L C Clark

Roswell Park Cancer Institute, Buffalo, New York, United States

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Publications (47)241.57 Total impact

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    ABSTRACT: The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 microg/d (n = 47), or 800 microg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 microg/d and 800 microg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 microg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations.
    Cancer Prevention Research 08/2010; 3(8):1035-43. · 4.89 Impact Factor
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    ABSTRACT: Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.
    Nutrition and Cancer 03/2008; 60(2):155-63. · 2.47 Impact Factor
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    ABSTRACT: Surveillance of large geographic areas for “clusters” of adverse health events, particularly cancers, has interested statisticians and epidemiologists. Recent statistical research involves so-called “focused” clustering of disease, i.e. aggregation of incident cases of disease in the vicinity of prespecified, putative foci of increased risk. We introduce a statistical test of focused clustering with optimal, or near-optimal power properties. This test, and two other recent tests of focused clustering are illustrated and compared using leukemia incidence data for 1978–1982 in a region of upstate New York, with inactive hazardous waste sites containing trichloroethylene acting as the suspected foci. Once potential problem areas are identified, more localized methods may be applied.
    Environmetrics 11/2006; 3(3):281 - 300. · 1.49 Impact Factor
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    ABSTRACT: Despite the documented antioxidant and chemopreventive properties of selenium, studies of selenium intake and supplementation and cardiovascular disease have yielded inconsistent findings. The authors examined the effect of selenium supplementation (200 microg daily) on cardiovascular disease incidence and mortality through the entire blinded phase of the Nutritional Prevention of Cancer Trial (1983-1996) among participants who were free of cardiovascular disease at baseline (randomized to selenium: n = 504; randomized to placebo: n = 500). Selenium supplementation was not significantly associated with any of the cardiovascular disease endpoints during 7.6 years of follow-up (all cardiovascular disease: hazard ratio (HR) = 1.03, 95% confidence interval (CI): 0.78, 1.37; myocardial infarction: HR = 0.94, 95% CI: 0.61, 1.44; stroke: HR = 1.02, 95% CI: 0.63, 1.65; all cardiovascular disease mortality: HR = 1.22, 95% CI: 0.76, 1.95). The lack of significant association with cardiovascular disease endpoints was also confirmed when analyses were further stratified by tertiles of baseline plasma selenium concentrations. These findings indicate no overall effect of selenium supplementation on the primary prevention of cardiovascular disease in this population.
    American Journal of Epidemiology 05/2006; 163(8):694-9. · 4.98 Impact Factor
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    ABSTRACT: Concerns about the toxicity of selenium has limited the doses used in chemoprevention. Based on previous studies, intakes of 400 microg/day and plasma selenium of 1000 ng/ml (Dietary Reference Intakes, Academy Press, New York, 2000, p. 384) were established as the no observed adverse effect level (NOAEL). This investigation summarizes the plasma response and toxicity reports from 24 men with biopsy-proven prostate cancer who were randomized to either 1600 or 3200 microg/day of selenized yeast as part of a controlled clinical trial testing selenium as a chemopreventive agent for prostate cancer progression. Subjects were on these doses for averages of almost 12 months. Plasma selenium levels were monitored throughout the course of follow-up. Symptoms of selenium toxicity were assessed by patient interview with specific questions regarding breath, hair and nail changes. Several liver and kidney function tests and hematology were measured at 6-month intervals. 8 subjects were randomized to the 1600 microg/day and 16 to the 3200 microg/day group. The mean plasma selenium levels achieved with supplementation were 492.2 ng/ml (SD = 188.3) and 639.7 ng/ml (SD = 490.7) for the 1600 and 3200 microg/ day doses, respectively. The 3200 microg/day group reported more selenium-related side effects. Blood chemistry and hematology results were all within normal limits for both treatment groups. More subjects on 3200 microg/day reported symptoms of selenium toxicity; however, these reports did not correspond to peaks in plasma selenium levels. We observed no obvious selenium-related serious toxicities. As selenium is used in more chemoprevention and therapeutic settings, additional information on selenium species, sequestration of selenium in specific organs, excretion, and toxicities is needed.
