 women were eligible for analysis. Amenorrhea occurred in 31.6% of women. Among women treated with chemotherapy (n = 596), older age at diagnosis (30–35 vs. 20–24 years: adjusted odds ratio [aOR] = 2.37; 95% confidence interval [CI], 1.30, 4.30) and nulligravidity (vs. gravid: aOR=1.50; 95% CI, 1.02, 2.21) were risk factors for amenorrhea. Among amenorrheic women, menses resumed in most (70.0%), and resumption occurred within 2 years of treatment for 90.0% of women. Survivors of breast cancer were more likely to resume menses at times greater than 1 year compared with lymphoma and pelvic-area cancers. Women diagnosed at older ages, those exposed to chemotherapy, and those exposed to any radiation experienced longer times to return of menses. Women who were older at diagnosis were more likely to have irregular cycles when menses returned. Conclusion(s) Treatment-induced amenorrhea is common in cancer survivors, although most women resume menses within 2 years. However, once resumed, older women are more likely to have irregular cycles. Age at diagnosis and pregnancy history affect the risk of amenorrhea.

In many biomedical studies that involve correlated data, an outcome is often repeatedly measured for each individual subject along with the number of these measurements, which is also treated as an observed outcome. This type of data has been referred as multivariate random length data by Barnhart and Sampson (1995). A common approach to handling such type of data is to jointly model the multiple measurements and the random length. In previous literature, a key assumption is the multivariate normality for the multiple measurements. Motivated by a reproductive study, we propose a new copula-based joint model which relaxes the normality assumption. Specifically, we adopt the Clayton-Oakes model for multiple measurements with flexible marginal distributions specified as semi-parametric transformation models. The random length is modeled via a generalized linear model. We develop an approximate EM algorithm to derive parameter estimators and standard errors of the estimators are obtained through bootstrapping procedures and the finite-sample performance of the proposed method is investigated using simulation studies. We apply our method to the Mount Sinai Study of Women Office Workers (MSSWOW), where women were prospectively followed for one year for studying fertility.

The role of endothelium-derived hyperpolarizing factor (EDHF) in either the healthy circulation or in those with hypercholesterolemia is unknown. In healthy and hypercholesterolemic subjects, we measured forearm blood flow (FBF) using strain-gauge plethysmography at rest, during graded handgrip exercise, and after sodium nitroprusside infusion. Measurements were repeated after l-NMMA, tetraethylammonium (TEA), and combined infusions. At rest, l-NMMA infusion reduced FBF in healthy but not hypercholesterolemic subjects. At peak exercise, vasodilation was lower in hypercholesterolemic compared to healthy subjects (274% vs 438% increase in FBF, p=0.017). TEA infusion reduced exercise-induced vasodilation in both healthy and hypercholesterolemic subjects (27%, p

Specific quantitative measurements have been recommended to assist in the interpretation of technetium-99m mercaptoacetyltriglycine (MAG3) renal studies. Our objective was to define the sex- and age-specific normal ranges for these recommended parameters.Data were obtained from a retrospective analysis of 106 subjects who were evaluated for kidney donation. The MAG3 clearance was calculated using a common camera-based method. The relative uptake, prevoid/postvoid and postvoid/maximum count ratios were determined using whole-kidney regions of interest (ROIs). Time to peak, time to half-peak, 20 min/maximum and 20 min/2-3 min count ratios were determined for cortical and whole-kidney ROIs. Residual urine volume was calculated on the basis of the pre- and postvoid bladder counts and voided urine volume.The mean camera-based MAG3 clearance was 321 +/- 69 mL/min/1.73 m2, essentially the same as the mean plasma sample MAG3 clearance in comparable populations. The percentages of relative uptake in the right and left kidneys were 49% and 51% +/- 4%, respectively; no difference was seen between men and women. Cortical values were lower than the whole-kidney values (p0.001); the mean cortical 20 min/maximum count ratio was 0.19 (SD, 0.07 and 0.04 for right and left kidneys, respectively). The mean postvoid/maximum whole-kidney count ratio was0.1, and the mean postvoid residual bladder volume was30 mL.Normal limits adjusted for age and sex have been established. Applying normal ranges to quantitative MAG3 parameters may assist in the interpretation of MAG3 scintigraphy and facilitate appropriate patient management.

Epidemiologists often use menstrual cycle patterns as indicators of endocrine function in environmental and occupational studies, yet few studies have considered whether menstrual cycle characteristics are associated with fertility or pregnancy outcome.We prospectively studied 470 women to determine whether cycle length or bleed length were associated with fertility or spontaneous abortion. Women completed daily diaries with information on menstrual bleeding, intercourse, birth control use, and covariates. For each menstrual cycle, women collected at least 2 urine samples, which were assayed for human chorionic gonadotropin to define early pregnancies. Women were followed for 1 year or until the end of a clinical pregnancy.Cycles with lengths of 30 to 31 days preceded cycles with the highest fecundity. Shorter cycles were less likely to be followed by conception (fecundity ratio [FR] = 0.6; 95% confidence interval [CI] = 0.4-1.0). Compared with 30- to 31-day cycles, conceptions after shorter and longer cycles were more likely to be spontaneously aborted (for shorter cycles, odds ratio [OR] = 3.0 [95% CI = 0.9-9.6] and for longer cycles, OR = 3.0 [0.9-10.6]). Cycles with 5 days of menstrual bleeding had the highest fecundity. Cycles with up to 4 days of bleeding had lower fecundity (for bleed lengths of 4 days, FR = 0.5 [0.3-0.8] and for bleed lengths less than 4 days, FR = 0.6 [0.3-0.9]). Spontaneous abortion was less likely after bleeds greater than 5 days (OR = 0.4 [0.1-1.1]) when compared with 5-day bleeds.Menstrual cycle characteristics appear to be associated with fertility and spontaneous abortion.

