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Colin B Begg

Publications and source records attributed to Colin B Begg.

At least 37 records · Page 2Linked to original sources
PubMed2004

A method for evaluating the impact of individual haplotypes on disease incidence in molecular epidemiology studies.

Estimation of the association between haplotypes and disease from a case-control study is considered. Assuming a single "disease haplotype'' leads to the increased risk, attention focusses on the relative risks associated with a single copy, or two copies of the disease haplotype, relative to individuals with no copies. In this setting, case frequencies of the haplotype pairs are in Hardy-Weinberg Equilibrium (HWE) only if the combined influence of the two copies of the disease haplotype on risk is multiplicative. Thus, imputation cannot rely on the assumption of HWE for cases. A method is presented for obtaining estimates of the relative risks, making use of the EM algorithm and the assumption of HWE only for controls. The method accounts for the additional variation in the estimates due to the imputation of expected frequencies of haplotype pairs from ambiguous genotypes. A simulation study shows that the resulting confidence intervals have nominal coverage, and that the methods based on the assumption of HWE for both cases and controls can lead to bias.

Journal Article↗
PubMed2004

Familial aggregation of melanoma risks in a large population-based sample of melanoma cases.

OBJECTIVE: Melanoma has been shown in numerous studies to be associated with sun exposure, and with host phenotypic factors of genetic origin. In this study we use information from a large series of incident cases of melanoma from an international population-based study to examine the patterns of incidence of melanoma in the first-degree relatives of these cases. METHODS: A total of 2508 incident cases of melanoma provided information on basic demographic data and pigmentary characteristics, in addition to detailed information on family history of melanoma. These data were used to examine the incidence rates ratios of melanoma in the relatives of cases in relation to population rates, and also with respect to phenotypic characteristics of the probands that have been shown to be associated with melanoma: mole counts, hair color, eye color, and skin sensitivity to the sun. RESULTS: The incidence rates reflect the underlying patterns of incidence in the source populations, with generally higher rates in the Australian sample, low rates in Italy, and intermediate rates in the USA and Canada. Also, rates are higher in men than in women, except at very young ages. Phenotypic characteristics of the probands were only weakly associated with the observed rates in the relatives although there is a strong inverse association with age at diagnosis. Cumulative risk of melanoma rises to 6.9% (6.1%) at age 80 in male (female) first-degree relatives of cases, and to 10.8% (9.5%) in relatives of cases diagnosed before age 50. CONCLUSIONS: Relatives of cases diagnosed with melanoma are at considerable lifetime risk of the disease, especially if the case is diagnosed at a young age.

Adult↗
PubMed2004

Two-stage designs for gene-disease association studies with sample size constraints.

Gene-disease association studies based on case-control designs may often be used to identify candidate polymorphisms (markers) conferring disease risk. If a large number of markers are studied, genotyping all markers on all samples is inefficient in resource utilization. Here, we propose an alternative two-stage method to identify disease-susceptibility markers. In the first stage all markers are evaluated on a fraction of the available subjects. The most promising markers are then evaluated on the remaining individuals in Stage 2. This approach can be cost effective since markers unlikely to be associated with the disease can be eliminated in the first stage. Using simulations we show that, when the markers are independent and when they are correlated, the two-stage approach provides a substantial reduction in the total number of marker evaluations for a minimal loss of power. The power of the two-stage approach is evaluated when a single marker is associated with the disease, and in the presence of multiple disease-susceptibility markers. As a general guideline, the simulations over a wide range of parametric configurations indicate that evaluating all the markers on 50% of the individuals in Stage 1 and evaluating the most promising 10% of the markers on the remaining individuals in Stage 2 provides near-optimal power while resulting in a 45% decrease in the total number of marker evaluations.

Biometry↗
PubMed2004

Benchmarking lung cancer mortality rates in current and former smokers.

