Correlation between pulse wave velocity and other measures of arterial stiffness in chronic kidney disease.

AIM: Pulse wave velocity (PWV), augmentation index (AIx) and time to first wave reflection (Tr) are all measures of arterial stiffness, but whether these parameters behave similarly in different populations is not well-understood. Given the large burden of cardiovascular disease in individuals with chronic kidney disease (CKD), assessing the relationship between vascular stiffness parameters in this population is important. METHOD: A subset of 152 participants enrolled in the Chronic Renal Insufficiency Cohort Study had vascular stiffness parameters (aortic PWV, central AIx, and Tr) measured using the SphygmoCor system. Linear association between these parameters was assessed using Pearson correlation coefficients. Reproducibility across operators of the device was also tested within individuals. RESULTS: Association was largest between PWV and heart rate-adjusted AIx (AIx-75). The correlation coefficient was 0.371 (p = 0.0003) for ideal studies and 0.305 (p = 0.0001) for all technically acceptable studies. The association between ideal PWV and AIx-75 measurements was 0.361 (p = 0.005) for men and 0.423 (p = 0.01) for women. Bland-Altman plots comparing the mean value of PWV (n = 31) or AIx-75 (n = 21) when measured by 2 different individuals against the difference in their respective values demonstrate that both measures of arterial stiffness are reproducible across multiple technicians. CONCLUSIONS: Thus, we conclude that PWV and AIx-75, despite measuring different quantities in different units, are related measures of arterial stiffness and are reproducible across multiple operators in the population with CKD.

Assessment of differences in HLA-A, -B, and -DRB1 allele mismatches among African-American and non-African-American recipients of deceased kidney transplants.

Among recipients of deceased donor kidney transplants, African-Americans experience a more rapid rate of kidney allograft loss than non-African-Americans. The purpose of this study was to characterize and quantify the HLA-A, -B, and -DRB1 allele mismatches and amino acid substitutions at antigen recognition sites among African-American and non-African-American recipients of deceased donor kidney transplants matched at the antigen level. In recipients with zero HLA antigen mismatches, the degree of one or two HLA allele mismatches for both racial groups combined was 47%, 29%, and 11% at HLA-DRB1, HLA-B, and HLA-A, respectively. There was a greater number of allele mismatches in African-Americans than non-African-Americans at HLA-A (P < .0001), -B (P = .096), and -DRB1 loci (P < .0001). For both racial groups, the HLA allele mismatches were predominantly at A2 for HLA-A; B35 and B44 for HLA-B; but multiple specificities for HLA-DRB1. The observed amino acid mismatches were concentrated at a few functional positions in the antigen binding site of HLA-A and -B and -DRB1 molecules. Future studies are ongoing to assess the impact of these HLA mismatches on kidney allograft loss.

Drug therapy of the idiopathic inflammatory myopathies: predictors of response to prednisone, azathioprine, and methotrexate and a comparison of their efficacy.

PURPOSE: To identify factors associated with responses to treatment with prednisone, methotrexate, or azathioprine in patients with idiopathic inflammatory myopathy, and to compare the efficacy of these drugs. PATIENTS AND METHODS: Data were collected on 113 adult patients meeting criteria for definite idiopathic inflammatory myopathy in this retrospective cohort study. Patients were categorized as responding completely, partially, or not at all to each therapeutic trial based upon clinical and laboratory criteria. RESULTS: Clinical group, presence of certain myositis-specific autoantibodies, and time from disease onset to diagnosis influenced rates of complete clinical response to these therapeutic agents. Patients with inclusion body myositis responded comparatively poorly to prednisone and the other drugs: 43% had no clinical response to prednisone and none responded completely to any medication. Patients with autoantibodies to aminoacyl-tRNA synthetases or to signal recognition particle proteins were likely to respond partially, but not completely, to prednisone. No patient with a long delay to diagnosis (greater than 18 months) responded completely, compared with 34% of those with a short delay (less than 3 months). A patient's response to the first course of prednisone predicted subsequent responses to prednisone and to azathioprine better than response to methotrexate. Men responded to methotrexate better than women. Among certain subgroups of patients, responses to methotrexate were better than to either azathioprine or retreatment with prednisone. CONCLUSION: Determining the clinical group, autoantibody status, and time from disease onset to diagnosis of patients with myositis provides useful information in predicting clinical responses to therapy, and these factors should be considered in designing future therapeutic trials. Methotrexate therapy may be superior to either azathioprine or further steroid treatment alone in certain patients who do not respond completely to an initial adequate course of prednisone.