SUMMARY In reproductive health studies, epidemiologists are often interested in examining the effects of covariates on menstrual cycle length which is a convenient, noninvasive measure of women’s ovarian and reproductive function. Previous literature (Harlow and Zeger, 1991) suggests that the distribution of cycle length is a mixture of a major symmetric distribution and a component featuring a long right tail. Motivated by the shape of this marginal distribution, we propose a mixture distribution for cycle length, representing standard cycles from a Normal distribution and nonstandard cycles from a shifted Weibull distribution. The parameters are estimated using an estimating equation derived from the score function of an independence working model. The fitted mixture distribution agrees well with the distribution estimated using nonparametric approaches. We propose two measures to help determine whether a cycle is standard or nonstandard, developing tools necessary to identify characteristics of the menstrual cycles that are biologically indicative of ovarian dysfunction. We model the effect of a woman’s age on the mean and variation of both standard and nonstandard cycle lengths using multiple measurements of women.

BACKGROUND: CYP17, which encodes cytochrome P450c17α, mediates both steroid 17a-hydroxylase and 17,20-lyase activities, and is essential for the production of glucocorticoids and sex steroids. There is evidence that a common polymorphism in CYPI7 (T27C) is associated with estrogen levels, making it a potential marker of disease risk. METHODS: This is the first study to examine the relationship between CYP17 and estradiol (E 2 ) using serum sampled exclusively from the early follicular phase of the menstrual cycle. We assessed the relationship between CYP17 and serum hormone levels, menstrual cycle length, bleed length, and age at menarche in 164 pre-menopausal women. RESULTS: Among women with body mass index (BMI) ≤25 kg/m 2 , those with the TC and CC genotypes had 19 and 42% higher E 2 (P for trend 0.007) and 14 and 30% higher dehydroepiandrosterone sulphate respectively (P for trend 0.10) than women with the TT genotype. Androstenedione levels did not differ between genotypes. Among women with BMI >25 kg/m 2 , hormone levels did not differ by genotype. Women with the C allele were also more likely to have menstrual cycle lengths

Summary In many longitudinal studies, a subject’s response profile is closely associated with his or her risk of experiencing a related event. Examples of such event risks include recurrence of disease, relapse, drop-out and non-compliance. When evaluating the effect of a treatment, it is sometimes of interest to consider the joint process consisting of both the response and the risk of an associated event. Motivated by a prevention of depression study among patients with malignant melanoma, we examine a joint model that incorporates the risk of discontinuation into the analysis of serial depression measures. We present a maximum likelihood estimator for the mean response and event risk vectors. We test hypotheses about functions of mean depression and withdrawal risk profiles from our joint model, predict depression from updated patient histories, characterize associations between components of the joint process and estimate the probability that a patient’s depression and risk of withdrawal exceed specified levels. We illustrate the application of our joint model by using the depression data.

Interferon (IFN)-alpha plus ribavirin is an effective treatment for hepatitis C virus (HCV) infection, but is associated with a high rate of depression. Depression has been linked to a worse outcome in multiple medical disorders including viral illnesses. We examined whether increased symptoms of depression during IFN-alpha/ribavirin therapy were associated with a reduced treatment response as assessed by clearance of HCV. Depressive symptoms were evaluated in 102 HCV-infected patients at baseline and after 4, 8, 12, and 24 weeks of pegylated IFN-alpha-2b plus ribavirin therapy using the Zung self-rating depression scale (SDS). Viral clearance was determined at 24 weeks by polymerase chain reaction (PCR). Only 34% of subjects (10 out of 29) with a 20-point or greater increase in SDS Index score were HCV PCR negative at 24 weeks, compared to 59% (24 out of 41) of patients with a 10-19 point increase in SDS Index and 69% (22 out of 32) of patients with a less than 10 point increase (chi2=7.6, df=2, p

We consider estimation of the regression coefficients in the multivariate positive stable frailty model with Weibull marginals introduced by Hougaard (1986). For general cluster sizes and various covariate patterns, we study the efficiency, relative to full maximum likelihood, of estimation from the independence working model and from the fixed effects model.

Multivariate survival data arises when subjects in the same group are related to each other or when there are multiple recurrences of the disease in the same subject. A common goal of survival analysis is to relate the outcome (time to event) to a set of covariates. In this paper, we focus on prognostic classification for multivariate survival data where identifying subgroups of patients with similar prognosis is of interest. We propose a computationally feasible method to identify prognostic groups with the widely used Classification and Regression Trees (CART) algorithm. The proposed method extends CART algorithm to multivariate survival data by introducing a gamma frailty to account for dependence among correlated events. The method is applied to a catheter infection data, and the performance of the method is also investigated by several simulation studies.

