Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Association between known risk factors and colorectal cancer risk in Indigenous people participating in the Ontario Familial Colon Cancer Registry.

Introduction: Colorectal cancer is one of the most common cancers in Ontario and imposes a high burden on many Indigenous populations. There are two aims for this short communication: ■ Highlight colorectal risk factor findings from a population-based case-control study■ Highlight trends and challenges of colorectal cancer research in Indigenous populations in Ontario. Methods: Prevalences of cigarette smoking, obesity, fruit and vegetable consumption, and family history of colorectal cancer were estimated using the Indigenous identifier in the Ontario Familial Colon Cancer Registry for 1999-2007 and then compared for cases and controls using age-adjusted odds ratios (ors) with 95% confidence intervals (cis). Results: The registry search identified 66 Indigenous cases and 23 Indigenous controls. Cigarette smoking (or: 1.88; 95% ci: 0.63 to 5.60) and obesity (or: 2.16; 95% ci: 0.72 to 6.46) were higher in cases, but not statistically significantly so. Conclusions: Findings were consistent with previous literature describing Indigenous populations. A small sample size and poor Indigenous identification questions make it challenging to comprehensively understand cancer risk factors and burden in Indigenous populations.

Rotating night shift work and menopausal age.

STUDY QUESTION: How are rotating night shift schedules associated with age at menopause among a large, national cohort of shift working nurses? SUMMARY ANSWER: Our findings suggest that working rotating night shifts with sufficient frequency may modestly accelerate reproductive senescence among women who may already be predisposed to earlier menopause. WHAT IS KNOWN ALREADY: Younger age at menopause has been associated with increased risk of adverse health outcomes, particularly those linked to reproduction. Night work has been associated with reproductive dysfunction, including disruption of menstrual cycle patterns. STUDY DESIGN, SIZE, DURATION: This cohort study was conducted among 80 840 women of the Nurses' Health Study 2 (NHS2), with prospective follow-up from 1991 through 2013. Loss-to-follow-up of the NHS2 is estimated to be <10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed the association between cumulative and current rotating night shift work and age at natural menopause over 22 years of follow-up (1991-2013). Cox proportional hazards models were used to estimate hazard ratios (HR) for menopause, adjusted for age, smoking status, body mass index, physical activity, alcohol consumption, reproductive factors and exogenous hormone use. MAIN RESULTS AND THE ROLE OF CHANCE: Over follow-up, 27 456 women (34%) reached natural menopause. Women who worked 20 or more months of rotating night shifts in the prior 2-year had an increased risk of earlier menopause (multivariable-adjusted (MV)-HR = 1.09, 95% CI: 1.02-1.16) compared to women without rotating night shift work. This risk was stronger among women undergoing menopause or otherwise censored under age 45 years (MV-HR = 1.25, 95% CI: 1.08-1.46), than it was for those continuing in the study when >45 years old (MV-HR = 1.05, 95% CI: 0.99-1.13). Working 10 or more years of cumulative rotating night work was also associated with higher risk of menopause among women reaching menopause under age 45 (MV-HR10-19 years = 1.22, 95% CI: 1.03-1.44; MV-HR≥20 years = 1.73, 95% CI: 0.90-3.35), though not over the age of 45 years (MV-HR10-19 years = 1.04, 95% CI: 0.99-1.10; MV-HR≥20 years = 1.01, 95% CI: 0.89-1.15). LIMITATIONS, REASONS FOR CAUTION: The degree to which observed effects of rotating night shifts on age at natural menopause are due to circadian disruption, rather than fatigue and stress associated with working more demanding schedules, is uncertain due to potential residual confounding by these factors. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of night work on menopausal timing among a larger national cohort of shift working women. Women already prone to earlier menopause may further truncate their reproductive lifetime by working schedules comprising day as well as night shifts. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by Center for Disease Control and Prevention/The National Institute for Occupational Safety and Health Grant 5R01OH009803 (PI: Schernhammer E), as well as UM1 CA176726 from the National Institute of Health. The funding sources had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the article; and decision to submit the article for publication. The authors have no conflicts of interest.

Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Peptic ulcer and its treatments have been associated to pancreatic cancer risk, although the evidence is inconsistent. METHODS: We pooled 10 case-control studies within the Pancreatic Cancer Case-control Consortium (PanC4), including 4717 pancreatic cancer cases and 9374 controls, and estimated summary odds ratios (OR) using multivariable logistic regression models. RESULTS: The OR for pancreatic cancer was 1.10 [95% confidence interval (CI) 0.98-1.23] for history of ulcer (OR = 1.08 for gastric and 0.97 for duodenal ulcer). The association was stronger for a diagnosis within 2 years before cancer diagnosis (OR = 2.43 for peptic, 1.75 for gastric, and 1.98 for duodenal ulcer). The OR was 1.53 (95% CI 1.15-2.03) for history of gastrectomy; however, the excess risk was limited to a gastrectomy within 2 years before cancer diagnosis (OR = 6.18, 95% CI 1.82-20.96), while no significant increased risk was observed for longer time since gastrectomy. No associations were observed for pharmacological treatments for ulcer, such as antacids, H2-receptor antagonists, or proton-pump inhibitors. CONCLUSIONS: This uniquely large collaborative study does not support the hypothesis that peptic ulcer and its treatment materially affect pancreatic cancer risk. The increased risk for short-term history of ulcer and gastrectomy suggests that any such association is due to increased cancer surveillance.

Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).

BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Attitudes toward HPV testing: interview findings from a random sample of women in Ontario, Canada.

As most women diagnosed with cervical carcinoma have been "inadequately screened," improvements in screening are critical. After abnormal Pap test findings (through liquid-based cytology), residual specimens now can be tested simultaneously for oncogenic types of Human Papilloma virus (HPV). If these "reflex" HPV tests are negative, Pap tests need not be repeated for 12 months. Women with positive oncogenic HPV tests, however, can be referred immediately for colposcopy. There has been concern that "stigma" issues could be associated with positive HPV status (because of its sexual transmission) that might cause women to avoid this reflex HPV testing. We addressed this concern by assessing whether stigma issues surface in relation to HPV testing. We randomly selected 20 women and administered to them semistructured telephone interviews that included responses to a scenario of reflex HPV-DNA testing. Interview transcripts were analyzed qualitatively. Highly limited knowledge levels were found about HPV, but, following education about screening options, there was no rejection of HPV testing. In conclusion, it appears that women favor reflex HPV testing due to its "convenience" and perceptions that it is "the least intrusive option more definitive than Pap testing."

Human breast cancer and lymphomas may share a common aetiology involving Mouse Mammary Tumour Virus (MMTV).

Mouse Mammary Tumour Virus (MMTV) causes breast tumours in mice, and has been implicated in the aetiology of murine lymphomas. Several recent human studies have detected MMTV-env DNA sequences in 30-40% of tumours from breast cancer patients but in less than 4% of normal breast tissue. MMTV DNA has been detected in simultaneously diagnosed primary lymphoma and breast cancer tissue, suggesting MMTV may be involved in the aetiology of both breast cancer and lymphoma. We further hypothesize that if lymphoma and breast cancer are both associated with a common aetiologic virus then women with prior lymphoma may have an increased risk of breast cancer and vice versa. Despite the significant increase in the incidence of both lymphoma and breast cancer over the last few decades, their aetiologies are not well understood. Intriguing evidence to date suggests that the aetiology of a subgroup of human breast cancers and lymphomas may have viral involvement, and this warrants further investigation.

Nonsteroidal anti-inflammatory drug use and breast cancer risk.