STUDY OBJECTIVES: To develop and validate a model for estimating the risk of lung cancer death in current and former smokers. The model is intended for use in analyzing a population of subjects who are undergoing lung cancer screening or receiving lung cancer chemoprevention, to determine whether the intervention has altered lung cancer mortality. DESIGN/SETTING/PATIENTS: Model derivation was based on analyses of the placebo arm of the Carotene and Retinol Efficacy Trial. Model validation was based on analyses of three other longitudinal cohorts. MEASUREMENTS: Observed and predicted number of deaths due to lung cancer. RESULTS: In internal validation, the model was highly concordant and well calibrated. In external validation, the model predictions were similar to what was observed in all of the validation analyses. The predicted and observed deaths within 6 years were very similar when assessed in the Johns Hopkins Hospital trial of chest radiography and sputum cytology screening (176 predicted, 184 observed, p = 0.53), the Memorial Sloan-Kettering Cancer Center trial of chest radiography and sputum cytology screening (108 predicted, 114 observed, p = 0.57), and the National Health and Nutrition Evaluation Survey part I (24 predicted, 21 observed, p = 0.52). CONCLUSIONS: The number of lung cancer deaths in a population of current or former smokers can be accurately predicted, making model-based evaluations of prevention and early detection interventions a useful adjunct to definitive randomized trials. We illustrate this potential use with a small example.

Adult↗
PubMed2003

The effect of clustering of outcomes on the association of procedure volume and surgical outcomes.

BACKGROUND: A large body of literature documents associations between the volume of cases a hospital or surgeon treats and clinical outcomes. Most of these studies have used conventional statistical methods that do not recognize the fact that hospitals or surgeons with similar volumes may have very different outcomes because of systematic differences in processes of care, a phenomenon that exaggerates the true statistical significance of the effect of volume on outcome. OBJECTIVE: To describe methods to assess the degree of this "clustering" of outcomes and to explore the impact of available statistical techniques that correct for clustering. DESIGN: Reanalysis of 3 previously published volume-outcome studies. SETTING: Medicare beneficiaries 65 years of age or older undergoing surgery for colon, prostate, or rectal cancer in the population defined by the Surveillance, Epidemiology, and End Results cancer registries during 1992 to 1996. PATIENTS: 3 data sets were analyzed to assess the impact of surgeon volume on outcomes: 1) 24 166 colectomies performed by 2682 surgeons, 2) 10 737 prostatectomies performed by 999 surgeons, and 3) 2603 rectal resections performed by 1141 surgeons. MEASUREMENTS: Volume-outcome trends were analyzed by a conventional method (logistic regression) and corrected for clustering. Two widely used statistical methods for analyzing clustered data, a random-effects model and generalized estimating equations, were used and compared, and the degree of clustering was presented graphically. RESULTS: Substantial clustering was observed in the analyses involving morbidity end points. The 2 statistical techniques produced noticeably different results in some analyses. CONCLUSIONS: The presence of clustering represents variations in outcomes among providers with similar volumes. Thus, in volume-outcome studies, the degree of clustering of outcomes should be characterized because it may provide insight into variations in quality of care.

Clinical Competence↗
PubMed2003

Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations.

CONTEXT: Serum prostate-specific antigen (PSA) testing is frequently used in early detection programs for prostate cancer. While PSA testing has resulted in an increase in prostate cancer detection, its routine use has been questioned because of a lack of specificity. OBJECTIVE: To determine whether year-to-year fluctuations in PSA levels are due to natural variation and render a single PSA test result unreliable. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of an unscreened population of 972 men (median age, 62 years) participating in the Polyp Prevention Trial (1991-1998). Five consecutive blood samples were obtained during a 4-year period and were assessed for total and free PSA levels. MAIN OUTCOME MEASURE: Abnormal PSA test result based on a PSA level higher than 4 ng/mL; a PSA level higher than 2.5 ng/mL; a PSA level above the age-specific cutoff; a PSA level in the range of 4 to 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; or a PSA velocity higher than 0.75 ng/mL per year. RESULTS: Prostate biopsy would have been recommended in 207 participants (21%) with a PSA level higher than 4 ng/mL; in 358 (37%) with a level higher than 2.5 ng/mL; in 172 (18%) with a level above the age-specific cutoff; in 190 (20%) with a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL; and in 145 (15%) with a velocity higher than 0.75 ng/mL per year. Among men with an abnormal PSA finding, a high proportion had a normal PSA finding at 1 or more subsequent visits during 4-year follow-up: 68 (44%) of 154 participants with a PSA level higher than 4 ng/mL; 116 (40%) of 291 had a level higher than 2.5 ng/mL; 64 (55%) of 117 had an elevated level above the age-specific cutoff; and 76 (53%) of 143 had a level between 4 and 10 ng/mL and a free-to-total ratio of less than 0.25 ng/mL. CONCLUSION: An isolated elevation in PSA level should be confirmed several weeks later before proceeding with further testing, including prostate biopsy.