    Journal of Trace Elements in Medicine and Biology 02/2004; 18(1):69-74. · 2.49 Impact Factor
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    ABSTRACT: The Nutritional Prevention of Cancer Trial was a double-blind, randomized, placebo-controlled clinical trial designed to test whether selenium as selenized yeast (200 microg daily) could prevent nonmelanoma skin cancer among 1312 patients from the Eastern United States who had previously had this disease. Results from September 15, 1983, through December 31, 1993, showed no association between treatment and the incidence of basal and squamous cell carcinomas of the skin. This report summarizes the entire blinded treatment period, which ended on January 31, 1996. The association between treatment and time to first nonmelanoma skin cancer diagnosis and between treatment and time to multiple skin tumors overall and within subgroups, defined by baseline characteristics, was evaluated. Although results through the entire blinded period continued to show that selenium supplementation was not statistically significantly associated with the risk of basal cell carcinoma (hazard ratio [HR] = 1.09, 95% confidence interval [CI] = 0.94 to 1.26), selenium supplementation was associated with statistically significantly elevated risk of squamous cell carcinoma (HR = 1.25, 95% CI = 1.03 to 1.51) and of total nonmelanoma skin cancer (HR = 1.17, 95% CI = 1.02 to 1.34). Results from the Nutritional Prevention of Cancer Trial conducted among individuals at high risk of nonmelanoma skin cancer continue to demonstrate that selenium supplementation is ineffective at preventing basal cell carcinoma and that it increases the risk of squamous cell carcinoma and total nonmelanoma skin cancer.
    CancerSpectrum Knowledge Environment 11/2003; 95(19):1477-81. · 14.07 Impact Factor
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    ABSTRACT: To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 micro g daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA. Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models. SS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29-0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of <or= 4 ng/mL (0.35, 0.13-0.87), although the interaction of baseline PSA and treatment was not statistically significant. Participants with baseline plasma selenium concentrations only in the lowest two tertiles (< 123.2 ng/mL) had significant reductions in prostate cancer incidence. A significant interaction between baseline plasma selenium and treatment was detected. To the end of the blinded treatment the NPC trial continued to show a significant protective effect of SS on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline PSA and plasma selenium concentrations.
    BJU International 06/2003; 91(7):608-12. · 3.13 Impact Factor
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    ABSTRACT: OBJECTIVE To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 µg daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA.MATERIALS AND METHODS Original secondary analyses of the NPC to 1993 showed striking inverse associations between SS and prostate cancer incidence. A subsequent report revealed that this effect was accentuated among men with the lowest baseline plasma selenium concentrations. The effects of treatment overall and within subgroups of baseline prostate-specific antigen (PSA) and plasma selenium concentrations were examined using incidence rate ratios and Cox proportional hazards models.RESULTSSS continued to significantly reduce the overall incidence (relative risk and 95% confidence interval) of prostate cancer (0.51, 0.29–0.87). The protective effect of SS appeared to be confined to those with a baseline PSA level of ≤ 4 ng/mL (0.35, 0.13–0.87), although the interaction of baseline PSA and treatment was not statistically significant. Participants with baseline plasma selenium concentrations only in the lowest two tertiles (< 123.2 ng/mL) had significant reductions in prostate cancer incidence. A significant interaction between baseline plasma selenium and treatment was detected.CONCLUSION To the end of the blinded treatment the NPC trial continued to show a significant protective effect of SS on the overall incidence of prostate cancer, although the effect was restricted to those with lower baseline PSA and plasma selenium concentrations.
