Inference for covariate-adjusted time-dependent prognostic accuracy measures.

Evaluating the prognostic performance of candidate markers for future disease onset or progression is one of the major goals in medical research. A marker's prognostic performance refers to how well it separates patients at the high or low risk of a future disease state. Often the discriminative performance of a marker is affected by the patient characteristics (covariates). Time-dependent receiver operating characteristic (ROC) curves that ignore the informativeness of the covariates will lead to biased estimates of the accuracy parameters. We propose a time-dependent ROC curve that accounts for the informativeness of the covariates in the case of censored data. We propose inverse probability weighted (IPW) estimators for estimating the proposed accuracy parameters. We investigate the performance of the IPW estimators through simulation studies and real-life data analysis.

Impact of HLA mismatch at first kidney transplant on lifetime with graft function in young recipients.

As HLA matching has been progressively de-emphasized in the American deceased donor (DD) kidney allocation algorithm, concerns have been raised that poor matching at first transplant may lead to greater sensitization and more difficulty finding an acceptable donor for a second transplant should the first transplant fail. We compared proportion of total observed lifetime with graft function after first transplant, and waiting times for a second transplant between individuals with different levels of HLA mismatch (MM) at first transplant. We studied patients recorded in the United States Renal Data System (1988-2009) who received a first DD transplant at age ≤21 years (n = 8433), and the subgroup who were listed for a second DD transplant following first graft failure (n = 2498). Compared with recipients of 2-3 MM first grafts, 4-6 MM graft recipients spent 12% less of their time and 0-1 MM recipients 15% more time with a functioning graft after the first transplant (both p < 0.0001); 4-6 MM recipients were significantly less likely (hazard ratio [HR] 0.87 [95% confidence interval 0.76, 0.98]; p = 0.03), and 0-1 MM recipients more likely (HR 1.26 [0.99, 1.60]; p = 0.06) to receive a second transplant after listing. The benefits of better HLA matching at first transplant on lifetime with graft function are significant, but relatively small.

Screening histories and contact with physicians as determinants of cervical cancer risk in Montreal, Quebec.

BACKGROUND: Cervical cancer (cca) is largely a preventable disease if women receive regular screening, which allows for the detection and treatment of preinvasive lesions before they become invasive. Having been inadequately screened is a common finding among women who develop cca. Our primary objective was to determine the Pap screening histories of women diagnosed with cca in Montreal, Quebec. Secondary objectives were to determine the characteristics of women at greatest risk of cca and to characterize the level of physician contact those women had before developing cca. METHODS: The Invasive Cervical Cancer Study, a population-based case-control study, consisted of Greater Montreal residents diagnosed with histologically confirmed cca between 1998 and 2004. Respondents to the 2003 Canadian Community Health Survey and a sample of women without cca obtained from Quebec medical billing records served as controls. RESULTS: During the period of interest, 568 women were diagnosed with cca. Immigrants and women speaking neither French nor English were at greatest risk of cca. Most of the women in the case group had been screened at least once during their lifetime (84.8%-90.4%), but they were less likely to have been screened within 3 years of diagnosis. Having received care from a family physician or a medical specialist other than a gynecologist within the 5 years before diagnosis was associated with a greater risk of cca development. CONCLUSIONS: Our findings provide evidence of the need for an organized population-based screening program. They also underscore the need for provider education to prevent missed opportunities for cca screening when at-risk women seek medical attention.

Risk of prostate cancer death in long-term users of warfarin: a population-based case-control study.

PURPOSE: Recent evidence suggests that warfarin use may be associated with a reduced risk of prostate cancer. We aimed to determine whether exposure to warfarin is also associated with a reduced risk of prostate cancer death. METHODS: A nested case-control study was conducted within a population-based cohort of 10,012 men aged ≥50 years with newly diagnosed prostate cancer between 1985 and 2002 and with no history of cancer since 1970 using the linked records of Saskatchewan Health and Saskatchewan Cancer Agency registry. We identified 2,309 cases who died of prostate cancer during follow-up. For each case, one control alive at the time of the case's death and matched for length of follow-up (±6 months) was randomly selected. Prescription counts were used to define warfarin exposure. Multivariate conditional logistic regression analysis was used to calculate the adjusted incidence rates of prostate cancer death in relation to warfarin use while adjusting for confounding by age, year of prostate cancer diagnosis, clinical stage and grade of cancer at diagnosis, Chronic Disease Score, and use of warfarin before diagnosis. RESULTS: Ever use of warfarin following a diagnosis of prostate cancer was associated with an adjusted rate ratio of 1.44 (95 % confidence interval (CI) 1.33-1.84) for prostate cancer death. The adjusted rate ratio with one-year use of warfarin was 1.77 (95 % CI 1.25-2.50) compared to never use. The unadjusted rate ratio with five-year use of warfarin was 0.64 (95 % CI 0.40-1.00) and remained unchanged in the adjusted analysis (0.65, 95 % CI 0.37-1.13), although no longer statistically significant. CONCLUSION: Our study does not provide conclusive evidence for a protective effect of long-term warfarin on prostate cancer-specific mortality. Moreover, short-term warfarin use may be associated with an increased risk of prostate cancer death.