The precision of estimating protein intake of patients with chronic renal failure. Background Biochemical methods for estimating protein intake are based on the concept that nitrogen-containing products of protein in diet plus the products arising from endogenous protein are excreted as either urea or non-urea nitrogen (NUN). This formulation is based on the fact that the urea is the principal end product of amino acid degradation and, hence, the urea appearance rate (or net urea production) is parallel to protein intake. The urea nitrogen appearance (UNA) rate is measured as the amount of urea excreted in urine plus the net amount accumulated in body water. A more difficult problem is how to estimate NUN, the sum of fecal nitrogen, and all forms of non-urea urinary nitrogen. Maroni, Steinman, and Mitch ( Kidney Int 27:58-65, 1985) proposed estimating nitrogen intake (I N MARONI ) from UNA plus NUN excretion rate of 0.031 g nitrogen/kg body weight/day, as they found NUN correlated with body weight but not with dietary nitrogen. Kopple, Gao, and Qing ( Kidney Int 27:486-494, 1997) proposed a different equation for estimating nitrogen intake (I N KOPPLE ) = 1.20 UNA + 1.74, concluding that dietary nitrogen directly correlates with fecal nitrogen and that NUN is constant for all patients. Their report prompted us to review all nitrogen balance measurements we had conducted in order to address the following questions. Does dietary protein increase fecal nitrogen excretion? Does NUN vary with weight or is it constant? How do the two methods (I N MARONI and I N KOPPLE ) compare in estimating dietary protein from UNA? Methods We examined nitrogen balance and its components measured in 33 patients with chronic renal failure (CRF) who were eating diets varying from 4.1 to 10.1 g nitrogen/day. We evaluated relationships between dietary nitrogen [intake nitrogen (I N )], NUN, fecal nitrogen, body weight, and the predictability of the two methods. Results Neither fecal nitrogen nor NUN were significantly correlated with I N ( r = 0.04 and r = -0.07, respectively). NUN significantly correlated with body weight ( P = 0.008). Measured I N averaged 5.75 ± 0.41 g nitrogen/day; the estimated I N MARONI value was 5.61 ± 0.27 g nitrogen/day; the estimated I N KOPPLE was 6.04 ± 0.44 g nitrogen/day. The prediction errors associated with the I N KOPPLE equation were slightly but not statistically higher than that associated with I N MARONI . Conclusion Fecal nitrogen is not correlated with I N . NUN is not constant but varies with weight, and the traditional method of estimating I N in stable chronic renal insufficiency (CRI) patients from UNA and weight as proposed by Maroni, Steinman, and Mitch is valid.

More than a dozen studies have examined the association between leanness and increased lung cancer risk. None of the prospective studies has been large enough to allow exclusion of smokers or persons with preexisting disease, two factors that cause both leanness and poor survival and thus may cause a spurious association between low body mass index and fatal lung cancer.Using Cox proportional hazards models, we examined this issue in a cohort of 941,105 U.S. adults enrolled in an American Cancer Society prospective study in 1982. During 14 years of follow-up, 14,066 people died of lung cancer.In analyses restricted to lifelong nonsmokers who did not report preexisting disease, leanness was not substantially associated with lung cancer mortality in men (rate ratio = 0.9; 95% confidence interval = 0.3-3.1) or in women (rate ratio = 1.2; 95% confidence interval = 0.7-2.1). However, leanness was associated with increased lung cancer risk in analyses that attempted to control for, rather than exclude, smokers and persons with preexisting disease.These data suggest that the association between leanness and lung cancer mortality is not causal but rather is an artifact of the effects of smoking and preexisting disease.

Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.

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. (Am J Psychiatry 2001; 158:1252–1257) Cancer patients, who experience marked physiologic, economic, and psychological stressors, have long been observed to have elevated prevalence rates of major depression, compared with the general population (1). Among cancer patients, the highest prevalence rates are exhibited by patients with either oropharyngeal cancer (2–4) or pancreatic cancer (5–7). Prospective or crosssectional studies of patients with pancreatic cancer have documented a remarkable point prevalence rate of depression of 50% (5–8). Although a number of neurochemical, neuroendocrine, neuroanatomical, and neuroimmune alterations have been associated with unipolar depression, few of these psychobiologic alterations have been systematically investigated in cancer patients with depression.

A latent variable model is considered for the analysis of twin data with an ordinal response. The underlying latent multivariate normally distributed variable is expressed in terms of genetic and environmental effects, and the variance components associated with these effects are estimated. We illustrate this approach with analysis of the NHLBI Twin Study. Model assessment is ascertained by proposing a goodness-of-fit test for ordered categorical data. Extensions of this approach for the investigation of how genetic effects vary over time are discussed.

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 disc...

Cluster randomized studies are common in community trials. The standard method for estimating sample size for cluster randomized studies assumes a common cluster size. However often in cluster randomized studies, size of the clusters vary. In this paper, we derive sample size estimation for continuous outcomes for cluster randomized studies while accounting for the variability due to cluster size. It is shown that the proposed formula for estimating total cluster size can be obtained by adding a correction term to the traditional formula which uses the average cluster size. Application of these results to the design of a health promotion educational intervention study is discussed.

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.

