J. Richard Landis

Average Partial Association in Three-way Contingency Tables: a Review and Discussion of Alternative Tests

Summary This paper reviews and discusses alternative methods for assessing average partial association in three-way contingency tables. Primary attention is directed at the relationship between two of the variables, while controlling for the effects of a set of covariables. One approach is a class of multivariate extensions of the Cochran-Mantel-Haenszel test to sets of (s x r) tables. These statistics are based on expected values and covariances from the multiple hypergeometric distribution for each table. As such they make no underlying assumption regarding second-order interaction, although the absence of such interaction is incorporated within the hypothesis being tested. Alternatively, a log-linear model can be used to investigate average partial association conditional on the assumption of no second-order interaction. If the fit of such a model is supported by the data, then likelihood ratio methods or functional asymptotic regression methods (FARM) can be used to test the significance of correspondingly appropriate parameters. These procedures are all illustrated with a data set relating atomic bomb radiation to the incidence of leukemia adjusted for age at exposure.

The Chronic Renal Insufficiency Cohort (CRIC) Study: Design and Methods

Insights into end-stage renal disease have emerged from many investigations but less is known about the epidemiology of chronic renal insufficiency (CRI) and its relationship to cardiovascular disease (CVD). The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for progression of CRI and CVD among CRI patients and develop models to identify high-risk subgroups, informing future treatment trials, and increasing application of preventive therapies. CRIC will enroll approximately 3000 individuals at seven sites and follow participants for up to 5 yr. CRIC will include a racially and ethnically diverse group of adults aged 21 to 74 yr with a broad spectrum of renal disease severity, half of whom have diagnosed diabetes mellitus. CRIC will exclude subjects with polycystic kidney disease and those on active immunosuppression for glomerulonephritis. Subjects will undergo extensive clinical evaluation at baseline and at annual clinic visits and via telephone at 6 mo intervals. Data on quality of life, dietary assessment, physical activity, health behaviors, depression, cognitive function, health care resource utilization, as well as blood and urine specimens will be collected annually. (125)I-iothalamate clearances and CVD evaluations including a 12-lead surface electrocardiogram, an echocardiogram, and coronary electron beam or spiral CT will be performed serially. Analyses planned in CRIC will provide important information on potential risk factors for progressive CRI and CVD. Insights from CRIC should lead to the formulation of hypotheses regarding therapy that will serve as the basis for targeted interventional trials focused on reducing the burden of CRI and CVD.

A one-way components of variance model for categorical data

A components of variance model for categorical data from unbalanced designs which is directly analogous to a one-way random effects ANO VA modelfor quantitative data is proposed. The variance components provide separate reliability measures for each of the response categories and disagreement measures between pairs of response categories in terms of (within subject) intraclass and interclass correlation coefficients. The estimation procedures involve usual MA NOVA calculations which can be expressed as compounded functions of the multinomial observations. Thus, the variances of these estimates can be obtainedfrom linearized Taylor series results. These procedures are illustrated with data from a psychiatric diagnosis study.

Chronic Renal Insufficiency Cohort (CRIC) Study: Baseline Characteristics and Associations with Kidney Function

BACKGROUND AND OBJECTIVES The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants. RESULTS A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP. CONCLUSIONS Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.

The interstitial cystitis data base study: Concepts and preliminary baseline descriptive statistics

OBJECTIVES To describe the design, patient population, and data and specimen collection aspects of the interstitial Cystitis Data Base (ICDB) Study and to provide preliminary descriptive statistics and inferential results from an interim analysis. METHODS All 424 study participants successfully enrolled in the ICDB Study prior to December 31, 1995, were selected for an interim analysis and were classified into 1 of 3 symptom severity subgroups. Statistical tests for associations among these symptom severity subgroups and a broad range of baseline characteristics were conducted using Mantal-Haenszel procedures to adjust for variation among clinical centers. RESULTS ICDB Study patients are predominantly female (91.5%), white (91.0%), with an average age at enrollment of 44.3 years. Nearly 45% of these patients underwent a cystoscopy at baseline screening, among whom there was an overall prevalence of 10.5% for Hunners patch and 90% for glomerulations. Urodynamic evaluation for the entire 424 patients demonstrated that volumes at first sensation and at maximal capacity were inversely associated with symptom severity subgroups. A broad range of symptoms were analyzed, indicating that nearly 40% of patients reported urinating 15 times or more during awake hours, and more than 20% reported voiding at least 4 times per night. Almost half (47.9%) reported constant urgency and 23.6% reported having severe pain. Patients in the severe symptom subgroup reported greater limitations in selected quality-of-life indicators than those with less severe symptoms. CONCLUSIONS This interim analysis of the ICDB Study data was compared to previous epidemiologic studies of IC and provides an essential foundation for further analytic investigations of baseline associations and longitudinal trends.