    BJU International 04/2003; 91(7):608 - 612. · 3.13 Impact Factor
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    ABSTRACT: Interest in the chemopreventive effects of the trace element selenium has spanned the past three decades. Of >100 studies that have investigated the effects of selenium in carcinogen-exposed animals, two-thirds have observed a reduction in tumor incidence and/or preneoplastic endpoints (G. F. Combs and S. B. Combs, The Role of Selenium in Nutrition Chapter 10, pp. 413-462. San Diego, CA: Academic Press, 1986, and B. H. Patterson and O. A. Levander, Cancer Epidemiol. Biomark. Prev., 6: 63-69, 1997). The Nutritional Prevention of Cancer Trial, a randomized clinical trial reported by Clark et al. (L. C. Clark et al., JAMA, 276: 1957-1963, 1996), showed as a secondary end point, a statistically significant decrease in lung cancer incidence with selenium supplementation. The adjusted hazard ratio (HR) was 0.56 [95% confidence interval (CI), 0.31-1.01; P = 0.05]. These results were based on active follow-up of 1312 participants. This reanalysis used an extended Nutritional Prevention of Cancer Trial participant follow-up through the end of the blinded clinical trial on February 1, 1996. The additional 3 years added 8 cases to the selenium-treated group and 4 cases to the placebo group, and increased follow-up to 7.9 years. The relative risk of 0.70 (95% CI, 0.40-1.21; P = 0.18) is not statistically significant. Whereas the overall adjusted HR is not significant (HR = 0.74; 95% CI, 0.44-1.24; P = 0.26), and the HR for current and former smokers was not significant, the trend is toward a reduction in risk of incident lung cancer with selenium supplementation. In a subgroup analysis there was a nominally significant HR among subjects with baseline plasma selenium in the lowest tertile (HR = 0.42; 95% CI, 0.18-0.96; P = 0.04). The analysis for the middle and highest tertiles of baseline showed HRs of 0.91 and 1.25. The current reanalysis indicates that selenium supplementation did not significantly decrease lung cancer incidence in the full population, but a significant decrease among individuals with low baseline selenium concentrations was observed.
    Cancer Epidemiology Biomarkers & Prevention 11/2002; 11(11):1285-91. · 4.32 Impact Factor
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    ABSTRACT: The Nutritional Prevention of Cancer Trial was a randomized, clinical trial designed to evaluate the efficacy of selenium as selenized yeast (200 microg daily) in preventing the recurrence of nonmelanoma skin cancer among 1312 residents of the Eastern United States. Original secondary analyses through December 31, 1993 showed striking inverse associations between treatment and the incidence of total [hazard ratio (HR) = 0.61, 95% confidence interval (CI) = 0.46-0.82], lung, prostate, and colorectal cancer and total cancer mortality. This report presents results through February 1, 1996, the end of blinded treatment. Effect modification by baseline characteristics is also evaluated. The effects of treatment overall and within subgroups of baseline age, gender, smoking status, and plasma selenium were examined using incidence rate ratios and Cox proportional hazards models. Selenium supplementation reduced total (HR = 0.75, 95% CI = 0.58-0.97) and prostate (HR = 0.48, 95% CI = 0.28-0.80) cancer incidence but was not significantly associated with lung (HR = 0.74, 95% CI = 0.44-1.24) and colorectal (HR = 0.46, 95% CI = 0.21-1.02) cancer incidence. The effects of treatment on other site-specific cancers are also described. The protective effect of selenium was confined to males (HR = 0.67, 95% CI = 0.50-0.89) and was most pronounced in former smokers. Participants with baseline plasma selenium concentrations in the lowest two tertiles (<121.6 ng/ml) experienced reductions in total cancer incidence, whereas those in the highest tertile showed an elevated incidence (HR = 1.20, 95% CI = 0.77-1.86). The Nutritional Prevention of Cancer trial continues to show a protective effect of selenium on cancer incidence, although not all site-specific cancers exhibited a reduction in incidence. This treatment effect was restricted to males and to those with lower baseline plasma selenium concentrations.
    Cancer Epidemiology Biomarkers & Prevention 07/2002; 11(7):630-9. · 4.32 Impact Factor
  • G F Combs, L C Clark, B W Turnbull
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    ABSTRACT: The nutritional functions of selenium (Se) are recognized as being due to a number of Se-containing proteins. It is not clear, however, whether any of these function in the anti-tumorigenic effects of Se most of which have been demonstrated for Se exposures greater than those required for selenoprotein expression. Indeed, other anti-tumorigenic mechanisms have been demonstrated for certain Se-metabolites. The Nutritional Prevention of Cancer Trial found supplemental Se (200 microg/day, as Se-enriched yeast) to be associated with significant reductions in cancer risks in subjects with pre-treatment plasma Se concentrations below ca. 120 ng/ml (1.5 nmoles/ml), which level would appear to require food-Se intakes of ca. 1.5 microg/kg body weight/day. However, the putative anti-carcinogenic Se-metabolite(s) should be more relevant than total plasma Se as a supplementation target for cancer prevention. These may be components of the non-protein-bound fraction of Se in plasma, which constitutes 2-4% of total plasma Se.
