New diagnostic and treatment guidelines for benign prostatic hyperplasia. Potential impact in the United States.

BACKGROUND: The Agency for Health Care Policy and Research (AHCPR) recently released the clinical practice guidelines for the diagnosis and treatment of benign prostatic hyperplasia. Prevalence estimates from a population-based cross-sectional study, the baseline component of a cohort study of the natural history of prostatism, were used to assess their potential impact in the United States. METHODS: The study group comprised a population-based sample of white men aged 50 to 79 years who were randomly selected within age- and residence-specific strata from the Olmsted County, Minnesota, population (1990 census, 105,720). These 1317 men completed symptom assessments and diagnostic evaluations that paralleled the AHCPR guidelines, including the measurement of urinary flow rates and, for a subset (n = 303), ultrasonic determination of postvoiding residual urine volume. RESULTS: The application of the AHCPR benign prostatic hyperplasia diagnostic guidelines to the study cohort (American Urologic Association Symptom Index > 7 and peak urinary flow rate < 15 mL/s) suggests that 17% of men aged 50 to 59 years, 27% of men aged 60 to 69 years, and 35% of men aged 70 to 9 years are eligible to discuss treatment options. Application of these percentages to the 1990 US white population suggests that approximately 5.6 million men aged 50 to 79 years are eligible to discuss treatment options. This number will double by the year 2020 owing to the aging of the population. CONCLUSION: The projected number of men potentially meeting AHCPR guidelines to discuss treatment options for benign prostatic hyperplasia could have a substantial impact on the health care system; this will be compounded by the aging of the population.

Predictive properties of serum-prostate-specific antigen testing in a community-based setting.

BACKGROUND: Most studies that have described the sensitivity and specificity of prostate-specific antigen (PSA) as a screening test have been conducted in urology practice settings or in media-based screening programs. The control patients from these settings may have a higher prevalence of urologic disorders that increase serum PSA levels than that of the general population in which screening efforts might take place, leading to biased estimates of sensitivity and specificity. OBJECTIVE: To determine the sensitivity and specificity of serum PSA levels for the early detection of prostate cancer in a population-based setting. PATIENTS AND METHODS: This population-based case-control study was conducted in Olmsted County, Minnesota, where the Rochester Epidemiology Project could identify all incident cases of prostate cancer through passive surveillance of medical care provided to local residents. Case patients were all 177 men (age range, 50-79 years) who were newly diagnosed as having prostate cancer from 1990 through 1992 and had a prediagnostic serum PSA determination (90% of all incident cases). Control patients were randomly selected from the Olmsted County population and had undergone a clinical examination to exclude prostate cancer. RESULTS: The median (25th and 75th percentiles) of serum PSA levels was 9.4 ng/mL (5.4 and 18.6 ng/mL, respectively) for case patients and 1.2 ng/mL (0.7 and 2.1 ng/mL, respectively) for control patients (P < .001). When sensitivity was plotted against 1-specificity, the area under the receiver operating characteristic curve was 0.94 (SE, 0.01). The predictive power declined somewhat with age, with areas under the curve of 0.96, 0.94, and 0.90 for men in their 50s, 60s, and 70s, respectively. When cases were restricted to the 155 men with clinically localized disease, the area under the curve was essentially unchanged (0.94; SE, 0.01) and still much greater than the estimates of 0.75 that were reported from urology practice- and media-based settings. CONCLUSIONS: In a community-based setting, serum PSA levels provide better discrimination between men with and without clinically localized prostate cancer than has been observed in studies that were conducted in urologic practices. These results suggest that previous decision analyses may have underestimated the predictive value of PSA for the detection of prostate cancer in a primary care or community-wide screening program.

Indinavir did not increase the short-term risk of adverse cardiovascular events relative to nucleoside reverse transcriptase inhibitor therapy in four phase III clinical trials.

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

5 alpha-reductase activity and prostate cancer: a case-control study using stored sera.