Trajectories of endurance activity following pulmonary rehabilitation in COPD patients.

Maintenance of physical activity following pulmonary rehabilitation remains a challenge for patients with chronic obstructive pulmonary disease (COPD). The objectives of this study were to identify patterns of endurance activity after completion of pulmonary rehabilitation and to characterise people who succeed and those who have difficulty maintaining endurance activity. In a longitudinal study embedded within a randomised clinical trial, 206 individuals with COPD underwent a 3-month pulmonary rehabilitation programme. Weekly duration of endurance activity was assessed at 4, 6, 8 and 12 months after the start of rehabilitation. Trajectory modelling was used to determine the most common patterns of activity during the post-rehabilitation phase from 4-12 months. Three distinct patterns were identified, two of which indicated difficulty in maintaining endurance activity: 61 individuals reported a high activity level at 4 months (2.7 h·week(-1)) and stayed high; 114 individuals started at a low activity level (mean 1.0 h·week(-1)) and stayed low; and 31 individuals started high (3.0 h·week(-1)) and declined. The low activity group was characterised by more severe disease and greater respiratory impairment. The high and declined group had less severe disease and respiratory impairment, but reported greater barriers to exercise. Pulmonary rehabilitation should include interventions aimed at minimising barriers, in order to induce long-term behaviour change.

Change in mortality risk over time in young kidney transplant recipients.

Mortality risk for kidney transplant recipients may change with increasing accumulated exposure to the "transplantation milieu." We sought to characterize changes over time in mortality rate and in age-, sex- and race-standardized mortality ratios (SMR) relative to the general population, and to estimate the association between increasing time since first transplant and mortality risk. A total of 18 911 patients who received a first transplant at <21 years old (1983-2006), and whose data were recorded in the USRDS, were studied. There were 2713 deaths over a median follow-up of 8.9 (interquartile range 4.0-14.5; maximum 23) years. Among those with graft function, mortality was highest in the first post transplant year; beyond the first year of the first transplant, age-adjusted mortality rates and SMRs decreased slightly over follow-up. Cause of death was cardiovascular for 34.6%, infection for 19.5%, malignancy for 5.8%, other for 21.4% and unknown for 18.7%. For every 1-year time increment after the end of the first post transplant year, age-adjusted all-cause and cardiovascular mortality rates fell by 1% (p = 0.06) and 16% (p = 0.007), respectively; infection-related mortality rate did not change over time (p = 0.5). These results suggest that exposure to the transplantation milieu has no cumulative negative effects on cardiovascular health over the long term.

Twin pregnancy: the impact of the Higgins Nutrition Intervention Program on maternal and neonatal outcomes.

Perinatal outcomes were compared between 354 twins treated with the Higgins Nutrition Intervention Program and 686 untreated twins. After differing distributions of key confounding variables were adjusted for, the twins in the intervention group weighed an average of 80 g more (P less than 0.06) than the nonintervention twins; their low-birth-weight rate was 25% lower (P less than 0.05) and their very-low-birth-weight rate was almost 50% lower (P less than 0.05). Although the rate of preterm delivery was 30% lower in the intervention group (P less than 0.05), the rates of intrauterine growth retardation were similar in the two groups. Fetal mortality was slightly higher (14 vs 12 per 1000, NS), but early neonatal mortality was fivefold lower (3 vs 19 per 1000, P less than 0.06) in the intervention group. Maternal morbidity was significantly lower (P less than 0.05) in the intervention group. There was a trend towards lower infant morbidity in the intervention group. These results suggest that nutritional intervention can significantly improve twin-pregnancy outcome.

Split-course radiation therapy of carcinoma of the base of the tongue: results of a prospective national collaborative clinical trial conducted by the Radiation Therapy Oncology Group.