Ciprofloxacin or Tamsulosin in Men with Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Randomized, Double-Blind Trial

Context Although the cause of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is unknown, physicians sometimes try to treat it with antibiotics or -receptor blockers. Contribution In this multicenter, double-blind factorial trial, 196 men with moderately severe CP/CPPS were randomly assigned to 6 weeks of treatment with ciprofloxacin, tamsulosin, both drugs, or placebo. Neither ciprofloxacin nor tamsulosin substantively reduced symptoms. Implications Ciprofloxacin and tamsulosin were not effective treatments for CP/CPPS. Cautions Patients had long-standing, refractory CP/CPPS and received trial treatments for only 6 weeks. Patients with new diagnoses who are given longer courses of the trial treatments might respond differently. The Editors Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder and accounts for approximately 2 million visits to physicians annually in the United States (1). The substantial impact of CP/CPPS includes bothersome lower urinary tract symptoms, sexual dysfunction, reduced quality of life (2-5), and increased health care expenditures (6). The syndrome is diagnosed only on the basis of symptoms, principally pain or discomfort in the pelvic region. No objective measures can help define the disease. Although bacteria can infect the prostate, most men with prostatitis have a negative midstream urine culture, indicating that bacteria may not be the cause of their symptoms (2). Such men are classified as having National Institutes of Health (NIH) category III prostatitis, the most common of the clinically defined prostatitis syndromes (7). It is by no means clear that the disease is characterized by inflammation of the prostate or that the prostate is responsible for symptoms in a substantial proportion of patients. Because of this uncertainty, the term CP/CPPS is used. Chronic prostatitis/chronic pelvic pain syndrome is commonly seen by primary care practitioners, internists, and urologists. In the Olmsted County Study of Urinary Symptoms and Health Status Among Men (8), a population-based study in Olmstead County, Minnesota, the overall prevalence rate of a physician-assigned diagnosis of prostatitis was 9%. Population-based surveys of symptoms have estimated that the prevalence of the syndrome ranges from 9% to 12% among men (9, 10). It is difficult to estimate the proportion of patients with symptoms lasting longer than 3 months whose disorder remains refractory to empirical therapy. These patients are commonly seen by urologists, but whether they represent a minor subpopulation of the overall symptomatic group or make up the majority of patients is unknown. We chose to study these patients because they present with a troubling, long-standing problem and are usually treated with agents of unclear benefit. Even if a relatively large number of men whose symptoms last 3 months or more are cured by standard empirical therapy and the clinical scenario we describe is uncommon, men with refractory symptoms still present a substantial problem to internists and urologists who have little information to guide therapy. Because the cause of CP/CPPS is unknown, affected men receive many empirical therapies. The 2 most common treatments prescribed by physicians are antimicrobial agents and -adrenergic receptor antagonists (2), although there is little objective evidence to support their use (11). Quinolones, such as ciprofloxacin, are commonly used to treat CP/CPPS because of their excellent penetration into the prostate and broad spectrum of coverage for uropathogens and other organisms traditionally believed to be associated with the syndrome (12). Tamsulosin, an -blocker, is an effective treatment for lower urinary tract symptoms in men with benign prostatic hyperplasia, and it has been hypothesized that tamsulosin may improve these symptoms in men with CP/CPPS. This randomized clinical trial was designed to evaluate whether ciprofloxacin or tamsulosin reduces symptoms of long-standing CP/CPPS of at least moderate severity, typical of the 488 men in our Chronic Prostatitis Cohort Study (2). The primary purpose of the trial was to test the most common prescription treatments given to men with CP/CPPS, who are commonly seen in our referral-based urologic practices. Methods Organization The Chronic Prostatitis Collaborative Research Network, a consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), conducted the trial. Urologists and their clinical associates recruited patients at 10 sites in the United States and 1 site in Canada. The NIDDK established an independent data and safety monitoring board to review the progress, safety, and final analysis of the trial. The individual institutional review boards at each of the 10 participating clinical centers approved the study, and all men gave written informed consent. Participants The design of this trial has been described in detail previously (13). Participating urologists