We report a nested case-control study of serum biomarkers of 5 alpha-reductase activity and the incidence of prostate cancer. From a cohort of more than 125,000 members of the Kaiser Permanente Medical Care Program who underwent multiphasic health examinations during 1964-1971, we selected 106 incident prostate cancer cases. A control was pair matched to each case on age, date of serum sampling, and clinic location. Serum levels of total testosterone, free testosterone, androsterone glucuronide, and 5 alpha-androstane-3 alpha,17 beta androstanediol glucuronide (3 alpha-diol G) were measured on the stored samples and scored as quartiles. Potential confounders included alcohol, smoking, and body mass index. The adjusted odds ratios and 95% confidence intervals for a one quartile score increase were 1.00 (0.75-1.34) for total testosterone, 1.14 (0.86-1.50) for free testosterone, 1.13 (0.84-1.53) for androsterone glucuronide, and 1.16 (0.86-1.56) for 3 alpha-diol G. A limitation of this study is that there are two different 5 alpha-reductase isoenzymes, only one of which is expressed in high levels within the prostate, yet both of which may affect serum biomarkers. Since the two isoenzymes are encoded on different chromosomes, variation in one would act as an independent source of measurement error in any analysis of serum biomarker effects of the other. Consequently, the odds ratios may be underestimated and the study, although negative, cannot exclude the previously hypothesized possibility that a positive relationship between intraprostatic 5 alpha-reductase activity and prostate cancer may exist. A clinical trial to test this hypothesis is under way.

Vitamin D and prostate cancer: a prediagnostic study with stored sera.

This study evaluates the risk of prostate cancer in relation to serum levels of the major vitamin D metabolites, 25-hydroxyvitamin D (25-D3) and 1,25-dihydroxyvitamin D (1,25-D). Between 1964 and 1971, more than 250,000 serum samples were collected from members of the Kaiser Permanente Medical Care Plan in Oakland and San Francisco and stored for future use. Levels of 25-D and 1,25-D were measured in samples from 90 black and 91 white men diagnosed with prostate cancer before December 31, 1987 and controls individually matched on age, race, and day of serum storage. Mean serum 1,25-D was 1.81 pg/ml lower in cases than in matched controls (P = 0.002). Risk of prostate cancer decreased with higher levels of 1,25-D especially in men with low levels of 25-D. However, mean 25-D was not significantly different in cases and controls. The association of lower 1,25-D with prostate cancer was found in men above the median age of 57 years at serum storage but not younger men and was similar in black and white men. In men > or = 57 years of age, 1,25-D was an important predictor of risk for palpable and anaplastic tumors but not for tumors incidentally discovered during surgery to treat the symptoms of benign prostatic hyperplasia or well differentiated tumors.

Incidence of migraine headache: a population-based study in Olmsted County, Minnesota.

To determine the incidence of clinically detected migraine headache in the defined population of Olmsted County, MN, 1979-1981, we screened over 6,400 patient records from several diagnostic rubrics using the unique resources of the Rochester Epidemiology Project for population-based studies. We identified 629 Olmsted County residents who fulfilled the International Headache Society's 1988 criteria for newly diagnosed migraine headache between 1979 and 1981. The overall age-adjusted incidence was 137 per 100,000 person-years for males and 294 per 100,000 person-years for females. The highest incidence in females was among those aged 20 to 24 years (689 per 100,000 person-years), and in males, the highest incidence was among those aged 10 to 14 years (246 per 100,000 person-years). From 1979 to 1981, there was a striking increase in the age-adjusted incidence in those under 45 years of age: the incidence increased 34% in women and 100% for men. This is the first population-based study of migraine incidence across all ages.

Incidence of cluster headaches: a population-based study in Olmsted County, Minnesota.

The epidemiology of cluster headache is virtually unknown. Using the unique resources of the Rochester Epidemiology Project for population-based studies, we identified 26 Olmsted County, Minnesota, residents who fulfilled the International Headache Society criteria for newly diagnosed cluster headache between 1979 and 1981. As part of a large study of migraine and cluster headache, we screened more than 6,400 patient records from several diagnostic rubrics to obtain this cohort, accomplished case ascertainment exclusively through medical record review, and assigned diagnoses by the consensus of two neurologists. The age-adjusted incidence was 15.6 per 100,000 person-years (p-y) (95% CI, 8.9 to 22.3) for males and 4.0 per 100,000 p-y for females (95% CI, 0.4 to 7.6). The overall age- and sex-adjusted incidence was 9.8 per 100,000 p-y (95% CI, 6.0 to 13.6) or approximately 1/25 that of migraine. The peak incidence was among men aged 40 to 49 years and women 60 to 69 years. There was a higher than expected prevalence of history of smoking among males with cluster headaches (p < 0.05), supporting the possibility that smoking predisposes to the development of cluster headaches in men.