In biomedical studies, frailty models arecommonly used in analyzing multivariate survival data, wherethe objective of the study is to estimate both the covariateeffect and the dependence between the multivariate survival times.However, inference based on these models are dependent on thedistributional assumption of frailty. We propose a diagnosticplot for assessing the frailty assumption. The proposed methodis based on the cross-ratio function and the diagnostic plotsuggested by Oakes (1989). We use kernel regression smoothingwith bandwidth choice by cross-validation, to obtain the proposedplot. The resulting plot is capable of differentiating betweenthe gamma and positive stable frailty models when strong associationis present. We illustrate the feasibility of our method usingsimulation studies under known frailty distributions. The approachis applied to data on blindness for each eye of diabetic patientswith adult onset diabetes and a reasonable fit to the gamma frailtymodel is found.

SUMMARY 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 (κ) 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.

SUMMARY We consider the statistical evaluation and estimation of vaccine efficacy when the protective effect wanes with time. We reanalyse data from a 5-year trial of two oral cholera vaccines in Matlab, Bangladesh. In this field trial, one vaccine appears to confer better initial protection than the other, but neither appears to offer protection for a period longer than about 3 years. Time-dependent vaccine effects are estimated by obtaining smooth estimates of a time-varying relative risk RR(t) using survival analysis. We compare two approaches based on the Cox model in terms of their strategies for detecting time-varying vaccine effects, and their estimation techniques for obtaining a time-dependent RR(t) estimate. These methods allow an exploration of time-varying vaccine effects while making minimal parametric assumptions about the functional form of RR(t) for vaccinated compared wit unvaccinated subjects.

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 Estimating Equation methodology.

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.

Nuclear magnetic resonance (NMR) spectroscopy, traditionally used in analytical chemistry, has recently been introduced to studies of metabolite composition of biological fluids and tissues. Metabolite levels change over time, and providing a tool for better extraction of NMR peaks exhibiting periodic behavior is of interest. We propose a method in which NMR peaks are clustered based on periodic behavior. Periodic regression is used to obtain estimates of the parameter corresponding to period for individual NMR peaks. A mixture model is then used to develop clusters of peaks, taking into account the variability of the regression parameter estimates. Methods are applied to NMR data collected from human blood plasma over a 24-hour period. Simulation studies show that the extra variance component due to the estimation of the parameter estimate should be accounted for in the clustering procedure.

Introduction: Habitual dietary sodium intake is associated with coronary flow reserve, a measure of microvascular function. We investigated the role of habitual dietary sodium in the expression of soluble cell adhesion molecules; these molecules are markers of endothelial dysfunction that are thought to contribute to the development of atherosclerosis. Hypothesis: Habitual dietary sodium is directly associated with soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) concentration. Methods: We recruited 475 predominantly healthy middle-aged male twins, including 214 monozygotic and dizygotic twin pairs and 47 unpaired twins, from the Vietnam Era Twin Registry. The twins had no previous history of coronary heart disease. Food intake was assessed using the Willett food-frequency questionnaire. We estimated habitual daily sodium consumption over the previous year from reported food intake. We measured sVCAM-1 and sICAM-1 concentration in blood using commercially available ELISA kits. We also obtained information on demographic characteristics and traditional CVD risk factors, including blood pressure. Mixed-effect regression analysis was used to examine individual-level effects and robust regression analysis was used to examine within-pair differences. Results: The twins’ mean age was 53.4 years (SD = 3.1), and 96% (455 out of 475) were white. An increase in dietary sodium of 1,000 mg/d was associated with a 12.2% higher sVCAM-1 concentration (95% CI: 3.1, 21.2; P = 0.009) after adjustment for total energy intake, various nutritional factors, demographic characteristics, and traditional CVD risk factors. For sICAM-1, the adjusted individual-level effect was only 3.1% and did not achieve statistical significance ( P = 0.39). Across quintiles of sodium consumption, sVCAM-1 concentration was directly associated with dietary sodium ( P for trend = 0.002) with the top quintile (sodium >1,505 mg/d) having a 22.9% higher sVCAM-1 concentration than the bottom quintile (sodium P = 0.03), yet differed by zygosity ( P interaction = 0.01). Among dizygotic pairs, a 1,000 mg/d within-pair difference in dietary sodium was associated with a 17.3% higher sVCAM-1 concentration in the twin with higher dietary sodium than in the co-twin with lower dietary sodium ( P = 0.005) after adjustment for potential confounders. Among monozygotic pairs, however, the within-pair difference was only 5.0% per 1,000 mg/d of sodium intake and did not reach statistical significance ( P = 0.25). Conclusions: Habitual dietary sodium is directly associated with sVCAM-1 concentration, a marker of abnormal endothelial function, independent of traditional CVD risk factors. However, shared genetic factors may mediate this association.

Objective: This study iizvestigated whether depressed patients exhibit exaggerated platelet reactivity. Method: In vivo platelet activatioiz, secretioz, and dose-response aggregation were measured in 12 depressed patients and eight normal comparison subjects after overizight bed rest aizd following orthostatic challenge. Results: The depressed patients exhibited increased platelet activation at baseli,ze, demonstrated by increased binding of monoclonal antibody (moAb) annexin V protein reacting with prothrombinase complex binding sites. Followizg orthostatic challeizge, the depressed patients exhibited increases in binding of moAbs PACI a,zd anti-LIBS1 agaiizst actii'atedglycoprotein Jib/lila and GEI2 against P-selecti,z expressed 111)01? secretion. The normal comparison subjects exhibited increases in platelet activatioz only with GE I 2. Conclusions: Depressed patients exhibit enhazced baseline platelet activation and respozsiveness in comparisoz with normal subjects. Heightened susceptibility to platelet acti- vation flltlV he a mechanism b�' which depression is a significant risk factor for ischemic heart azd cerebrovascular disease and/or mortality after myocardial infarction. (AmJ Psychiatry 1996; 153:1313-1317)

Abstract 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.