One hundred forty-one patients with carcinoma of the base of tongue were randomized to receive either continuous course radiotherapy (6600 rad in 30/33 fractions over 7-8 weeks) or split course therapy (3000 rad in 10 fractions over 2 weeks, a three-week rest, 3000 rad in 10 fractions over 2 weeks). Both treatment groups tolerated the treatment well, but the continuous course group required more treatment modifications. The results of therapy, as judged by control of primary tumor, control of metastatic lymph nodes, time to failure and overall survival were comparable in the two treatment groups.

Protocol variations and their influence on the final outcome: critical review of the split-course base of tongue study of the RTOG.

A critical review of the protocol variations in an RTOG prospective randomized multi-institutional clinical trial has been conducted. The objective of the review was to identify variables that might have affected the results of the study. Compliance with general guidelines and specific technical treatment parameters of the Split-Course Radiation Therapy Protocol for Carcinoma of the Base of the Tongue (RTOG #71-02) was analyzed. A +/- 5% variation of the time-dose-fractionation factors, using the NSD and TDF formulae and their respective protocol ratios (ratio between actual case NSD and TDF level and what the protocol recommended), has been defined as fully acceptable. Seventy-two percent of the 141 study cases were within this category. Minor variation has been defined as one resulting in a +/- 6% to +/- 15% deviation from the study values (15.3% of cases). Major and unacceptable variation was a deviation of +/- 16% or more from the research plan (12.7% of cases). After identifying the different variations and correlating them with the clinical results, we conclude that these deviations did not affect the final results to a significant or identifiable degree.

Split-course versus continuous pelvis irradiation in carcinoma of the uterine cervix: a prospective randomized clinical trial of the Radiation Therapy Oncology Group.

In August 1980, the Radiation Therapy Oncology Group (RTOG) completed a prospective randomized clinical trial for the comparison of a split-course versus a standard continuous course of pelvic irradiation for carcinoma of the uterine cervix Stages II-B, III-A, III-B, and IV-A. The split-course consisted of 10 fractions of 250 rad each, 5 times a week, up to 2500 rad followed by a rest period of approximately 2 weeks and then another 2500 rad was given (250 X 10). The continuous course consisted of 30 fractions of 170 rad each, 5 times per week, for a total of 5100 rad. In both groups the external pelvis irradiation was followed by intracavitary brachytherapy in the uterus and vagina, with tandem-colpostat or tandem only, for a dose of 3000 rad at point A for the former, or at 2 cm from the center of the linear source for the latter. In cases where brachytherapy was not possible, a boost of external irradiation with reduced field, with a dose of 1600 rad (200 X 8) was advised. Three hundred and one patients were registered, of which 287 are currently evaluable. No differences between the treatments were detected for the following study end-points: treatment tolerance in terms of acute normal tissue reactions and completion of therapy, tumor control in the pelvis, severe late normal tissue reactions, and survival. In the entire study population the estimated tumor control in the pelvis at two years after initiation of therapy was: 81% for Stage II-B, 67% for III-A, 53% for Stage III-B, and 32% for Stage IV-A. The estimated two-year survival was: 70% for Stage II-B, 58% for III-A, 46% for III-B, and 23% for IV-A.

The decreased incidence of aseptic necrosis in renal transplant recipients--a case control study.

Before 1971 the incidence of aseptic necrosis in renal transplant recipients was 29%, and after 1971 it was 5%. To investigate the reasons for this decreased incidence and to elucidate the causes of aseptic necrosis we studied all 26 transplant patients with aseptic necrosis and 42 controls matched for year of transplantation, age, and sex. Development of aseptic necrosis was not related to duration of dialysis before transplant, severity of uremia at the time the patient started dialysis, adequacy of dialysis before transplantation, transplant dysfunction at the time aseptic necrosis was diagnosed, hyperparathyroidism before or after transplantation, lack of Vitamin D supplementation after transplantation, or fatty infiltration of liver. Total steroid dose 1 month after transplantation was actually lower in aseptic necrosis compared with the control group (2.47 +/- 0.3 g vs. 3.6 +/- 0.3 g SEM g) and was similar after 4 months (6.72 +/- 0.55 g vs. 7.14 +/- 0.6 g), as were total numbers of i.v. doses of methylprednisolone or hydrocortisone. However, blood urea nitrogen (BUN) during the dialysis period was significantly higher in the aseptic necrosis group. Of the aseptic necrosis group, 27% had a previous transplant compared with 5% of controls. Half the aseptic necrosis group (5/10) had parenchymal iron on liver biopsy one year after transplant compared with 15% (2/13) of those without aseptic necrosis. Patients transplanted before 1971 (with and without aseptic necrosis) received significantly more i.v. hydrocortisone and less i.v. methylprednisolone, had higher BUN levels at the time of starting dialysis, and had lower serum calcium and higher serum phosphate at transplantation compared with patients transplanted in or after 1971. The incidence of aseptic necrosis following transplantation has decreased during the past 13 years for reasons that are unclear. Risk factors for aseptic necrosis may include previous transplantation, severe iron overload that may lead to marrow fibrosis and osteopenia, and increased protein catabolism/turnover during dialysis.

Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-I and its binding proteins.

BACKGROUND: Secondary erythrocytosis is classically defined by an increase in erythropoietin (EPO) production. Despite increased levels of EPO often seen in secondary erythrocytosis, some of these forms such as that seen after renal transplantation remain undefined. Our group has recently investigated the in vivo function of insulin-like growth factor-I (IGF-I) in erythropoiesis both in humans and in a murine model of chronic renal failure. These data, and the recently recognized role of IGF-I in polycythemia vera, suggested that IGF-I might be involved in secondary erythrocytosis. METHODS: Renal transplant recipients who developed erythrocytosis after transplantation were compared to normal individuals and to renal transplant recipients without erythrocytosis. We measured fasting serum EPO and IGF-I in all three groups. Because binding proteins may modify IGF-I function, IGF-I-binding proteins (IGFBP) 1 and 3, major binding proteins of IGF-I, were also measured. RESULTS: Renal transplant recipients have significantly elevated serum of IGF-I and IGFBP3 compared to normal individuals. When transplant recipients with and without posttransplant erythrocytosis were compared, similar levels of IGF-I were found; however, the group with erythrocytosis had significantly elevated IGFBP1 and IGFBP3. No other significant differences including EPO levels were found between the groups. CONCLUSIONS: Erythrocytosis after renal transplantation represents an anomaly of both IGF-I and its major binding proteins. Further studies are under way to better define this dysregulation and determine whether IGF-I can play a more generalized role in secondary forms of erythropoiesis.

The diagnostic and prognostic value of renal allograft biopsy.

We prospectively studied 89 patients to assess the diagnostic use of renal allograft biopsy in the first three months after transplantation. These biopsies were done in patients in whom diagnosis was not clear or clinical rejection was deemed to be severe. Clinical diagnosis at initial biopsy was compared with the morphological diagnosis. To determine if morphological data improved the prognostic usefulness of the clinical data, we performed multiple logistic regression relating clinical variables at initial biopsy and histological changes in the transplant to the outcome of 120 patients one year after biopsy. The clinical and morphological diagnosis differed in 41 of 89 patients (46%). Of 120 patients in the prognostic study, 35 returned to dialysis during the first year following transplantation. Using multiple logistic regression, a categorical variable that took into account both the serum creatinine and its rate of change before biopsy was the best clinical predictor of return to dialysis. Further increase in chi 2 occurred with type of donor, number of transfusions, and age. Using the clinical variables we produced an index, from 0 to 1 to predict outcome. Only 8 had index less than 0.2, of whom 7 returned to dialysis. The best morphological predictor of outcome was interstitial hemorrhage. Further increase in chi 2 was obtained with vascular endothelial proliferation, glomerular endothelial swelling, and glomerular necrosis. With an index derived from the morphological variables only 11 had index less than 0.2, of whom 9 returned to dialysis. Combining both clinical and morphological data, the best predictor of return to dialysis was interstitial hemorrhage, followed by creatinine, glomerular endothelial swelling, and type of donor. Using both clinical and morphological variables we produced another index to predict outcome. A group of 65 patients had index greater than 0.8, of whom 63 (94%) did not return to dialysis, and 18 patients had index less than 0.2, 17 of whom returned to dialysis. The remaining 12 patients in the dialysis group and 15 in the nondialysis group had indices greater than 0.2 less than 0.8. We conclude that a transplant biopsy yields important diagnostic and prognostic information. Unexpected diagnoses were made in 46% of cases. The addition of morphological data to the clinical data available at time of biopsy greatly improved the prediction of return to dialysis.

The repeatability of three methods for measuring prospective patients' values in the context of treatment choice for end-stage renal disease.