Adult↗
PubMed2003

Adherence to surveillance among patients with superficial bladder cancer.

BACKGROUND: Patients diagnosed with superficial bladder cancer who have not undergone total cystectomy are at high risk for recurrence, and bladder surveillance with cystoscopy is recommended for such patients every 3-6 months. We examined the degree to which bladder cancer patients undergo the recommended surveillance procedures and identified patient and primary care provider characteristics associated with nonadherence to these recommendations. METHODS: We used information obtained from the Surveillance, Epidemiology, and End Results (SEER) Program-Medicare-linked database to identify 6717 patients aged 65 years or older who were diagnosed with superficial bladder cancer from 1992 through 1996 and who survived for at least 3 years after diagnosis but did not have a total cystectomy. We used information obtained from Medicare claims forms to examine the frequency with which these patients had a surveillance examination of the bladder during each of five contiguous 6-month intervals from month 7 to month 36 following diagnosis. We examined characteristics of patients and their physicians that were associated with low-intensity surveillance (defined as having an examination during fewer than two of the five possible follow-up intervals). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Only 40% of the entire cohort had an examination during all five intervals; 1216 patients (18.1%) had low-intensity surveillance. Patient characteristics that were independently associated with low-intensity surveillance were being age 75 years or older (adjusted OR = 1.54, 95% CI = 1.35 to 1.74), nonwhite (adjusted OR = 1.94, 95% CI = 1.57 to 2.40), and having favorable tumor histology (adjusted OR = 0.59, 95% CI = 0.48 to 0.72 for poorly differentiated versus referent well-differentiated tumor grade) and high comorbidity (adjusted OR = 1.72, 95% CI = 1.30 to 2.27). Residence in an urban area or in a census tract with low median income was also associated with low-intensity surveillance. CONCLUSIONS: The actual practice of surveillance for patients with superficial bladder cancer differs substantially from the standards recommended in clinical guidelines.

Aged↗
PubMed2003

Variations in lung cancer risk among smokers.

BACKGROUND: Although there is no proven benefit associated with screening for lung cancer, screening programs are attracting many individuals who perceive themselves to be at high risk due to smoking. We sought to determine whether the risk of lung cancer varies predictably among smokers. METHODS: We used data on 18 172 subjects enrolled in the Carotene and Retinol Efficacy Trial (CARET)-a large, randomized trial of lung cancer prevention-to derive a lung cancer risk prediction model. Model inputs included the subject's age, sex, asbestos exposure history, and smoking history. We assessed the model's calibration by comparing predicted and observed rates of lung cancer across risk deciles and validated it by assessing the extent to which a model estimated on data from five CARET study sites could predict events in the sixth study site. We then applied the model to evaluate the risk of lung cancer among smokers enrolled in a study of lung cancer screening with computed tomography (CT). RESULTS: The model was internally valid and well calibrated. Ten-year lung cancer risk varied greatly among participants in the CT study, from 15% for a 68-year-old man who has smoked two packs per day for 50 years and continues to smoke, to 0.8% for a 51-year-old woman who smoked one pack per day for 28 years before quitting 9 years earlier. Even among the subset of CT study participants who would be eligible for a clinical trial of cancer prevention, risk varied greatly. CONCLUSIONS: The risk of lung cancer varies widely among smokers. Accurate risk prediction may help individuals who are contemplating voluntary screening to balance the potential benefits and risks. Risk prediction may also be useful for researchers designing clinical trials of lung cancer prevention.

Aged↗
PubMed2003

Kin-cohort evaluation of relative risks of genetic variants.

The kin-cohort study, an embedded retrospective cohort of first-degree relatives of probands, has been used frequently in conjunction with case-control studies to evaluate penetrance of high-risk genotypes. However, in principle, the kin-cohort approach can be used in conjunction with a case-control study in which family history data are carefully recorded to examine and validate the observed association of any candidate genotype with disease. Its utility for this purpose is governed by the relative efficiency of the kin-cohort analysis to test hypotheses about the relevant genotype-disease odds ratios, which in turn depends strongly on various factors, notably the magnitude of the disease incidence rate and the prevalence of the aberrant genotype. In this study, we compare the efficiencies of the two analytic approaches, case-control vs. kin-cohort, and illustrate the results in the context of cancer epidemiology. The kin-cohort analysis can provide substantial, important supplementary information for relatively common cancers such as breast, lung, colorectal, and prostate, and is also relatively efficient in general for the evaluation of the stronger and more rare genetic risk factors. Genet Epidemiol 24:220-229, 2003.