A general formula is derived for the variance of Kendall's coefficient of concordance for absolutely continuous bivariate distributions generated by frailties. The formula is specialized to the case of Gumbel's Type II distribution of extreme values, which arises when the frailty has a positive stable distribution. A new diagnostic is suggested for the goodness of fit of a bivariate frailty distribution, based on the value of Kendall's tau for a truncated sample. It is shown that as a function of the proportion of the sample truncated, this truncated tau characterizes the original frailty distribution. The methods are applied to some cable insulation failure data.

Bone density is greater in blacks than in whites regardless of age. In adults, bone formation was shown previously to be much lower in blacks than in whites. A lower bone turnover in adult blacks may preserve a high bone density acquired earlier in life. Whether there is a difference in bone turnover in blacks and whites early in life is not known. Bone resorption is known to parallel bone formation, and thus in the present study we looked for racial differences in bone turnover in children by measuring the nocturnal urinary excretion of three markers of bone resorption: hydroxyproline and the pyridinium cross-links, pyridinoline and deoxypyridinoline. Sixty-four black and 145 white children ages 6 through 15 years were studied. We found excretion of hydroxyproline to be similar in whites and blacks. Urinary excretion of the cross-links was about 10% to 15% lower in blacks, but only the excretion of pyridinoline in boys was significantly lower in blacks (p = 0.031). Overnight urinary calcium excretion was about 30% lower in blacks than in whites (p = 0.0016 for boys and p = 0.008 for girls), as has been reported previously by others. In summary, the excretion rates of bone resorptive products in white and black children were similar, suggesting nearly equal bone turnover in the two racial groups, a finding that contrasts with observations made previously in adults.

The T235 allele of the angiotensinogen gene (AGT) has been associated with hypertension. Blood pressure increases faster over time in black children than in white children, and in adults hypertension is more prevalent in blacks. We sought evidence for a role for angiotensinogen to contribute to racial differences in blood pressure in a study of 148 white and 62 black normotensive children (mean age, 14.8 yr). The frequency of the T235 allele was 0.81 in blacks and 0.42 in whites (chi 2 = 77.3, P = 0.0001). The mean angiotensinogen level was 19% higher in blacks than in whites (P = 0.0001 for males, P = 0.004 for females). Genotype was positively related to serum angiotensinogen in white children (P = 0.0001 for males, P = 0.004 for females), but a similar relationship was absent in blacks where the frequency of M235 may have been too low to discern an association. Longitudinal blood pressure (measured twice yearly) adjusted for body mass index showed a marginally significant relationship to the angiotensinogen level (P = 0.07). An independent relationship of serum angiotensinogen with body mass index (P = 0.0001) and race (P = 0.0003) was also observed. In summary, T235 was more frequent, and the level of angiotensinogen was higher in blacks than in whites. Such a racial difference in the renin-angiotensin system may contribute to the disparity in blood pressure levels of white and black young people.

The need to assess agreement arises in many scenarios in biomedical sciences when measurements were taken by different methods on the same subjects. When the endpoints are survival outcomes, the study of agreement becomes more challenging given the special characteristics of time-to-event data. In this article, we propose a new framework for assessing agreement based on survival processes that can be viewed as a natural representation of time-to-event outcomes. Our new agreement measure is formulated as the chance-corrected concordance between survival processes. It provides a new perspective for studying the relationship between correlated survival outcomes and offers an appealing interpretation as the agreement between survival times on the absolute distance scale. We provide a multivariate extension of the proposed agreement measure for multiple methods. Furthermore, the new framework enables a natural extension to evaluate time-dependent agreement structure. We develop nonparametric estimation of the proposed new agreement measures. Our estimators are shown to be strongly consistent and asymptotically normal. We evaluate the performance of the proposed estimators through simulation studies and then illustrate the methods using a prostate cancer data example.

