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.

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.

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.

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.

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.

A comparison of the urinary excretion of bone resorptive products in white and black children.

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.

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.

Acute and chronic effects of nonsteroidal antiinflammatory drugs on glomerular filtration rate in elderly patients.

To assess the effects of nonsteroidal antiinflammatory drugs (NSAIDs) on glomerular filtration rate (GFR) in elderly patients with and without renal insufficiency, we conducted an open-label, randomized, prospective three-period cross-over study. Twenty-nine patients at least 65 years old were assigned to groups with preserved GFR (> 1.16 mL/s [70 mL/min]) or with renal insufficiency (GFR 0.50-1.16 mL/s [30-70 mL/min]). Patients received 800 mg ibuprofen three times daily, 20 mg piroxicam daily, or 200 mg sulindac twice daily for 1 month. Three-hour inulin and two-day creatinine clearances were measured before and after the first and last doses of NSAIDs. Ibuprofen, piroxicam, and sulindac decreased inulin clearance after single-doses in both groups of patients. In patients with renal insufficiency, creatinine clearance did not change after administration of ibuprofen for 1 month (0 +/- 0.06 mL/s, mean +/- standard error), but was decreased similarly with administration of either piroxicam or sulindac (-0.12 +/- 0.06 mL/s [-7.2 +/- 3.6 mL/min], P < 0.02). One patient with preserved GFR, but with other risk factors for NSAID-associated renal impairment, met our criteria for withdrawal by experiencing at least a 40 mumol/L (0.5 mg/dL) increase in serum creatinine above their baseline value. Our data indicate that NSAIDs do not adversely affect GFR in patients with preserved renal function unless they have another risk factor for NSAID-associated renal impairment. In contrast, patients with renal insufficiency may have significant chronic decrements in GFR with long-acting NSAIDs such as piroxicam and sulindac, but not with short-acting ibuprofen. Such patients should have renal function monitored while being treated with long-acting NSAIDs.

Better discrimination of hip fracture using bone density, geometry and architecture.

Bone density predicts the risk of hip fracture. Because hip strength is determined by bone geometry and architecture as well as density, we tested which variables in geometry and architecture were independent discriminators of hip fracture and, if combined with density, improved the discrimination of fracture from non-fracture over bone density alone. The design was a case-control study. The subjects were Caucasian women over the age of 60 years who had sustained a hip fracture after the age of 58 years (n = 22), and controls matched for age and weight (n = 43) and unmatched controls (n = 317) with no history of hip fracture. Variables in density, geometry and architecture were obtained from dual-energy X-ray absorptiometry images and from radiographs of the upper end of the femur. In a univariate model, of the measures of bone mass, the best discriminator of hip fracture was bone mineral density of the neck of femur; of the geometric measurements, it was hip axis length; and of the measurements of bone architecture, it was Singh grade. In a multivariate model, these three variables were shown to be independent discriminators of hip fracture. When hip axis length was combined with bone mineral density, there was significant improvement in discrimination of hip fracture (p = 0.014), and when Singh grade was combined with hip axis length and bone mineral density there was a further significant improvement (p = 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children.

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.

Familial influences on the adrenal androgen excretion rate during the adrenarche.

The regulation of adrenal androgen (AA) production in both children and adults has not been defined. We report here on two different studies that examined familial influences on AA production early in life when such production is accelerated, a period known as the adrenarche. AA production was estimated from measurements of excretion of AA in urine samples collected overnight. The first study used a twin model where genetic and environmental components to the variance in AA excretion were determined in white monozygotic (MZ) and dizygotic (DZ) twins. The intraclass correlation coefficient for weight-adjusted AA excretion was .730 (P < .0001) in MZ twins and .511 (P = .007) in DZ twins. There was a significant genetic component to the weight-adjusted AA excretion rate, with a heritability of 58%. Environmental effects accounted for 17% of the variation. Black children were previously shown to have higher AA levels than white children. Therefore, in the second study we looked for evidence that race affected familial influences on AA excretion. To estimate familial aggregation of AA excretion, intraclass correlations were determined in siblings from black and white families. AA excretion rates were measured twice-yearly for up to 4.5 years, and an individual's average excretion rate was used in the analysis. The intraclass correlation coefficient for the weight-adjusted AA excretion in black siblings was .492 (P = .0021), and for white siblings it was .372 (P = .0003). Intraclass correlation coefficients for AA excretion rates were not significantly different in the two racial groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The reirradiation of recurrent bronchogenic carcinoma with external beam irradiation.

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.

Racial differences in aldosterone excretion: a longitudinal study in children.

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.