Case-Control Studies↗
PubMed2003

Surgeon volume compared to hospital volume as a predictor of outcome following primary colon cancer resection.

BACKGROUND AND OBJECTIVES: A strong association between high hospital procedure volume and survival following colon cancer resection has been demonstrated. However, the importance of surgeon case volume as a determinant of outcome has been less well studied, and it is unclear whether hospital or surgeon volume is the more powerful predictor of outcomes. METHODS: A retrospective population-based cohort study utilizing the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database identified 24,166 colon cancer patients aged 65 years and older who had surgery for a primary tumor diagnosed in 1991-1996 in a SEER area. Hospital and surgeon-specific procedure volume was ascertained based on the number of claims submitted over the 6-year study period. Outcome measures were mortality at 30 days and 2 years, overall survival, and the frequency of operations requiring an intestinal stoma. Age, sex, race, comorbid illness, cancer stage, socioeconomic status, emergent hospitalization, and the presence of obstruction/perforation were used to adjust for differences in case-mix. RESULTS: After adjusting for surgeon procedure volume, high hospital procedure volume remained a strong predictor of low post-operative mortality rates (P < 0.001 for each outcome with and without adjustment for surgeon procedure volume). Surgeon-specific procedure volume was also an important predictor of surgical outcomes (P = 0.002 for 30-day mortality, P = 0.001 for 2-year mortality), although this effect was attenuated after adjusting for hospital volume (P = 0.03 for 30-day mortality, P = 0.02 for 2-year mortality). Hospital volume and surgeon volume were each an important predictor of the ostomy rate. Among high volume institutions and surgeons, individual providers with unusually high ostomy rates could be identified. CONCLUSIONS: Both hospital and surgeon-specific procedure volume predict outcomes following colon cancer resection; but hospital volume may exert a stronger effect. Therefore, efforts to optimize the quality of colon cancer surgery should focus on multidisciplinary aspects of hospital care rather than solely on intraoperative technique.

Aged↗
PubMed2003

Variations among individual surgeons in the rate of positive surgical margins in radical prostatectomy specimens.

PURPOSE: Cancer at the resection margin (a positive surgical margin) after radical prostatectomy is associated with an increased risk of recurrence even after adjusting for other known risk factors, including pretreatment serum prostate specific antigen (PSA), clinical stage, grade and pathological stage (level of extracapsular extension, seminal vesicle invasion and pelvic lymph node status). Of these prognostic factors only surgical margin status can be influenced by surgical technique. We examined variations in the rate of positive surgical margins among surgeons after controlling for the severity of disease and volume of cases per surgeon. MATERIALS AND METHODS: A total of 4,629 men were treated with radical prostatectomy by 1 of 44 surgeons at 2 large urban centers between 1983 and 2002 for clinical stage T1-T3NxM0 prostate cancer. Patients were excluded if they had previously received androgen deprivation therapy or radiation therapy to the pelvis. Positive surgical margins were defined as cancer at the inked resection margin. Other risk factors analyzed were serum PSA, grade (Gleason sum), extracapsular extension level (none, invasion into the capsule, present [not otherwise specified], focal extracapsular extension or established extracapsular extension), seminal vesicle invasion, pelvic lymph node metastases, surgery date, surgeon and volume of cases per surgeon. RESULTS: For the 26 surgeons who each treated more than 10 patients in the study the rate of positive surgical margins was 10% to 48%. On multivariable analysis higher serum PSA, extracapsular extension level, higher radical prostatectomy Gleason sum, surgery date, surgical volume and surgeon were associated with surgical margin status after controlling for all other clinical and pathological variables. CONCLUSIONS: While the clinical and pathological features of cancer are associated with the risk of a positive margin in radical prostatectomy specimens, the technique used by individual surgeons is also a factor. Lower rates of positive surgical margins for high volume surgeons suggest that experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin rates and improve cancer control with radical prostatectomy.

Clinical Competence↗
PubMed2002

Adjuvant chemotherapy use for Medicare beneficiaries with stage II colon cancer.