Background The accuracy of computer-aided diagnosis (CAD) software is best evaluated by comparison to a gold standard which represents the true status of disease. In many settings, however, knowledge of the true status of disease is not possible and accuracy is evaluated against the interpretations of an expert panel. Common statistical approaches to evaluate accuracy include receiver operating characteristic (ROC) and kappa analysis but both of these methods have significant limitations and cannot answer the question of equivalence: Is the CAD performance equivalent to that of an expert? The goal of this study is to show the strength of log-linear analysis over standard ROC and kappa statistics in evaluating the accuracy of computer-aided diagnosis of renal obstruction compared to the diagnosis provided by expert readers. Methods Log-linear modeling was utilized to analyze a previously published database that used ROC and kappa statistics to compare diuresis renography scan interpretations (non-obstructed, equivocal, or obstructed) generated by a renal expert system (RENEX) in 185 kidneys (95 patients) with the independent and consensus scan interpretations of three experts who were blinded to clinical information and prospectively and independently graded each kidney as obstructed, equivocal, or non-obstructed. Results Log-linear modeling showed that RENEX and the expert consensus had beyond-chance agreement in both non-obstructed and obstructed readings (both p < 0.0001). Moreover, pairwise agreement between experts and pairwise agreement between each expert and RENEX were not significantly different (p = 0.41, 0.95, 0.81 for the non-obstructed, equivocal, and obstructed categories, respectively). Similarly, the three-way agreement of the three experts and three-way agreement of two experts and RENEX was not significantly different for non-obstructed (p = 0.79) and obstructed (p = 0.49) categories. Conclusion Log-linear modeling showed that RENEX was equivalent to any expert in rating kidneys, particularly in the obstructed and non-obstructed categories. This conclusion, which could not be derived from the original ROC and kappa analysis, emphasizes and illustrates the role and importance of log-linear modeling in the absence of a gold standard. The log-linear analysis also provides additional evidence that RENEX has the potential to assist in the interpretation of diuresis renography studies.

Background— We assessed the contribution of endothelium-derived hyperpolarizing factors to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was used to inhibit K + Ca channel activation and fluconazole was used to inhibit cytochrome P450 2C9–mediated epoxyeicosatrienoic acid synthesis. We hypothesized that endothelium-derived hyperpolarizing factors contribute to resting vascular tone by K + Ca channel activation and epoxyeicosatrienoic acid release and that endothelium-derived hyperpolarizing factors compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and Results— In 103 healthy subjects and 71 nonhypertensive subjects with multiple risk factors, we measured resting forearm blood flow (FBF) using venous occlusion plethysmography before and after intra-arterial infusions of N G -monomethyl- l -arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF and on bradykinin- and acetylcholine-mediated vasodilation were studied. Resting FBF decreased with TEA and L-NMMA in all subjects ( P P =0.04) and to TEA was lower ( P =0.04) in healthy subjects compared with those with risk factors. Fluconazole decreased resting FBF in all subjects, and the addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K + Ca channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects ( P P Conclusions— First, by activating TEA-inhibitable K + Ca channels, endothelium-derived hyperpolarizing factors, together with nitric oxide, contribute to resting microvascular dilator tone. The contribution of K + Ca channel activation compared with nitric oxide is greater in those with multiple risk factors compared with healthy subjects. Second, activation of K + Ca channels is only partly through epoxyeicosatrienoic acid release, indicating the presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine, stimulates K + Ca channel–mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K + Ca channel-mediated vasodilation compensates for the reduced nitric oxide activity. Thus, enhanced endothelium-derived hyperpolarizing factor activity in conditions of nitric oxide deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00166166.

We consider repeated measures interval-observed data with informative dropouts. We model the repeated outcomes via an unobserved random intercept and it is assumed that the probability of dropout during the study period is linearly related to the random intercept in a complementary log-log scale. Assuming the random effect follows the power variance function (PVF) family suggested by Hougaard (2000), we derive the marginal likelihood in a closed form. We evaluate the performance of the maximum likelihood estimation via simulation studies and apply the proposed method to a real data set.

The menstrual cycle is an important indicator of underlying hormonal function. Although menstrual cycle variability (sometimes referred to as 'regularity') is associated with a variety of demographic, behavioral, occupational, and environmental factors, as well as with several chronic diseases, few studies have examined its association with fecundity. We investigated whether a woman's menstrual cycle variability was associated with the likelihood of her achieving pregnancy. In this prospective study, we analyzed 3,536 menstrual cycles from 401 women (aged 19-41) recruited from 1990-1994. The women provided daily diaries recording menstrual bleeding, intercourse, and birth control use. Urine samples were assayed for human chorionic gonadotropin to identify early pregnancies during each menstrual cycle. Each woman's menstrual cycle variability was defined by the standard deviation of her cycle lengths during followup. The median follow-up was eight cycles. The outcome was her per-cycle probability of pregnancy. We found that women with high menstrual cycle variability had a reduced (51% lower) per cycle probability of pregnancy (fecundity ratio: 0.49; 95% confidence interval: 0.31, 0.77) compared with women with minimal variability. This relationship was independent of a woman's age and her mean cycle length. Thus, researchers and clinicians using menstrual cycle characteristics as indicators of endocrine or reproductive health should include measures of cycle variability in addition to the more commonly examined cycle length.

Aldosterone production, estimated from urinary excretion of aldosterone and the plasma aldosterone level, was found in a previous cross-sectional study to be lower in black children than white children. The present study examined aldosterone excretion longitudinally to determine whether the aldosterone excretion rate changed with time and if the racial difference in aldosterone excretion persisted. Urine samples were collected every 6 months for up to 5.5 yr in 351 white and 170 black children for measurements of aldosterone, sodium (Na+), and potassium (K+) excretion. Results were expressed per mumol urinary creatinine. Mean values for excretion rates for the total longitudinal period were determined. Na+ excretion was not significantly different in the two groups, whereas K+ excretion was 18% lower in blacks than whites (P = 0.0001). Body weight and urinary Na+ and K+ excretion were significantly related to aldosterone excretion. After adjusting for these variables, the aldosterone excretion rate was 35% lower in blacks than whites (P = 0.0001), a racial difference that did not change with age. Aldosterone excretion rates showed no longitudinal trend to either increase or decrease. The physiological relevance of the lower aldosterone excretion rate in black children remains unknown.