Is vasectomy a risk factor for prostate cancer?

Recently, several case-control studies have suggested that vasectomy may predispose to prostate cancer. Other studies have found no increase in risk. All of these studies have a number of limitations. Taken together, these studies do not provide convincing evidence that vasectomy increases the risk of prostate cancer. However, in view of the high prevalence of prostate cancer and the growing worldwide importance of vasectomy as a form of contraception, further epidemiological research is warranted. After briefly commenting on the experimental studies we will examine the epidemiological studies in more detail. This will be done by first summarising the designs and main findings of the most relevant published studies and then discussing methodological issues relating to the studies taken as a whole. Finally, we will present conclusions and offer recommendations for future research.

Hemolysis and acute renal failure following a Portuguese man-of-war sting.

Portuguese man-of-war stings occur frequently at North American beaches. Most produce only local pain and pruritus. A 4-year-old girl who developed a hemolytic reaction and acute renal failure following a severe sting is described. As neither sequela has been previously reported, it is speculated that either the large dose of venom or chance intravenous inoculation may have been responsible. Evidence of hemolysis should be sought in small children with extensive Portuguese man-of-war stings.

Population-based studies of varicella complications.

Population-based data on varicella complications are presented using information both from national sample surveys of hospitalizations and physician office visits and from reviews of medical records for all cases occurring within one community (Olmsted County, Minnesota) during a specified period. Acute cerebellar ataxia is the most common neurologic complication of varicella and occurs about once in 4,000 varicella cases among children younger than 15 years of age. Among adults, varicella pneumonia is the most common complication and results in hospitalization about once in every 400 varicella cases. Overall, varicella accounts for approximately 4,000 hospitalizations and 364,000 physician office visits annually in the United States and represents an important continuing source of childhood and adult morbidity.

Epidemiology of herpes zoster in children and adolescents: a population-based study.

Medical records were reviewed for all 173 cases of herpes zoster diagnosed among residents of Rochester, Minnesota, less than 20 years of age during the period 1960 through 1981. The incidence of zoster increased with age from 20 cases per 100,000 person-years in those residents less than five years of age to 63 cases per 100,000 person-years in those aged 15 to 19. Morbidity was less than has been described in adults, as only two patients required hospitalization and no postherpetic neuralgia or other late complications were diagnosed. The single case of subsequent cancer found in 1,288 person-years of follow-up was not significantly different from the number expected based on cancer incidence in the general Rochester population. The incidence of childhood zoster in patients with acute lymphocytic leukemia was 122 times higher than in children without an underlying malignancy. Chickenpox in the first year of life was found to be a risk factor for childhood zoster, with a relative risk between 2.8 and 20.9. Neither chickenpox in the second year of life nor recent vaccinations were found to be risk factors for childhood zoster.

Effect of several recruitment strategies on response rates at baseline in a prospective cohort investigation. The Olmsted County Study of Urinary Symptoms and Health Status among Men.

Epidemiologic survey response rates were studied in relation to maneuvers introduced to improve acceptance: (a) variation in invitation letters, (b) the use of a brochure with the recruitment mailing, and (c) options for interview location. The baseline population-based survey of a prospective cohort investigation of the natural history of benign prostatic hyperplasia was used. Invitations to participate were mailed to eligible, randomly selected men aged 40 to 79 years from the Olmsted County, Minnesota, population during 1989 to 1991. Of the 3874 men identified, 2119 (55%) participated. Overall, there was no difference in response rate according to invitation characteristics (chi 2(5) = 8.02, P = 0.16). Nevertheless, response rates varied with age (chi 2(7) = 30.9, P < 0.001) and home location (rural versus Rochester city; chi 2(1) = 76.9, P < 0.001). This suggests the innovations used to bolster acceptance did not materially improve response rates. Further, since response rates were highest for men aged 60 to 74 years, men with more symptoms and free time may have joined the cohort more often than others.

Pharmacoepidemiology in pre-approval clinical trial safety monitoring.