In the context of the choice of treatment for end-stage renal disease (ESRD), three approaches to value assessment were examined for their repeatability over time within subjects. If formal decision analyses are to be used to advise patients about treatment choice, then repeatable value assessment methods, an essential component of such analyses, are needed. The methods assessed were standard gamble (SG), time trade-off (TTO), and visual analogue (VA). Sixty-six nephrology clinic patients were interviewed on two occasions, 10 days apart, by one of two interviewers. An information session was conducted 1 week before the first interview. Subjects were taught about the treatments using an information package developed expressly for the study and a video produced by a pharmaceutical company for use in this decision context. Patients differed widely in the values provided for the various treatments of ESRD, with responses that ranged across the entire scale (0 to 100). The repeatability of the three methods was poor, with the coefficients of repeatability (95% range of differences from one occasion to the next) observed as +/- 27.4 for SG, +/- 38.4 for TTO, and +/- 36.5 for VA. When subsets defined by characteristics that may have improved the repeatability were analyzed, the magnitude of the error did not vary substantially. The poor repeatability of these methods raises questions about their use for decision analyses applied to the individual context.

Terminal digit preference, random error, and bias in routine clinical measurement of blood pressure.

We examined the presence, magnitude, and consequences of systematic and random errors caused by terminal digit preference in the measurement of highest systolic blood pressure during prenatal visits in 28,841 non-referred pregnant women who delivered between 1 January 1982 and 31 March 1990. In the overall distribution of terminal digit readings, 78% were read to 0, 15% to even digits other than 0, 5% to 5, and only 2% to odd digits other than 5. This preference for 0's was consistent across the entire distribution of blood pressure and for a variety of maternal characteristics. The relative frequency of the cutoff value of 140 mmHg (i.e. the percentage of readings on 140 mmHg) within the range containing the value (i.e. 138-142 mmHg) was similar to the relative frequency of other multiples of 0. This was true whether the comparison was made in the overall study sample, or in a pre-selected low-risk subgroup or high-risk subgroup, indicating no systematic bias. On the other hand, a strong tendency to read blood pressure values to the nearest 0 had a marked effect on the classification of hypertension. Changing the definition of hypertension from > or = 140 mmHg to > 140 mmHg produced a reduction in prevalence of hypertension from 25.9 to 13.3% in the overall study sample, from 15.4 to 6.3% in the low-risk subgroup, and from 43.3 to 25.3% in the high-risk subgroup. Epidemiologic studies that compare prevalences of hypertension in different populations based on routine clinical measurement of blood pressure and a single cutoff point should assess the consequences of terminal digit preference in defining hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

The psychological and physical health of family members caring for an elderly person with dementia.

Most elderly persons with dementia are cared for at home, usually by the spouse or an adult child. The objective of the present study was to determine whether there is an excess of psychological and physical health problems among family caregivers (CGs) of elderly persons with dementia. Data were obtained by interview from close family members of dementia patients (CGs), and from a comparison group made up of close family members of patients undergoing cataract surgery (non-caregivers, NCGs). CGs had significantly higher levels of depression and physical symptoms than NCGs. The association between caregiving and the health variables was stronger among subjects who were the patient's spouse than among those who were the patient's child. Furthermore, greater behavioral disturbance in the demented patient was associated with higher levels of morbidity in the CG. The results suggest that CGs might benefit from careful monitoring of their health status, and from greater access to specialized support services.

Use of physician services among family caregivers of elderly persons with dementia.

It is well known that there is an excess of physical and psychological health problems among family caregivers of elderly persons with Alzheimer's disease and other dementias. The objective of this study was to determine whether the higher level of morbidity translates into a higher level of medical care utilization. Data from a previously completed longitudinal study of caregivers for elderly persons with dementia were merged with data on physician visits obtained from the computerized records of the Quebec Health Insurance Board. Utilization of physician care (adjusted for age, sex, number of chronic diseases, and depression) was no higher for family caregivers of elderly patients with Alzheimer's disease and other dementias than for comparable family members of older persons without dementia. The annual cost of physician care was almost identical among caregivers and noncaregivers. However, the pattern of utilization for the two groups was somewhat different: there was a significantly higher frequency of physician utilization among caregivers for services billed by psychiatrists and internal medicine specialists. In multivariate analysis, physician utilization was significantly associated with having more than one chronic condition and with increased age. Future studies should focus on determining whether caregivers neglect their own health care needs as a result of the exigencies of the caregiving role.

Exposure to environmental tobacco smoke and the risk of lung cancer: a meta-analysis.

