Patricia M. Grambsch

Child Sexual Behavior Inventory: Normative and clinical comparisons.

A normative sample of 880 children was contrasted with a sample of 216 sexually abused children on the Child Sexual Behavior Inventory (CSBI), a 35-item behavior checklist assessing sexual behavior in children 2-12 years old. The CSBI total score differed significantly between the 2 groups after controlling for age, sex, maternal education, and family income, with sexually abused children showing a greater frequency of sexual behaviors than did the normative sample. Test-retest reliability, interitem correlations, cross-validation, and correlations with abuse characteristics were also reported

Penalized Survival Models and Frailty

Interest in the use of random effects in the survival analysis setting has been increasing. However, the computational complexity of such frailty models has limited their general use. Although fitting frailty models has traditionally been difficult, standard algorithms for fitting Cox semiparametric and parametric regression models can be readily extended to include penalized regression. We demonstrate that solutions for gamma shared frailty models can be obtained exactly via penalized estimation. Similarly, Gaussian frailty models are closely linked to penalized models. Fitting frailty models with penalized likelihoods can be made quite efficient by taking advantage of computational methods available for penalized models. We have implemented penalized regression for the coxph function of S-Plus and illustrate the algorithms with examples using the Cox model.

Primary sclerosing cholangitis: Refinement and validation of survival models

The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.

Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial

Blood pressure (BP) control rates around the world are suboptimal. Part 2 of the National Health and Nutrition Educational Survey (NHANES) III indicates that only 27.4% of hypertensive Americans aged 18 to 74 years have a BP of <140/90 mm Hg. We wanted to assess BP control during the first 2 years and to describe the baseline characteristics of patients enrolled in the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Study, an international clinical trial that compares outcomes in hypertensive patients randomized to initial treatment with either controlled-onset extended-release verapamil or the investigator’s choice of atenolol or hydrochlorothiazide. At randomization, BP was <140/90 mm Hg in only 20.3% of the 16 602 subjects (average±SD age 65.6±7.4 years; 56% women, 84% white/7% black/7% Hispanic). The average BP at enrollment was 148/85 mm Hg for patients taking BP medications (n=13 879) and 161/94 mm Hg for previously untreated patients (n=2723). After medication titration, with a transtelephonic computer that recommended an increase in the dose or number of antihypertensive agents whenever the BP was 140/90 mm Hg, 84.8% of the subjects attained the goal BP. During 2 years of treatment, BP control was maintained in 67% to 69% of the subjects (69% to 71% for systolic BP of <140 mm Hg and 90% for diastolic BP of <90 mm Hg). These data suggest that the control of systolic BP is more difficult than the control of diastolic BP. The US national goal of having 50% of hypertensives with a BP of <140/90 mm Hg may be achievable if a forced titration strategy is used. Interested investigators, free care and medications, and well-educated subjects may make the attainment of such a goal easier in the CONVINCE study than in the general population.

The Incidence of Peyronie’s Disease in Rochester, Minnesota, 1950 through 1984

Peyronies disease was diagnosed in 101 male residents of Rochester, Minnesota between 1950 and 1984. Mean patient age at diagnosis was 53 years. The average age-adjusted annual incidence rate of 25.7 and a prevalence rate of 388.6 per 100,000 male population were noted. The steady increase in incidence with time may reflect an increasing tendency to obtain medical help. However, the possibility of a true increase in the incidence rate cannot be ruled out. An effort was made to identify possible risk factors and other disease associations. Rheumatoid arthritis and hypertension were more common among the patients compared to the Rochester population. In contrast, no excess of diabetes mellitus was observed among patients with Peyronies disease.

Diagnostic plots to reveal functional form for covariates in multiplicative intensity models

We show how plots based on the residuals from a proportional hazards model may be used to reveal the correct functional form for covariates in the model. A smoothed plot of the martingale residues was suggested for this purpose by Therneau, Grambsch, and Fleming (1990, Biometrika 77, 147-160); however, its consistency required that the covariates be independent. They also noted that the plot could be biased for large covariate effects. We introduce two refinements which overcome these difficulties. The first is based on a ratio of scatter plot smooths, where the numerator is the smooth of the observed count plotted against the covariate, and the denominator is a smooth of the expected count. This is related to the Arjas goodness-of-fit plot (1988, Journal of the American Statistical Association 83, 204-212). The second technique smooths the martingale residuals divided by the expected count, using expected count as a weight. This latter approach is related to a GLM partial residual plot, as well as to the iterative methods of Hastie and Tibshirani (1990, Biometrics 46, 1005-1016) and Gentleman and Crowley (1991, Biometrics 47, 1283-1296). Applications to survival data sets are given.