Separation of different UDP glucuronosyltransferase activities according to charge heterogeneity by chromatofocusing using mouse liver microsomes. Three major types of aglycones.

Hepatic UDP glucuronosyltransferase (EC 2.4.1.17) (GT) enzymes in control, phenobarbital- and 3-methylcholanthrene-induced microsomes from C57BL/6N mice have been fractionated according to charge heterogeneity on a chromatofocusing system using a pH 9.5 to 6 gradient. Transferase activities for eleven different substrates were determined on column fractions. Activities toward 3-hydroxybenzo[a]pyrene, phenolphthalein and estrone (type 1 substrates) were enhanced by both effector compounds and always eluted primarily at pH 8.5. In control and phenobarbital-induced microsomes, activities toward testosterone, 4-hydroxybiphenyl, morphine, naphthol and 9-hydroxybenzo[a]pyrene (type 2 substrates) eluted primarily at about pH 6.7. Activities toward p-nitrophenol, 4-methylumbelliferone and 2-hydroxybiphenyl (type 3 substrates) in control and phenobarbital-induced microsomes exhibited two peaks which eluted at pH 8.5 and 6.7. 3-Methylcholanthrene treatment increased almost exclusively activities which eluted at pH 8.5 for each of the three types of substrates. The pH value of elution corresponds to the approximate isoelectric point of the eluted protein. Immunoabsorption studies with an antibody preparation raised against a purified low pI form confirmed that a 51,000-dalton transferase form, GTM1, eluted primarily at pH 6.7 and that a 54,000-dalton form, GTM2, eluted at pH 8.5. A mathematical treatment of the ratios of activity after 3-methylcholanthrene treatment to that after phenobarbital treatment versus pH produced six patterns of activity. A minimum of two enzymes at the low pH region and one enzyme at the high pH region, all with broad-substrate specificity, could account for these patterns.

Confounding by indication: the case of calcium channel blockers.

PURPOSE: To review conceptual issues regarding confounding by indication in the context of studies of calcium channel blockers (CCBs). METHODS: Review of literature, with special attention to two articles in the current issue. RESULTS: Conflicting arguments about the presence of uncontrollable confounding by indication in studies of CCBs are reviewed and criticized. Studies with potential confounding by indication can benefit from appropriate analytic methods, including separating the effects of a drug taken at different times, sensitivity analysis for unmeasured confounders, and instrumental variables and G-estimation. CONCLUSIONS: Whether confounding by indication accounts for observed associations is often difficult to determine; this is the case in studies of CCBs. When confounding by indication is suspected, a variety of methods to deal with it may be useful. Copyright (c) 2000 John Wiley & Sons, Ltd.

Administrative and artificial censoring in censored regression models.

Administrative censoring, in which potential censoring times are known even for subjects who fail, is common in clinical and epidemiologic studies. Nonetheless, most statistical methods for failure-time data do not use the information contained in these potential censoring times. Robins has proposed two approaches for using this information to estimate parameters in an accelerated failure-time model; the methods generally require the analyst to treat as censored some subjects whose failure time is observed. This paper provides a rationale for this "artificial censoring", discusses some of its consequences, and illustrates some of these points with data from a randomized trial of breast cancer screening.

Standardized estimates from categorical regression models.

We consider the problem of interpreting categorical regression models, such as the polytomous logistic model, the continuation-ratio model, the stereotype model, and the cumulative-odds model. We present a method to convert categorical regression coefficients into estimates of standardized fitted probabilities, probability differences and probability ratios. We use a delta-method approach to estimate standard errors. We then present a small simulation study to compare different transforms for setting confidence limits, and provide an illustration of our approach in an observational study of drug therapy of polymyositis.

Restriction as a method for reducing bias in the estimation of direct effects.