Symptomatic local failure following thoracic irradiation for bronchogenic carcinoma presents a clinical challenge to the Radiation Oncologist. We retrospectively evaluated the efficiency of reirradiation with external beam radiation of 30 patients. The median dose of initial irradiation was 6,000 cGy in 6 weeks. The median time following initial irradiation to recurrence was 12 months. The median dose of retreatment was 3,030 cGy in 3 weeks. Of the symptomatic patients, 88% and 70% subjectively responded to initial irradiation and to reirradiation, respectively. Retreatment toxicity included radiation esophagitis (6 patients), dry desquamation (4 patients), and symptomatic radiation pneumonitis (1 patient). Based on this study, doses of external beam radiation in the range of 2,000-3,000 cGy in 2 to 3 weeks appear safe and effective in reirradiating recurrent bronchogenic carcinoma.

The prevalence of hypertension is greater for blacks than whites. Whether black children have higher blood pressure than white children is less clear. We investigated this issue through a prospective longitudinal assessment of blood pressure in 345 white children and 164 black children. Each child had his or her blood pressure measured every 6 months for 2 to 5.5 years. The means for systolic and diastolic blood pressures for each individual were calculated, and the rate of change in blood pressure over time for each subject was estimated. The mean blood pressure and the mean rate were compared between gender-specific black and white groups. For both boys and girls, the mean systolic blood pressure was 2 mm Hg higher in black children than white children (P = .0008). Boys had a higher systolic blood pressure than girls (P = .0048). The mean diastolic blood pressure was 1.5 mm Hg higher in black children than in white children (P = .0270); no significant gender difference in diastolic blood pressure was observed. Age, weight, height, and body mass index were highly correlated with blood pressure. When accounting for these variables, for girls the racial difference in systolic blood pressure remained significant, whereas the difference in diastolic blood pressure in boys and girls was no longer significant. The rate of increase in blood pressure over time was significantly greater in blacks than whites: for systolic blood pressure, P = .0002, and for diastolic blood pressure, P = .009.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessing agreement is often of interest in biomedical sciences to evaluate the similarity of measurements produced by different raters or methods on the same subjects. We investigate the agreement structure for a class of frailty models that are commonly used for analyzing correlated survival outcomes. Conditional on the shared frailty, bivariate survival times are assumed to be independent with Weibull baseline hazard distribution. We present the analytic expressions for the concordance correlation coefficient (CCC) for several commonly used frailty distributions. Furthermore, we develop a time-dependent CCC for measuring agreement between survival times among subjects who survive beyond a specified time point. We characterize the temporal pattern in the time-dependent CCC for various frailty distributions. Our results provide a better understanding of the agreement structure implied by different frailty models.

Objectives To address the fact that a decrease in the relative renal uptake of 99mTc-mercaptoacetyltriglycine (MAG3) on serial MAG3 scans may indicate a loss of function and require a change in management by providing guidance as to what constitutes a meaningful change in serial relative function measurements as well determining the normal variation of other common MAG3 renogram parameters. Methods A prospective study was conducted in 24 male urology patients with stable renal function. The mean age was 66.5 ± 7.9 (SD) years; the mean serum creatinine was 1.38 ± 0.57 (SD) mg/dL, and the MAG3 renal scans were performed a mean of 11 ± 8 days apart. Each MAG3 scan included a measurement of relative function as well as the time to maximum counts and 20 minutes to maximum count ratios for both cortical and whole kidney regions of interest. Results The Pearson and intraclass correlations for the baseline and repeat measurements of relative renal function were both 0.98. Bland-Altman plots showed no bias between the baseline and repeat relative uptake measurements. The mean difference between 2 repeated measurements of the relative MAG3 uptake was 0.04 ± 2.88% (SD) for the left kidney and 0.08 ± 3.07% (SD) for the right kidney. Comparable results were obtained for the other renogram parameters. Conclusions Measurements of relative renal uptake of MAG3 and common renogram parameters are highly reproducible; a decrease in relative uptake ≥7% (ie, 50%-43%) implies a loss in renal function.

Phthalate exposure is ubiquitous and may affect child and adolescent health through both in utero exposure and direct exposure during childhood. Variability in exposure within women is not well documented. We analyzed 90 first-morning urine samples collected by ten reproductive-age women for phthalate metabolites and creatinine. Monoethyl [122 ng/mL (geometric mean concentration = 139 microg/g creatinine)], monobutyl [85.4 ng/mL (97.0 microg/g creatinine)], monobenzyl [37.2 ng/mL (42.2 microg/g creatinine)], and mono-2-ethylhexyl phthalate [9.4 ng/mL (10.7 microg/g creatinine)] were detected in most (94.4%) samples. The concentrations ranged from 23.8-1090 ng/mL, 43-437 ng/mL, 12.4-186 ng/mL, and 1.3-31.1 ng/mL, respectively. We observed considerable variation in phthalate concentrations by day for individual women. The intraclass correlation coefficient, indicating the proportion of variance explained by differences between subjects, ranged from 0.40 (monobutyl) to 0.68 (monoethyl). Monobenzyl and monoethyl phthalates showed higher levels on weekends as compared with weekdays (p = .01 for both). We found no significant difference between monoester levels from different menstrual cycles. Phthalate concentrations vary considerably for an individual and may require multiple samples for accurate assessment

We represent Cox's (1972) score statistic and its variance in a form analogous to Hoeffding's (1948) ‘U-statistics’, and suggest how these representations may be used to investigate asymptotic properties in nonstandard situations.