Findings from previous epidemiological studies are inconclusive, though they suggest nonsteroidal anti-inflammatory drug (NSAID) use is associated with a reduction in breast cancer risk. In addition, animal studies report that NSAIDs inhibit mammary tumor development. The association between NSAID use and breast cancer risk was evaluated using a case-control study design. Cases were a random sample of women diagnosed with a first primary cancer of the breast, aged 25-74 years, identified through the Ontario Cancer Registry, and diagnosed between July 1996 and September 1998. Controls were an age-matched random sample of the female population of Ontario. Cases (n = 3133) and controls (n = 3062) completed a mailed questionnaire with information on their past use of NSAID and other medications, as well as many risk factors thought to be associated with breast cancer. Multivariate logistic regression analysis was used to obtain adjusted odds ratio (OR) estimates. Use of any NSAID medication (daily use for > or =2 months) was found to be associated with a significant 24% reduction in breast cancer risk (OR = 0.76; 95% confidence interval: 0.66, 0.88). The reduced risk was strongest for use lasting > 8 years, compared with nonusers (OR = 0.68; 95% confidence interval: 0.54, 0.86). No marked trends were observed for time since first use or last use or age at first use. Our results suggest a reduction in breast cancer risk associated with any regular NSAID use. NSAID use is a modifiable factor, and any protective effect attributed to its use could be of great public health importance.

A qualitative study of subject recruitment for familial cancer research.

PURPOSE: Familial epidemiological studies of cancer raise familiar ethical issues relating to informed consent and recruitment of participants. When the family is the unit of study, however, additional complexity arises. Educating and recruiting participants must be tailored to the relatives', as well as the proband's needs. An understanding of the prospective participants' concerns will aid the development of strategies for recruitment and will facilitate informed and voluntary consent. In the present study, qualitative methods were used to investigate these issues. METHODS: Focus groups with cancer patients, relatives of cancer patients, and individuals from the general population were separately conducted to identify issues that concern people who are asked to participate in family studies. RESULTS: Many of the issues which arose in the course of the focus group discussions were similar to those in any study. Yet, some of the themes emerging from the discussions were specific to familial research. In particular, participants expressed that the study should be endorsed by a trusted and familiar source; group discussions might facilitate the consent process; the benefit of the research should be clear and personal, as well as benefit the participants' family members; risks of participation should be explicit (e.g., insurance discrimination); and education about the disease and its familial nature would maintain commitment to the study. Finally, participants expressed concerns about being approached by programs to facilitate the identification and recruitment of other family members for research on family health issues. CONCLUSIONS: Findings from this study will aid future familial studies in developing a protocol that both adequately informs potential participants of the nature of familial research and maximize participation.

Ontario familial colon cancer registry: methods and first-year response rates.

The Ontario Familial Colon Cancer Registry (OFCCR) is a novel registry that collects family history information, epidemiologic data, blood samples and tumour specimens from a population-based sample of colorectal cancer patients and their families. Families are classified as either high familial risk, intermediate familial/other risk or low (sporadic) risk for colorectal cancer. Obtaining high response rates in genetic family studies is especially challenging because of both the time commitment required and issues of confidentiality. The first-year response rate was 61%, resulting in 1,395 participating probands. In an attempt to assess potential response bias, we compared participants with non-participants. The age and sex of participants did not differ from non-participating probands; however, cases in rural areas were somewhat more likely to participate. To date, 57% of 1,587 relatives participated; females were more likely to participate, and relatives of low familial risk were least likely to participate. The OFCCR is an excellent resource that will facilitate the study of genetic and environmental factors associated with colorectal cancer.

Antidepressant medication use and breast cancer risk.

Experimental and epidemiologic studies suggest that antidepressant medication use may be associated with breast cancer risk. This hypothesis was investigated using a population-based case-control study; cases diagnosed in 1995-1996 were identified using the Ontario Cancer Registry, and controls were randomly sampled from an Ontario Ministry of Finance database. Data were collected using a self-administered questionnaire, and multivariate logistic regression was used to estimate odds ratios and 95% confidence intervals. Adjusted odds ratio estimates ranged from 0.7 to 0.8 and were not statistically significant for "ever" use of antidepressants, tricyclics, and selective serotonin reuptake inhibitors. Compared with no antidepressant use, use of tricyclic antidepressants for greater than 2 years' duration was associated with an elevated risk of breast cancer (odds ratio (OR) = 2.1, 95% confidence interval (CI): 0.9, 5.0). Of the six most commonly reported antidepressant medications, only paroxetine use was associated with an increase in breast cancer risk (OR = 7.2, 95% CI: 0.9, 58.3). Results from this study do not support the hypothesis that "ever" use of any antidepressant medications is associated with breast cancer risk. Use of tricyclic medications for greater than 2 years, however, may be associated with a twofold elevation, and use of paroxetine may be associated with a substantial increase in breast cancer risk.