A meta-analysis was carried out to calculate a pooled estimate of relative risk of lung cancer following exposure to environmental tobacco smoke (ETS) and to determine whether there was any heterogeneity in the pooled estimates according to selected characteristics of the studies. A total of 35 case-control and five cohort studies providing quantitative estimates of the association between lung cancer and exposure to ETS published between January 1981 and March 1999 were identified. Using fixed- and random-effects models, we calculated pooled estimates of relative risk for exposure to ETS from subjects' parents (during childhood), spouses, and coworkers. As well, we investigated whether the pooled estimates of relative risk varied by study location, degree of control of potential confounding variables, proportion of cases confirmed histologically, proportion of surrogate respondents, nonresponse rates, and year of publication. The relative risk of lung cancer among non smoking women ever exposed to ETS from their husbands' smoking was 1.20 (95% confidence interval (CI): 1.12-1.29). The pooled relative risk was 1.19 (95% CI: 1.10-1.29) for case-control studies and 1.29 (95% CI: 1.04-1.62) for cohort studies. In various subgroup and meta-regression analyses, we found no statistically significant differences by selected characteristics of the studies. In addition, we found that the risk of lung cancer increased consistently with increasing levels of exposure. The 11 studies reporting relative risks among male non smokers yielded a pooled relative risk of 1.48 (95% CI: 1.13-1.92) for ever exposed to ETS, and the relative risk of lung cancer for ever being exposed to ETS at work was a 1.16 (95% CI: 1.05-1.28). These results are consistent with the hypothesis that exposure to ETS increases the risk of lung cancer. While there may be alternative explanations to the data, it is more likely that the observed association is not an artifact and that ETS causes lung cancer in non smokers.

Association between vitamin A status and lung function level in children aged 6--9 years in Wukro wereda, Northern Ethiopia.

BACKGROUND: In developing countries, studies using morbidity recalls to evaluate the benefits of vitamin A on respiratory health in children under 6 years of age have been inconclusive. This relationship has not been examined in older children. Spirometric measurements, an objective means of assessing respiratory health, require the subject's collaboration and have been successfully used in children over 6 years of age. This report describes a cross-sectional analysis of the relationship between lung function and vitamin A status in an area endemic to vitamin A deficiency. METHODS: The data on which this report is based were gathered prior to the implementation of a prospective trial of the effect of vitamin A supplementation on lung function level in Northern Ethiopia. Vitamin A status was assessed by the Modified Relative Dose Response (MRDR) method and lung function assessed by spirometry in 702 rural children aged 6--9 years. Demographic, personal health, household, environmental and socioeconomic data were gathered by questionnaire. RESULTS: In children with low vitamin A reserve, the unadjusted forced expiratory volume in one second (FEV(1)) was 48.8 ml (P = 0.006) lower than in those with adequate reserve. This difference was 23.1 ml (P = 0.04) when adjusted for age, gender and height and 14.1 ml (P = 0.20) when adjusted for children's demographic, general health, lung function and household-related characteristics. CONCLUSION: Although these findings suggest that vitamin A plays a relatively minor role in determining FEV(1) level, interpretation is limited by the cross-sectional design. Further clarification of its role requires a trial of vitamin A supplementation.

Three-dimensional computer-assisted analysis of sector biopsy of the prostate.

OBJECTIVES: To assess the relationship between tumor volume, gland volume, number of sectors submitted to biopsy, and prostatic biopsy detection rate. METHODS: Using a three-dimensional mathematical model of the prostate, we assessed detection rates achieved with 4-, 6-, 8-, 10-, and 12-sector biopsies for glands ranging from 20 to 100 cc and peripheral zone tumors ranging from 0.3 to 1.4 cc. RESULTS: Quadrant and sextant biopsy approaches only yielded from 6.2% to 13.4% and 8.6% to 18.3%, respectively, of lesions in a 40-cc gland. Conversely, 10- and 12-sector approaches yielded, respectively, from 19.8% to 48.8% and 25.4% to 62% of lesions for the same gland size. When assessed according to the density of sampling, one biopsy core used for every 1 .5 to 3.5 cc of prostatic tissue detected 42.5% of 0.5-cc lesions. For the same lesion size, the density of sampling per biopsy core was then decreased to intervals extending from 3.6 to 7.5 cc, 7.6 to 12.5 cc, and 12.6 to 25 cc. These sampling density intervals yielded, respectively, 25.0%, 15.8%, and 9.8% detection rates. CONCLUSIONS: On the basis of our results, a gland volume-based biopsy algorithm is likely to result in improved detection of clinically significant prostate cancer.