Applications of pharmacoepidemiology to the pre-approval safety monitoring of investigational drugs are examined and compared with the post-approval applications. Pre-approval epidemiologic assessments of drug safety can complement clinical assessments of rare, serious adverse events occurring in open label uncontrolled clinical trials. Applications include retrospective identification of patient risk factors for adverse drug events and incidence comparisons based on historical controls. While similar in concept to applications of pharmacoepidemiology in the analyses of uncontrolled open label post-marketing surveillance studies, answers are often needed in days rather than weeks and the emphasis is on whether human studies can continue. Advance planning of historical data sources is essential as is an effective clinical trial data management system. Implications for methodologic research and for drug development are discussed.

Behavior of the exposure odds ratio in a case-control study when the hazard function is not constant over time.

In case-control studies of adverse drug effects there is rarely much evidence to support the assumption that the hazard function among users is constant during therapy. Nonetheless, this assumption is often implicitly made. We will use both clinical reasoning and a simple model to show how non-constancy of the hazard function affects odds ratio interpretation. When the hazard function is non-constant and there is more than one temporal pattern of drug usage, the odds ratio will estimate a weighted mean of incidence ratios with weights dependent on the corresponding fractions of person-time. If the duration-specific incidence ratios differ widely, the odds ratio will depend not only on the drug but also on its usage pattern in the study population. This may explain some of the large regional odds ratio variation for dipyrone-related agranulocytosis in the International Agranulocytosis and Aplastic Anemia Study (JAMA 1986; 256: 1749-1757.

Pharmacoepidemiology as a focus for clinical epidemiology in developing countries.

We present a concept of pharmacoepidemiology as a branch of clinical epidemiology having particular relevance to public health in developing countries. Planning to incorporate pharmacoepidemiology into the clinical epidemiology curriculum of the International Clinical Epidemiology Network (INCLEN) is discussed and an outline of training programs in pharmacoepidemiology at INCLEN universities is given.

Time-dependent variability in repeated measurements of cholesterol levels: clinical implications for risk misclassification and intervention monitoring.

Intraindividual variability (IIV) in total cholesterol levels based on measurements taken 1 week apart is compared with an estimate based on measurements taken 2 years apart. Single-subject 95% confidence intervals around the mean of two repeated measurements were Xi +/- 21 and +/- 28 mg/dl, respectively, and Xi +/- 30 and +/- 40 mg/dl for a single measurement. Comparing these results with published estimates over varying time intervals shows a trend of decreasing IIV with shorter intervals, suggesting that confidence interval widths based on short-term repeated measurements and those based on longer-term repeated measurements may differ more than previously assumed. The practical consequences are that: (1) the level of misclassification inherent in the National Cholesterol Education Program (NCEP) guidelines may be less than had been estimated; and (2) reliable cholesterol reductions resulting from dietary or other interventions may be somewhat easier to detect. These findings have implications for the cost-effectiveness of cholesterol screening strategies and interventions to reduce cholesterol.

Adverse effects of medications on urinary symptoms and flow rate: a community-based study.

The relationship between urinary symptoms and medication use was investigated in a community-based cross-sectional study involving a random sample of 2115 men 40-79 years of age in Olmsted County, Minnesota. The American Urological Association Symptom Index (AUASI) was generated from a validated self-administered questionnaire. Medication use was assessed by in-person interviews. While 1087 men reported daily medication use, only 136 reported daily use of medications known to affect urinary function adversely, including antidepressants (42), antihistamines (23), and bronchodilators (43). Age-adjusted AUASI scores were higher in men reporting daily use of antidepressants, and the association persisted after additionally adjusting for the Depression and Anxiety subscales of the General Psychological Well-Being Scale (adjusted mean difference, 2.1; 95% confidence interval (CI), 0.5-3.6; p = 0.008). The adjusted AUASI was also higher among men who took antihistamines daily (adjusted mean difference, 2.3; 95% CI, 0.3-4.3; p = 0.03). Lower age-adjusted urinary flow rates occurred with antidepressants, but not with antihistamines or bronchodilators. Clinicians evaluating men for causes of voiding dysfunction in accordance with the Agency for Health Care Policy and Research practice guideline for the diagnosis and management of benign prostatic hyperplasia should be aware that daily use of antidepressants or antihistamines may be associated with AUASI scores that are two to three points higher than in men not taking these medications.

Fatal upper gastrointestinal hemorrhage or perforation among users and nonusers of nonsteroidal anti-inflammatory drugs in Saskatchewan, Canada 1983.