The direct effect of a treatment on some outcome is that part of the treatment's effect not referred through a specified covariate intermediate on the pathway between treatment and outcome. Such direct effects are often of primary interest in a data analysis. Unfortunately, standard methods of analysis (for example, stratification or modelling) do not, in general, produce consistent estimates of direct effects whether or not the covariate is 'controlled'. Robins and co-authors have proposed two methods for estimation of direct effects applicable when reliable information is available on the covariate. We propose a third approach for reducing bias: data restriction. By restricting the analysis to strata of the data in which the effect of treatment on the covariate is small, we can (under certain assumptions) reduce bias in estimating treatment's direct effect. We discuss these points with reference to difference and ratio measures of treatment effect. The approach will sometimes be applicable even with an unmeasured or poorly measured covariate. We illustrate these points with data from an observational study of the effect of hormone replacement therapy on breast cancer.

Invited commentary: propensity scores.

The propensity score is the conditional probability of exposure to a treatment given observed covariates. In a cohort study, matching or stratifying treated and control subjects on a single variable, the propensity score, tends to balance all of the observed covariates; however, unlike random assignment of treatments, the propensity score may not also balance unobserved covariates. The authors review the uses and limitations of propensity scores and provide a brief outline of associated statistical theory. They also present a new result of using propensity scores in case-cohort studies.

Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors.

BACKGROUND: The effect on allograft survival of the transplantation of kidneys from living donors without the previous initiation of long-term dialysis is controversial. METHODS: Using data from the U.S. Renal Data System, we performed a retrospective cohort study of 8481 patients who were or who were not treated by long-term dialysis before receiving a kidney transplant from a living donor. The relative rate of allograft failure for patients who received a transplant without previously undergoing long-term dialysis, as compared with patients who underwent long-term dialysis before transplantation, was assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including the transplantation center and median household income. The association between the receipt of a kidney transplant from a living donor without previous dialysis ("preemptive transplantation") and the risk of biopsy-confirmed acute rejection within six months after transplantation was evaluated by conditional logistic-regression analysis, with adjustment for the transplantation center. RESULTS: Transplantation of a kidney from a living donor without previous long-term dialysis was associated with a 52 percent reduction in the risk of allograft failure during the first year after transplantation (rate ratio, 0.48; P=0.002), an 82 percent reduction during the second year (rate ratio, 0.18; P=0.001), and an 86 percent reduction during subsequent years (rate ratio, 0.14; P=0.001), as compared with transplantation after dialysis. The reduction in the rate of allograft failure during the first year was attenuated when adjustment was made for the timing of acute rejection within the first year (rate ratio, 0.69; 95 percent confidence interval, 0.44 to 1.10; P=0.10). Increasing duration of dialysis was associated with increasing odds of rejection within six months after transplantation (P=0.001). CONCLUSIONS: Preemptive transplantation of kidneys from living donors without the previous initiation of dialysis is associated with longer allograft survival than transplantation performed after the initiation of dialysis.

Postmenopausal hormone use, screening, and breast cancer: characterization and control of a bias.

Previous investigators have suggested that screening-related biases may explain associations between postmenopausal hormone use and breast cancer. To investigate these biases, we studied postmenopausal women in the Nurses' Health Study from 1988 to 1994. Hormone use is associated with increased subsequent screening. Among women not screened in the previous 2 years, the probability difference, comparing current hormone users with others, for having mammography in the following 2 years is 19.5%; among women previously screened, the difference is 4.9%. These differences persist after control for other factors. If the increase in screening is causal, screening by mammogram could be intermediate in the causal pathway to breast cancer diagnosis. To deal with this problem, we restrict attention to a subset of the cohort in which the effect of postmenopausal hormone use on screening is small (women previously screened). In this subset, the rate ratio comparing breast cancer rates among current postmenopausal hormone users with others is 1.28. In a sensitivity analysis, the bias could not by itself plausibly account for the associations in our data. Our data provide evidence of an association between postmenopausal hormone use and breast cancer that is not solely the product of a detection bias.

Effect of treatment with zidovudine on subsequent incidence of Kaposi's sarcoma.