PURPOSE: Clinical trials have not demonstrated that adjuvant chemotherapy improves survival for patients with resected stage II colon cancer. Nevertheless, patients may receive this treatment despite its uncertain benefit. The objective of this study was to determine the extent to which adjuvant chemotherapy is used for patients with stage II colon cancer. PATIENTS AND METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 3,151 patients aged 65 to 75 with resected stage II colon cancer and no adverse prognostic features. The primary outcome was chemotherapy use within 3 months of surgery ascertained from claims submitted to Medicare. Relationships between patient characteristics and adjuvant chemotherapy use were measured and their significance was assessed using multivariable logistic regression. Survival for treated and untreated patients was compared using a Cox model. RESULTS: Twenty-seven percent of patients received chemotherapy during the 3 postoperative months. Younger age at diagnosis, white race, unfavorable tumor grade, and low comorbidity were each associated with a greater likelihood of receiving treatment. Sex, the number of examined lymph nodes in the tumor specimen, the urgency of the surgical admission, and median income was each unrelated to treatment. Five-year survival was 75% for untreated patients and 78% for treated patients. After adjusting for known between-group differences, the hazard ratio for survival associated with adjuvant treatment was 0.91 (95% confidence interval, 0.77 to 1.09). CONCLUSION: A substantial percentage of Medicare beneficiaries with resected stage II colon cancer receive adjuvant chemotherapy despite its uncertain benefit.

Aged↗
PubMed2002

Lack of effect of a low-fat, high-fruit, -vegetable, and -fiber diet on serum prostate-specific antigen of men without prostate cancer: results from a randomized trial.

PURPOSE: To determine whether a diet low in fat and high in fruits, vegetables, and fiber may be protective against prostate cancer by having an impact on serial levels of serum prostate-specific antigen (PSA). METHODS: Six hundred eighty-nine men were randomized to the intervention arm and 661 to the control arm. The intervention group received intensive counseling to consume a diet low in fat and high in fiber, fruits, and vegetables. The control group received a standard brochure on a healthy diet. PSA in serum was measured at baseline and annually thereafter for 4 years, and newly diagnosed prostate cancers were recorded. RESULTS: The individual PSA slope for each participant was calculated, and the distributions of slopes were compared between the two groups. There was no significant difference in distributions of the slopes (P =.99). The two groups were identical in the proportions of participants with elevated PSA at each time point. There was no difference in the PSA slopes between the two groups (P =.34) and in the frequencies of elevated PSA values for those with elevated PSA at baseline. Incidence of prostate cancer during the 4 years was similar in the two groups (19 and 22 in the control and intervention arms, respectively). CONCLUSION: Dietary intervention over a 4-year period with reduced fat and increased consumption of fruits, vegetables, and fiber has no impact on serum PSA levels in men. The study also offers no evidence that this dietary intervention over a 4-year period affects the incidence of prostate cancer during the 4 years.

Diet, Fat-Restricted↗
PubMed2002

On the use of familial aggregation in population-based case probands for calculating penetrance.

BACKGROUND: Estimating the lifetime risk associated with (i.e., the penetrance of) genetic abnormalities that predispose individuals to cancer is important for genetic counseling. (Penetrance may be estimated from the degree of familial aggregation of cancer, that is, the extent to which cancers cluster in families.) Early penetrance studies of BRCA1 and BRCA2 mutations used high-risk families with multiple cases of breast cancer, a study design that led to very high penetrance estimates. However, such studies were subject to potential ascertainment biases. To offset such biases, recent studies have used data from family members of probands ascertained from population-based incident cases of cancer. The use of case probands is, however, also subject to bias because all risk factors are over-represented in case patients. To draw attention to this problem, literature on the penetrance of breast cancer in BRCA1 and BRCA2 carriers is reviewed. METHODS: A theory is presented to show that the use of case probands is itself biased, leading to inflated penetrance estimates. The strategy is unbiased only if all carriers share an identical risk. Any unexplained heterogeneity of risk caused by unknown genetic or shared environmental factors within families leads to an inflated estimate of penetrance. RESULTS: Eight published studies using population-based methods are reviewed. All but one of the family-based studies used case probands. CONCLUSIONS: Penetrance estimates from case proband studies must be inflated if other factors influence breast cancer risk in addition to the specific genetic abnormality. Thus, women with such genetic abnormalities and a strong family history of breast cancer are likely to possess a much higher risk for breast cancer than women with such abnormalities but without a strong family history. Methodologic techniques to improve the prediction of cancer risk are needed.

Bias↗