Diminished survival in asymptomatic primary biliary cirrhosis: A prospective study

Data from 73 asymptomatic patients with primary biliary cirrhosis were analyzed to determine clinical course and long-term survival. Of these, 44 entered a D-penicillamine treatment trial; 29 qualified but chose not to participate. Median follow-up was 7.6 yr (range, 2.8-12.2 yr). Liver biopsy at the initial visit showed advanced disease (fibrosis, cirrhosis) in 61% of the patients. During prospective clinical follow-up, which was available for 37 of the 44 study patients, one or more symptoms of liver disease developed in 33 (89%); esophageal varices were found in 15 (41%), and histologic progression to cirrhosis was found in 20 (67%) of the 30 precirrhotic patients. Significant (p less than 0.01) biochemical progression was reflected by a decrease in mean serum albumin concentrations and an increase in mean serum bilirubin levels in 32 patients followed for 4-6 yr. Survival data were available for all 73 patients; 17 died (11 secondary to liver failure), and 1 underwent liver transplantation. These patients had a 4-fold increase in mortality rate (p less than 0.001) compared with the U.S. population matched for age, race, and sex.

Influence of positive lymphocyte crossmatch and hla mismatching on vanishing bile duct syndrome in human liver allografts

Among the first 52 recipients of primary liver allo-grafts with follow-up of 2 weeks or greater, 6 patients had biopsy-confirmed vanishing bile duct syndrome (VBDS) and required retransplantation. Five of these six patients had positive lymphocyte crossmatches. Of the 46 remaining liver transplant recipients, 11 had positive crossmatches. Thus, the incidence of VBDS was 5/16 in recipients with a positive crossmatch and 1/36 in recipients with a negative crossmatch. The positive-crossmatch group was significantly more likely to develop VBDS than the negative-crossmatch group (P<0.004, log rank test). Additional HLA studies comparing degree of donor-recipient mismatch at the various HLA loci showed no significant difference between the groups for class I disparity. However, class II mismatch was of borderline significance (P<0.056). When evaluated individually, the DQ mismatch (P<0.04) appeared to be more important than the DR mismatch

Rationale and Design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial

The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial is a randomized, prospective, double-blind, parallel-group, two-arm, actively controlled, multicenter, international 5-year clinical trial involving 15,000 patients. CONVINCE will compare the incidence of fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or cardiovascular-disease-related death in two antihypertensive treatment regimens. One treatment arm begins with controlled onset-extended release (COER)-verapamil, which has its major antihypertensive effect 6-12 hours after administration. The other arm (standard of care (SOC)) begins with either hydrochlorothiazide (HCTZ) or atenolol, one of which is preselected by the investigator for an individual patient prior to randomization. Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint (separately), death or hospitalization related to cardiovascular disease, efficacy in lowering blood pressure to goal, primary events occurring between 6 am and noon, all-cause mortality, withdrawals from blinded therapy, cancer, and hospitalizations due to bleeding. Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease. Initial medications include COER-verapamil (180 mg/d), HCTZ (12.5 mg/d), or atenolol (50 mg/d). Initial doses are doubled if blood pressure (BP) does not reach goal (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ is added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. An ACE-inhibitor is recommended (although nearly any open-label medication is allowed) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications. Patients take two sets of tablets daily, one in the morning and one in the evening. Although most patients switch from an established antihypertensive medication to randomized treatment, untreated patients with stages I-III hypertension (SBP between 140 and 190 or DBP between 90 and 110 mm Hg) are eligible. Outcomes are monitored by an independent Data and Safety Monitoring Board. Enrollment began during the third quarter of 1996, and follow-up is to be completed in the third quarter of 2002.

Soluble interleukin-2 receptor level as an indicator of liver allograft rejection

We studied the serum levels of soluble interleukin-2 receptors (SIL-2R) in liver allograft recipients: a control group without rejection or CMV disease, a group with only rejection episodes, and a group with only cytomegalovirus disease. Rejection was diagnosed by the presence of compatible laboratory and histologic abnormalities and absence of other causes of graft dysfunction. CMV disease was diagnosed by isolation of CMV in blood or liver specimen cultures or identification of cytomegalic inclusions in the liver biopsy specimen. Of 82 consecutive recipients treated with cyclosporine and prednisone, 12 were in the control group, 20 in the rejection group, and 5 in the CMV disease group. The remaining 45 had other or multiple complications. In the control group the SIL-2R levels (determined by an ELISA) decreased by a mean of 4% per day after transplantation; in the rejection group the levels increased by a mean of 17% per day in the 10 days prior to the diagnosis of rejection; in the CMV disease group the levels tended to increase prior to the diagnosis of CMV disease. The rejection group had significantly higher SIL-2R levels than the control group at comparable times. Thus, SIL-2R levels were significantly increased at the time of allograft rejection compared with levels in a control group, and recipients with CMV disease had increased levels of SIL-2R but they were not as high as in recipients with rejection episodes.