recruited both newly referred patients and patients with established CP/CPPS from their referral-based clinical practices at 10 tertiary medical centers in North America. Trial referrals came from primary care providers, internists, and other urologists. The primary diagnostic criterion was pain or discomfort in the pelvic region for at least 3 months in the previous 6 months. Severity of symptoms was assessed by using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (14, 15). This instrument is a validated questionnaire, completed by the patient, consisting of 4 questions about pain, 3 about voiding symptoms, and 2 about quality of life. The scores in these 3 individual domains (pain, voiding, and quality of life) are combined without weighting to yield the NIH-CPSI total score. Eligible men were required to have at least moderate symptoms, defined as an NIH-CPSI score of at least 15 of 43 possible points, at the time of randomization. We excluded men who had a documented urinary tract infection (midstream urine culture > 100000 colonies/mL) within the past 3 months, a history of active genital herpes within the previous year, a history of genitourinary cancer, inflammatory bowel disease, active urethral stricture, prostate or bladder surgery, or neurologic disease affecting the bladder. We used ligase chain reaction to screen for Chlamydia in urethral urine samples and excluded men whose tests yielded positive results. Previous treatment with antimicrobial agents or -adrenergic receptor blockers, including the study drugs, had to be completed at least 4 weeks before eligibility screening. Additional details of the eligibility criteria are available elsewhere (13). Study Design and Interventions Men were randomly assigned in equal proportions within a 2 2 factorial design to receive placebo; ciprofloxacin alone, 500 mg twice daily; tamsulosin alone, 0.4 mg once daily; or a combination of both drugs (Table 1). Patients were treated for 6 weeks, at which time the primary end point was assessed. Symptoms at 9 and 12 weeks after randomization (6 weeks after completion of treatment) were also assessed to evaluate longer-term treatment response. The 2 baseline screening contacts and the primary end point contact at 6 weeks were clinic visits; interim contacts at 3, 9, and 12 weeks were conducted by telephone. Table 1. Study Design Each patient was randomly assigned by computer. A permuted block randomization schedule with varying block sizes was used, stratified by clinical site. The research pharmacist at each site provided the blinded study drugs in 2 tamper-evident bottles. All clinical investigators, research nurses, and patients were blinded to treatment assignments until all patients had completed follow-up. Outcomes The primary outcome was the change in the NIH-CPSI total score from baseline to 6 weeks. The NIH-CPSI was administered at each of the 2 baseline screening visits, 1 to 3 weeks apart, and every 3 weeks thereafter until 12 weeks. The average of the 2 scores before randomization was used as the baseline score. Evaluation of the responsiveness of the NIH-CPSI indicates that a 4-point change on a scale of 0 to 43 points represents a difference detectable by the patient. Secondary outcomes included changes in the pain, voiding, and quality-of-life subscales of the NIH-CPSI; physical and mental summary scores on the Medical Outcomes Study 12-Item Short-Form Health Survey (16); and a 7-point patient-reported global response assessment. Responders for the global response assessment were defined as men reporting that they were markedly improved or moderately improved at 6 weeks compared with baseline. Men for whom the global response assessment was missing were considered nonresponders and were included in the denominator for the assessment of response rates. Adverse events were monitored throughout the study and graded according to the National Cancer Institute Common Toxicity Criteria (ctep.cancer.gov/reporting/ctc.html). Patients were asked at each contact to report any adverse events that had occurred since the previous contact. The questions were open-ended, and researchers did not ask about any specific categories of adverse events. All events, regardless of whether they were expected reactions to the study drugs, were recorded. Attribution to treatment was also assessed. However, because it was difficult to determine whether certain adverse events, such as pain, were related to treatment or to CP/CPPS, all events were analyzed. Statistical Analysis For each of the 2 primary treatment comparisons, the recruitment goal of 184 patients provided 80% power, at a 2-sided significance level of 5%, to detect a 4-point treatment difference in the NIH-CPSI total score between baseline and 6 weeks. We recognized that although patients could detect this difference, most might not perceive it as a major improvement. However, we did not want to miss even a minor change in

The effect of bystander CPR on survival of out-of-hospital cardiac arrest victims