The analysis of data from epidemiologic and environmental studies presents challenges such as skewness of distribution, rounding and multiple measurements over time. To model trends over time based on repeated measurements, we propose a general latent model suitable for highly skewed data. The model assumes that the observed outcome is determined by an unobservable outcome that follows a Weibull distribution. To accommodate correlations among repeated responses over time, we introduce a general random effect from the power variance function (PVF) family of distributions, including the gamma distribution often employed in the literature. The resulting marginal likelihood has a closed form without resorting to numerical or approximation methods. We study estimation and hypothesis testing under these models, with different choices of random effect distributions. Simulation studies are conducted to evaluate their performance. Finally, we apply the proposed method to exposure data collected from the Michigan polybrominated biphenyl (MIPBB) study.

Background Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. Purpose Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. Methods Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. Results We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. Limitations Because we cannot completely control for external factors, a relevant question is whether or not ‘short-term’ neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. Conclusions This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon-alpha. Clinical Trials 2009; 6: 480—490. http://ctj.sagepub.com

The cardioprotective property of the Mediterranean diet has been attributed to its antioxidant capacity, but direct investigation of this mechanism has been limited.We examined the association between the Mediterranean diet and an established plasma marker of oxidative stress, the ratio of reduced to oxidized glutathione (GSH/GSSG), in a well-controlled study of twins.We administered the Willett food-frequency questionnaire to 138 monozygotic and dizygotic twin pairs and to 21 unpaired twins and derived a score measuring adherence to the Mediterranean diet. Fasting plasma GSH and GSSG concentrations were measured to calculate the GSH/GSSG ratio. The higher the ratio, the lower the oxidative stress. Mixed-effect regression analysis was used to partition the association into between- and within-twin pair differences. When within-pair effects are examined, twins are matched for sociodemographic and familial factors.A one-unit increment in the diet score was associated with a 7% higher GSH/GSSG ratio (P = 0.03) after adjustment for energy intake, other nutritional factors, cardiovascular disease risk factors, and medication use. The association persisted within twin pairs: a one-unit within-pair absolute difference in the diet score was associated with a 10% (95% CI: 2.7, 18.0) higher GSH/GSSG ratio in the twin with the higher score than in the co-twin with the lower score (P = 0.007). Results were similar in monozygotic and dizygotic twin pairs.The association between the Mediterranean diet and plasma oxidative stress is robust and is not confounded by genetic or shared environmental factors. Decreased oxidative stress is a plausible mechanism linking the Mediterranean diet to reduced cardiovascular disease risk.

Assessing agreement is often of interest in clinical studies to evaluate the similarity of measurements produced by different raters or methods on the same subjects. We present a modified weighted kappa coefficient to measure agreement between bivariate discrete survival times. The proposed kappa coefficient accommodates censoring by redistributing the mass of censored observations within the grid where the unobserved events may potentially happen. A generalized modified weighted kappa is proposed for multivariate discrete survival times. We estimate the modified kappa coefficients nonparametrically through a multivariate survival function estimator. The asymptotic properties of the kappa estimators are established and the performance of the estimators are examined through simulation studies of bivariate and trivariate survival times. We illustrate the application of the modified kappa coefficient in the presence of censored observations with data from a prostate cancer study.

The purpose of the study was to compare diuresis renography scan interpretation generated by a renal expert system with the consensus interpretation of 3 expert readers. Methods: The expert system was evaluated in 95 randomly selected furosemide-augmented patient studies (185 kidneys) obtained for suspected obstruction; there were 55 males and 40 females with a mean age ± SD of 58.6 ± 16.5 y. Each subject had a baseline 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) scan followed by furosemide administration and a separate 20-min acquisition. Quantitative parameters were automatically extracted from baseline and furosemide acquisitions and forwarded to the expert system for analysis. Three experts, unaware of clinical information, independently graded each kidney as obstructed/probably obstructed, equivocal, and probably nonobstructed/nonobstructed; experts resolved differences by a consensus reading. These 3 expert categories were compared with the obstructed, equivocal, and nonobstructed interpretations provided by the expert system. Agreement was assessed using weighted κ, and the predictive accuracy of the expert system compared with expert readers was assessed by the area under receiver-operating-characteristic (ROC curve) curves. Results: The expert system agreed with the consensus reading in 84% (101/120) of nonobstructed kidneys, in 92% (33/36) of obstructed kidneys, and in 45% (13/29) of equivocal kidneys. The weighted κ between the expert system and the consensus reading was 0.72 and was comparable with the weighted κ between experts. There was no significant difference in the areas under the ROC curves when the expert system was compared with each expert using the other 2 experts as the gold standard. Conclusion: The renal expert system showed good agreement with the expert interpretation and could be a useful educational and decision support tool to assist physicians in the diagnosis of renal obstruction. To better mirror the clinical setting, algorithms to incorporate clinical data must be designed, implemented, and tested.