We report a cohort study of fatal upper GI hemorrhage and/or perforation in relation to use of nonsteroidal anti-inflammatory drugs (NSAIDs) among the one million residents of Saskatchewan Canada in 1983. All hospitalized cases of GI hemorrhage and/or perforation with a fatal outcome were identified using the records linkage system of the Saskatchewan Department of Health. Discharge summaries and autopsy records were reviewed to select the cases of upper GI hemorrhage or upper GI perforation and to exclude cases in which known risk factors were present. The 134,060 residents who filled one or more prescriptions for an NSAID in 1983 were identified and individually linked to their hospital records by patient identification number. The age- and gender-specific incidence of fatal upper GI hemorrhage and/or perforation in the absence of risk factors in users was compared to that in nonusers, controlling for recent history of upper GI disease. Fatal upper GI hemorrhage or perforation in temporal association with NSAIDs is extremely rare in persons younger than 75 years of age. No temporally-related cases occurred in male NSAID users age 75 and older, but NSAID usage in this group was limited. Among women age 75 and older, the rate in users was higher than in nonusers, with the highest rate being in female NSAID users age 75 and older with a recent history of upper GI disease. Total mortality among women age 75 and older was slightly lower among users than among nonusers. Physicians who prescribe NSAIDs to patients age 75 and older should be aware of the potential risks, particularly in those with predisposing factors such as a history of upper GI disease.

Demographics, health behaviors, and past drug use as predictors of recall accuracy for previous prescription medication use.

Drug data for pharmacoepidemiologic studies are often ascertained by self-report, but little research has addressed the factors influencing its accuracy. Stratified random sampling was used to select individuals for a study comparing interview data on past prescription drug use with dispensation information from the Group Health Cooperative of Puget Sound pharmacy database. The strata included age, gender, and recency of use. Recall accuracy and its determinants were evaluated for repetitively used non-steroidal anti-inflammatory drugs (NSAIDs), short-term NSAIDs (only a single dispensation), and post-menopausal estrogens. We investigated whether recall accuracy was influenced by education, marital status, race, smoking, alcohol consumption, cumulative drug history, the number of different NSAIDs or estrogens dispensed (both by name and dosage), and the number of dispensations of the drug in question. For repetitively used NSAIDs, recall accuracy was positively associated with the number of NSAID dispensations (the odds of recall were 1.7 [95% confidence interval {CL}: 1.3-2.2] times greater for each additional four dispensations of the NSAID), the total number of drugs dispensed and the number of different NSAIDs dispensed. For estrogen and short-term NSAID use, only higher educational attainment improved recall accuracy: the odds of recall were 4.1 (95% CI: 1.4-11.7) and 2.1 (95% CI: 1.0-4.7) times greater for those with some college compared with those with only a high school degree, respectively. This study demonstrates that predictors of recall accuracy for previous medication use differ by the type of drug and the repetitiveness of its use.

The natural history of prostatism: the effects of non-response bias.

BACKGROUND: In epidemiological studies, non-response may raise the question of generalizability to the target population. Most investigations have not been able to access data that could provide information about the potential impact of non-response bias. METHODS: A 55% response rate was realized at baseline for a prospective cohort investigation of the natural history of benign prostatic hyperplasia in Olmsted County, Minnesota, during 1989-1991 (the Olmsted County Study of Urinary Symptoms and Health Status Among Men). This prompted a preliminary study of potential non-response bias among full participants, partial participants and complete non-responders. The medical diagnostic index maintained by the Rochester Epidemiology Project was used to ascertain the prevalence of specific conditions in the 9 years prior to study inception. RESULTS: The age-adjusted period prevalence rate for benign prostatic hyperplasia (%) was 9.6 (95% confidence interval [CI]: 8.1-11.0) for full participants, 8.2 (95% CI: 5.8-10.6) for partial participants and 5.3 (95% CI: 3.6-6.9) for complete non-responders. Other urologic diagnoses followed the same pattern. However, age-adjusted prevalence rates for general medical examination history and major non-urologic morbidities were decidedly similar across response groups. CONCLUSIONS: These data suggest response may have been driven, in part, by concerns about urologic disease. However, the similarity in non-urologic diagnoses and general medical examinations provide some preliminary reassurance that the 55% response rate did not necessarily compromise generalizability.