Despite much investigation of zidovudine, little has been reported regarding its effect on the development of most individual AIDS-defining illnesses, including Kaposi's sarcoma (KS). We used observational data from the Multicenter AIDS Cohort Study (MACS) to estimate the effect of zidovudine use on the subsequent incidence of KS. To do this, we examined and adjusted for predictors of zidovudine use. CD4 lymphocyte counts, the development of HIV-related symptoms and AIDS, and changes in these factors were important predictors of zidovudine use. We used these associations to control for confounding by these and other factors with the G-estimation approach. We found no evidence that zidovudine use affected the time to KS in the MACS; the point estimate (95% confidence interval [CI]) for increase in time to KS was zero (-28%-68%). The relative risk was 1.0 (95% CI, 0.54-1.84). Randomized trials suggest that zidovudine may prevent KS. We discuss possible explanations for differences between results.

Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo-1 and anti-signal recognition particle autoantibodies.

In idiopathic inflammatory myopathy (IIM; or, polymyositis/dermatomyositis), the myositis-specific autoantibodies anti-Jo-1 and anti-signal recognition particle (anti-SRP), appear to define clinically and immunogenetically distinct groups of patients. We show here that the month during which the onset of weakness occurs is not random in patients with anti-Jo-1 auto-antibodies (average month April, P less than 0.02) and in those with anti-SRP autoantibodies (average month November, P less than 0.02); both groups of patients also experience rapid onset of disease. By contrast, patients classified into the traditional categories of polymyositis and dermatomyositis do not have recognizable seasonal patterns and do not differ in the rate of onset of disease. These findings suggest that searches for seasonal patterns in the onset of autoimmune disorders characterized by disease-specific autoantibodies may provide useful clues to etiology.

Estimating the effect of zidovudine on Kaposi's sarcoma from observational data using a rank preserving structural failure-time model.

Researchers commonly express scepticism about using observational data to estimate the effect of a treatment on an outcome the treatment is intended to affect. In this paper, we consider using data from the Multicenter AIDS Cohort Study (MACS) to determine whether zidovudine prevents the development of Kaposi's sarcoma among HIV-positive gay men. Several methodologic issues common to observational data characterized the study: information on potentially important confounders was missing at some study visits; investigators did not always know the time of changes in treatment level, nor the value of confounders at that time, and the censoring process depended strongly on time-varying covariates related to outcome. We describe application to our data of Robins' paradigm for defining, modelling and estimating the effect of a time-varying treatment and show how to modify his approach to deal with the methodologic issues we have mentioned. Further, we demonstrate that relative risk regression is less well equipped to deal with these issues. We compare our results to the findings from randomized trials, and conclude that observational studies may sometimes be useful in evaluating the effect of treatment on an intended outcome.

Lack of evidence of an association between mitral-valve prolapse and stroke in young patients.

BACKGROUND: Previous studies have reported a high prevalence of mitral-valve prolapse among patients with embolic stroke (28 to 40 percent), especially among young patients (those < or =45 years old); this finding has practical implications for prophylaxis. However, diagnostic criteria for prolapse have changed and are now based on three-dimensional analysis of the shape of the valve; use of the current criteria reduces markedly the frequency of such a diagnosis and increases its specificity. Previously described complications must therefore be reconsidered. METHODS: In a case-control study, we reviewed data on 213 consecutive patients 45 years old or younger with documented ischemic stroke or transient ischemic attack between 1985 and 1995; they underwent complete neurologic and echocardiographic evaluations. The prevalence of prolapse in these patients was compared with that in 263 control subjects without known heart disease, who were referred to our institution for assessment of ventricular function before receiving chemotherapy. RESULTS: Mitral-valve prolapse was present in 4 of the 213 young patients with stroke (1.9 percent), as compared with 7 of the 263 controls (2.7 percent); prolapse was present in 2 of 71 patients (2.8 percent) with otherwise unexplained stroke. The crude odds ratio for mitral-valve prolapse among the patients who had strokes, as compared with those who did not have strokes, was 0.70 (95 percent confidence interval, 0.15 to 2.80; P=0.80); after adjustment for age and sex, the odds ratio was 0.59 (95 percent confidence interval, 0.12 to 2.50; P=0.62). CONCLUSIONS: Mitral-valve prolapse is considerably less common than previously reported among young patients with stroke or transient ischemic attack, including unexplained stroke, and no more common than among controls. Using more specific and currently accepted echocardiographic criteria, therefore, we could not demonstrate an association between the presence of mitral-valve prolapse and acute ischemic neurologic events in young people.