    BioFactors 02/2001; 14(1-4):153-9. · 3.00 Impact Factor
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    ABSTRACT: We evaluated the effects of dietary selenomethionine supplementation on colonic polyamine levels and the ability of L-selenomethionine supplementation to modulate the carcinogenic activity of azoxymethane (AOM) in the rat colon. Four-week-old male F344 rats were treated with 15 mg/kg body weight of AOM once a week for 2 weeks. Dietary selenomethionine at a concentration of either 1 or 2 ppm was administered in AIN-76A rodent diet to AOM-treated animals for 16 weeks. Aberrant crypt foci (ACF), precursor lesions of colon cancer, were investigated after the 16 week treatment course. Selenomethionine given in the diet at 2 ppm markedly reduced the number of aberrant crypt foci. The multiplicity of ACFs (i.e. the number of aberrant crypts/focus) and the percentage of microadenomas were also affected by selenomethionine in a dose dependent manner. However, evaluation of the colonic tissue polyamine levels between control and treated groups showed no significant difference. These results demonstrate that selenomethionine can modulate the development of AOM-induced premalignant lesions through a polyamine-independent mechanism.
    Cancer Letters 12/2000; 160(2):193-8. · 5.02 Impact Factor
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    ABSTRACT: This paper considers a latent class model to uncover subpopulation structure for both biomarker trajectories and the probability of disease outcome in highly unbalanced longitudinal data. A specific pattern of trajectories can be viewed as a latent class in a finite mixture where membership in latent classes is modelled with a polychotomous logistic regression. The biomarker trajectories within a latent class are described by a linear mixed model with possibly time-dependent covariates and the probabilities of disease outcome are estimated via a class specific model. Thus the method characterizes biomarker trajectory patterns to unveil the relationship between trajectories and outcomes of disease. The coefficients for the model are estimated via a generalized EM (GEM) algorithm, a natural tool to use when latent classes and random coefficients are present. Standard errors of the coefficients are calculated using a parametric bootstrap. The model fitting procedure is illustrated with data from the Nutritional Prevention of Cancer trials; we use prostate specific antigen (PSA) as the biomarker for prostate cancer and the goal is to examine trajectories of PSA serial readings in individual subjects in connection with incidence of prostate cancer.
    Statistics in Medicine 06/2000; 19(10):1303-18. · 2.04 Impact Factor
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    ABSTRACT: Bowman Birk inhibitor (BBI) is an anticarcinogenic serine protease inhibitor that may inhibit the protease activity of prostate-specific antigen (PSA) and the growth of human prostate cancer xenografts in nude mice. Human prostate cancer xenografts were established by implanting LNCaP cells into the prostate glands of NCRNU-M athymic nude mice. The animals with established tumors were maintained on a control diet or diets supplemented with 1% BBI or 1%, 2%, or 3% BBI concentrate (BBIC) for 6 weeks. The serum PSA concentrations were determined before and after the BBI or BBIC treatment period. The final tumor loads were determined at autopsy. Treatment with BBI or BBIC decreased the final tumor load and increased the tumor doubling time and PSA density in the nude mice bearing human prostate cancer xenografts. BBI and/or BBIC could be useful for prostate cancer treatment.
    The Prostate 01/2000; 41(4):243-52. · 3.57 Impact Factor
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    ABSTRACT: Statistical methodology is presented for the analysis of multiple events with random effects and measurement error. We model multiple events in a general space using a random measure, and define point process regression models with residual random effects. Our approach to parameter estimation and significance testing is to start with a simple naive model of Poisson process regression, and then to adjust for random effects and any possible covariate measurement error. We illustrate the techniques with data from a randomized clinical trial for the prevention of recurrent skin tumors. 1 Introduction Consider the statistical analysis of a follow-up (or reliability) study in which individual subjects (or units) may experience a series of recurrent events over time. Subjects are heterogeneous and covariates are available from each subject. The event times for each subject can be viewed as a realization of a stochastic point process. To analyze such data, a variety of parametric point...