The effect of bystander cardiopulmonary resuscitation (CPR) was studied in 2142 emergency medical service (EMS) cardiac arrest runs. When bystander CPR was administered to cardiac arrest victims, 22.9% of the victims survived until they were admitted to the hospital and 11.9% were discharged alive. In comparison, the statistics for cardiac arrest victims who did not receive bystander CPR were 14.6% and 4.7%, respectively (p less than 0.001). A critical factor in patient survival was the amount of time that elapsed before the EMS personnel arrived and administered CPR. Patients who received bystander CPR were more likely to have ventricular fibrillation when the EMS arrived. Other factors relating to patient survival were the location of the victim at the time of the cardiac arrest and the age of the victim. Understanding these factors is important in developing community strategies to treat patients with cardiac arrest out of hospital.

Quality of Life Is Impaired in Men with Chronic Prostatitis: The Chronic Prostatitis Collaborative Research Network

OBJECTIVE: Health-related quality of life (HRQOL) impairment may be a central component of chronic prostatitis for men afflicted with this condition. Our objective was to examine HRQOL, and factors associated with HRQOL, using both general and condition-specific instruments.DESIGN: Chronic Prostatis Cohort (CPC) study.SETTING: Six clinical research centers across the United States and Canada.PARTICIPANTS: Two hundred seventy-eight men with chronic prostatitis.MEASUREMENTS AND MAIN RESULTS: The Short Form 12 (SF-12) Mental Component Summary (MCS) and Physical Component Summary (PCS), and the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) were measures used. CPC subjects’ MCS scores (44.0±9.8) were lower than those observed in the most severe subgroups of patients with congestive heart failure and diabetes mellitus, and PCS scores (46.4±9.5) were worse than those among the general U.S. male population. Decreasing scores were seen in both domains with worsening symptom severity (P<.01). History of psychiatric disease and younger age were strongly associated with worse MCS scores, whereas history of rheumatologic disease was associated with worse PCS scores. Predictors of more severe NIH-CPSI scores included lower educational level and lower income; history of rheumatic disease was associated with higher scores.CONCLUSIONS: Men with chronic prostatitis experience impairment in the mental and physical domains of general HRQOL, as well as condition-specific HRQOL. To optimize the care of men with this condition, clinicians should consider administering HRQOL instruments to their patients to better understand the impact of the condition on patients’ lives.

Randomized Multicenter Feasibility Trial of Myofascial Physical Therapy for the Treatment of Urological Chronic Pelvic Pain Syndromes

PURPOSE We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. MATERIALS AND METHODS We recruited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of 1 hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. RESULTS There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). CONCLUSIONS We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study.

Biopsy features are associated with primary symptoms in interstitial cystitis: results from the interstitial cystitis database study ☆

The purpose of this study was to investigate associations between bladder biopsy features and urinary symptoms for patients enrolled in the Interstitial Cystitis Database (ICDB) Study. Bladder biopsies were obtained during baseline screening in the ICDB Study and were evaluated for histopathologic features. Multivariable models for nighttime voiding frequency, urinary urgency, and pain were developed, incorporating biopsy features from the most diseased area of the bladder as predictors, adjusting for significant clinical factors, and clinical center variation. Among 204 interstitial cystitis (IC) patients providing biopsy specimens, cystoscopic pathology findings were not statistically associated (P >0.1) with primary IC symptoms, although the presence of Hunners ulcer (n = 12) was suggestive of increased urinary frequency. Within a multivariable predictive model for nighttime voiding frequency, adjusting for age and minimum volume per void, 4 pathology features were noted: (1) mast cell count in lamina propria on tryptase stain; (2) complete loss of urothelium; (3) granulation tissue in lamina propria; and (4) vascular density in lamina propria on factor VIII (F8) stain were statistically significant (P <0.01). Similarly, in a multivariable model for urinary urgency, minimum volume, and percentage of submucosal granulation tissue remained statistically significant (P <0.01). Finally, the percentage of mucosa denuded of urothelium and the percentage of submucosal hemorrhage remained highly associated (P <0.01) with pain in a multivariable predictive model. The fact that the presence or severity of glomerulations was not selected for any of these predictive models suggests that cystoscopic findings of glomerulations are not predictive of IC symptoms. Furthermore, these results suggest an important role for certain pathologic features in the predictive modeling of IC symptoms.