The risk of breast cancer following reproductive surgery.

Alteration of exposure to ovarian hormones, by eliminating or impairing the function of one or both ovaries, may affect the risk of breast cancer. To assess the relationship between reproductive surgical procedures and breast cancer risk, we conducted a retrospective cohort study involving 524,709 Ontario women who underwent tubal ligation or other salpingectomy, hysterectomy and/or ovariectomy between 1979 and 1993. Data on type and year of surgery were obtained from hospital records and linked with breast cancer diagnoses recorded in the Ontario Cancer Registry. Observed breast cancers were compared with age- and calendar-period expected rates in Ontario. A decreased risk of breast cancer was observed among women who had undergone either hysterectomy (observed/expected [O/E] = 0.87, P < 0.001) or unilateral ovariectomy (O/E = 0.74, P < 0.001). Bilateral ovariectomy and tubal ligation were associated with reduced risk when the surgery occurred before the age of 45 years, and tubal ligation was protective if performed after the age of 54 years. There was no trend in risk with increasing follow-up. Our data support the hypothesis that reduced levels of endogenous oestrogen may be protective for breast cancer in women.

Comparison of self-reported and physician-reported antidepressant medication use.

PURPOSE: Self-reported medication histories obtained in pharmacoepidemiologic case-control studies are subject to non-differential misclassification and to recall bias. The accuracy of self-reported antidepressant medication use has never been evaluated, but it is important in light of the hypothesis that antidepressant medications may be associated with cancer risk. METHODS: Within a case-control study of several cancer sites, we compared self-reported antidepressant medication use with antidepressant use recorded in physicians' records. All female cases (n = 147) and controls (n = 119) who reported antidepressant medication use, and a 10% random sample (n = 114) of those who reported no antidepressant use, were asked to provide consent to contact, and the name(s) of their physician(s). These physicians completed a data abstraction form including information on antidepressant prescriptions recorded in patients' medical records. RESULTS: Substantial agreement was found between subject- and physician-reported antidepressant medication use (kappa = 0.60 [95% confidence interval (CI), 0.47-0.74]; agreement = 80%), and use of specific antidepressant medications (agreement ranged from 82 to 100%), while moderate agreement was observed for duration of use (weighted kappa = 0.56 (95% CI, 0.32-0.79)), and date of first use [weighted kappa = 0.48 (95% CI, 0.23-0.72)]. The level of agreement did not differ markedly between cases and controls, except for duration of use, where agreement was somewhat greater for cases. CONCLUSIONS: The similar level of agreement among cases and controls suggests that differential misclassification (e.g., recall bias) is unlikely in the reporting of most aspects of antidepressant medication use by women. Furthermore, the overall accurate self-reporting of antidepressant use suggests that there should be minimal non-differential antidepressant exposure misclassification.

Effect of a manager training program on sanitary conditions in restaurants.

OBJECTIVE: To evaluate the effectiveness of a food manager training and certification program in increasing compliance with restaurant sanitary codes. METHODS: Using routine sanitary inspection records, the authors compared pre- and post-training inspection scores for 94 restaurants falling into three groups: a "mandatory" group (managers' attendance was mandated for these restaurants); a "voluntary" group (managers attended the training voluntarily); and a control group (no staff attended the training program). RESULTS: Restaurants for which managers were mandated to attend a training and certification program demonstrated a significant improvement in inspection scores, an improvement that was sustained over a two-year follow-up period. The mean inspection scores for a control group did not change significantly over time. However, improvements were not noted in all areas of food safety. CONCLUSIONS: Food manager training and certification programs may be an effective way to improve the sanitary conditions of restaurants and reduce the spread of foodborne illnesses.