    06/1999;
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    Bruce W. Turnbull, Larry C Clark
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    ABSTRACT: this paper, we consider a modification of the proportional hazards failure time regression model, also used by Liang et al. (1990), which includes a threshold lag effect for some of the covariates. The likelihood ratio test is proposed for testing the hypothesis that the changepoint is equal to some specified value. Asymptotic properties of the test statistic are derived. Examples and an application are given. For simplicity of exposition, we start with the two-sample problem where there is a single binary covariate, assigned treatment say. The more general case is described in Section 5. Proofs appear in the Appendix
    06/1999;
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    ABSTRACT: This paper presents a computer program for use in the design of long-term clinical trials with multiple treatment arms in which the primary outcome variables are censored survival times. The treatment arms may be structured as a one-way or multi-way factorial design. It is assumed that patients are entered and randomized to a treatment arm during an accrual period. The patients are then followed for a fixed period during which there may be dropouts. Various distributional assumptions can be used to model the survival times. These include an option in which there is an effect of treatment only after a lag or delay time. The program then computes the power of various statistical tests of hypotheses concerning treatment differences, interactions and trends. The power computations are "exact" in that they use the Monte Carlo method to obtain Type I and II error probabilities. However the program also outputs the normal approximations for comparison, although they are typically not accurate in these situations. Fisher's LSD method is used to adjust for the multiple comparisons. By comparing the power for various sets of design parameters, such as sample size, numbers of factor levels, patient accrual rate, and length of followup, an appropriate design can be constructed. Two examples are provided. The first is a simple one-way layout with multiple treatment arms; the second a two-way factorial design for a proposed large scale cancer chemoprevention trial.
    06/1999;
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    ABSTRACT: Prostate cancer is the second leading cause of cancer deaths in men, therefore it is increasingly important to understand its biology and epidemiology. New approaches for the primary and secondary prevention of prostate cancer are needed, including innovative uses of chemoprevention. This review provides an overview of the epidemiological data suggesting that higher intakes of selenium may reduce the risk of prostate cancer. In addition, a discussion of preclinical data is presented. Special emphasis is placed on the following areas: (1) chemical forms of selenium and antitumorigenic activity, (2) in vitro effects of selenite versus monomethylated selenium, and (3) current clinical intervention trials with selenium in prostate cancer. Chemoprevention, especially with dietary forms of selenium, is a promising new approach that presently is undergoing intensive investigation.
    Seminars in Urologic Oncology 06/1999; 17(2):91-6.
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    ABSTRACT: Statistical methodology is presented for the regression analysis of multiple events in the presence of random effects and measurement error. Omitted covariates are modeled as random effects. Our approach to parameter estimation and significance testing is to start with a naive model of semi-parametric Poisson process regression, and then to adjust for random effects and any possible covariate measurement error. We illustrate the techniques with data from a randomized clinical trial for the prevention of recurrent skin tumors. KEY WORDS: Consistency; Cox model; Estimating equations; Frailty; Measurement error; Omitted covariates; Point process; Poisson regression; Proportional intensities; Robust estimator; Selenium; Skin cancer; Specification analysis; Unobserved heterogeneity; Validation data. 1.
    Journal of the American Statistical Association 03/1999; · 2.11 Impact Factor
  • The Journal of Urology 01/1999; 162(5). · 3.75 Impact Factor

Publication Stats

3k Citations
241.57 Total Impact Points

Institutions

  • 2002–2008
    • Roswell Park Cancer Institute
      • Department of Epidemiology
      Buffalo, New York, United States
  • 1994–2006
    • The University of Arizona
      • • Department of Family and Community Medicine
      • • Department of Pathology
      • • College of Medicine
      Tucson, AZ, United States
  • 2003
    • Memorial Sloan-Kettering Cancer Center
      • Epidemiology & Biostatistics Group
      New York City, NY, United States
  • 2002–2003
    • Arizona Research Center
      Phoenix, Arizona, United States
  • 1985–2001
    • Cornell University
      • • Department of Nutritional Sciences
      • • Department of Statistical Science
      • • Operations Research and Information Engineering
      Ithaca, NY, United States
  • 1991
    • National Institutes of Health
      Maryland, United States
    • Birzeit University
      • Department of Mathematics
      Al Bīrah, WE, Palestinian Territory