Population-based Risk Estimates Research Articles

Human papillomavirus-associated subsequent malignant neoplasms among childhood cancer survivors

ObjectiveEmerging evidence suggests a higher risk of human papillomavirus-associated subsequent malignant neoplasms (HPV-SMNs) in childhood cancer survivors. However, comprehensive population-based risk estimates for HPV-SMNs are lacking. MethodsWe utilized longitudinal data obtained from the Surveillance, Epidemiology, and End Results program between 1975 and 2018 to establish a cohort comprising childhood cancer individuals who survived for at least 5 years. Standardized incidence ratio (SIR) with corresponding 95 % confidence interval (95 %CI) was used to evaluate the relative risk of HPV-SMNs. The competing risk regression model was performed to identify risk factors associated with HPV-SMNs. ResultsA total of 35,397 childhood cancer survivors were included. Among them, 42 individuals subsequently developed HPV-SMNs (median time from primary cancer, 25 years). HPV-SMN anatomic sites included cervix (N=16), oropharynx (N=15), anus (N=5), vulva\\vagina (N=5), and penis (N=1). The 40-year cumulative incidence rate of HPV-SMNs was estimated to be 0.51 %. All survivors had a 10-fold increased risk of developing HPV-SMNs compared to individuals of similar age in the general population (SIR 10.1, 95 %CI 7.3–13.6). The competing risk regression model indicted that age at diagnosis and the type of primary malignancy could potentially influence the development of HPV-SMNs. Furthermore, multivariable Cox regression analysis confirmed that the presence of HPV-SMNs significantly increased the risk of mortality for survivors (hazard ratio 2.63, 95 %CI 1.68–4.14). ConclusionsChildhood cancer survivors have a significantly elevated risk of developing HPV-SMNs, accompanied by poor survival outcomes. Encouraging HPV vaccination and robust surveillance protocols may improve long-term health outcomes in childhood cancer survivors.

Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants

Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown. To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features. This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023. Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays. Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models. A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015. This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.

Pediatric cancer incidence among individuals with overgrowth syndromes and overgrowth features: A population-based assessment in seven million children.

Overgrowth syndromes (e.g., Beckwith-Wiedemann) are associated with an increased risk of pediatric cancer, although there are few population-based estimates of risk. There are also limited studies describing associations between other overgrowth features (e.g., hepatosplenomegaly) and pediatric cancer. Therefore, cancer risk among children with these conditions was evaluated with data from a large, diverse population-based registry linkage study. This study includes all live births in Texas during the years 1999-2017. Children with overgrowth features and syndromes were identified from the Texas Birth Defects Registry; children with cancer were identified by linkage to the Texas Cancer Registry. Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the association between each overgrowth syndrome/feature and cancer, which were adjusted for infant sex and maternal age. In the total birth cohort (n=6,997,422), 21,207 children were identified as having an overgrowth syndrome or feature. Children with Beckwith-Wiedemann syndrome were 42 times more likely to develop pediatric cancer (95% CI, 24.20-71.83), with hepatoblastoma being the most common, followed by Wilms tumor. The presence of any isolated overgrowth feature was associated with increased cancer risk (HR, 4.70; 95% CI, 3.83-5.77); associations were strongest for hepatosplenomegaly (HR, 23.04; 95% CI, 13.37-39.69) and macroglossia (HR, 11.18; 95% CI, 6.35-19.70). This population-based assessment confirmed prior findings that children with either overgrowth syndromes or features were significantly more likely to develop cancer. Overall, this study supports recommendations for cancer surveillance in children with these conditions and may also inform future research into cancer etiology.

Abstract P2-09-01: Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes

Abstract Introduction: The risk of specific clinical subtype of breast cancer (defined by ER and HER2 status) among women in the general population who are carriers of germline pathogenic variants (PVs) in cancer predisposition genes is not well-defined. Methods: A total of 13,153 women with breast cancer (ER+/HER2-: 9381; ER+/HER2+: 1462; ER-/HER2+: 690; and ER-/HER2-: 1620) and 25,005 unaffected women (controls) from nine studies within the CAnceR RIsk Estimates Related to Susceptibility (CARRIERS) consortium that were not enriched for family history or early onset disease were included in the present analysis. A multiplex amplicon-based panel was used to perform germline sequencing for cancer predisposition genes. Case-control associations for each of the four clinical subtype of breast cancer was performed for PVs in 5 common breast cancer predisposition genes (ATM, BRCA1, BRCA2, CHEK2 and PALB2) utilizing a logistic regression model adjusting for study, age at diagnosis, race/ethnicity and family history of breast cancer. Results: The frequency of PVs in 5 genes was 3.8% for ER+/HER2-, 6.2% for ER+/HER2+, 4.2% for ER-/HER2+ and 9.3% for ER-/HER2- subtypes. PVs in BRCA1 and BRCA2 were associated with high risk (Odds Ratio (OR) >4) for all clinical subtypes of breast cancer, but the risk was highest (OR>8) for ER-/HER2- breast cancer. PVs in PALB2 were associated with high risk (OR>4) of ER-/HER2- and ER+/HER2+ subtypes and moderate risk (OR: 2-4) of ER+/HER2- breast cancer. Irrespective of the HER2 status, PVs in ATM were associated with a moderately increased risk (OR: 2-4) of ER+ breast cancer but the risk of ER- breast cancer was not elevated. In contrast, PVs in CHEK2 were associated with high risk (OR>4) of ER+/HER2+ breast cancer and moderate risk (OR: 2-4) of ER+/HER2- and ER-/HER2+ breast cancer, but the risk of ER-/HER2- breast cancer was not elevated. Conclusions: This study provides population-based estimates of risk of specific clinical subtypes of breast cancer which will be useful for genetic counseling and targeting appropriate screening strategies in PV carriers based on subtype specific risks of breast cancer. Citation Format: Siddhartha Yadav, Chunling Hu, Nicholas J. Boddicker, Eric Polley, Steven Hart, Rohan Gnanaolivu, Jie Na, Hongyan Huang, Song Yao, Celine M. Vachon, Lauren Teras, Jack A. Taylor, Dale P. Sandler, Julie R. Palmer, Janet E. Olson, Susan Neuhausen, Elena Martinez, Sara Lindstroem, Loic Le Marchand, Charles Kooperberg, Christopher Haiman, Mia M. Gaudet, James V. Lacey, Kimberly A. Bertrand, Leslie Bernstein, Paul W. Auer, Christine Ambrosone, Jeffrey N. Weitzel, Peter Kraft, David E. Goldgar, Katherine L. Nathanson, Susan M. Domchek, Fergus J. Couch, CARRIERS Consortium. Population-based risk estimates of clinical subtypes of breast cancer among carriers of germline pathogenic variants in cancer predisposition genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-01.

Risk factors and survival outcomes of metachronous contralateral upper tract urothelial carcinoma

Because population-based risk estimates for metachronous contralateral UTUC are lacking. In this study, we aimed to evaluate the risk and survival of metachronous contralateral upper tract urothelial carcinoma (UTUC) on a large population-based level. A total of 23,075 patients were identified from the Surveillance, Epidemiology, and End Results database (1973–2015), 144 (0.6%) patients developed metachronous contralateral UTUC (median of 32 months after diagnosis). The cumulative incidence at 10, 20, and 30 years of follow-up was 1.1%, 1.6%, and 2.6%, respectively. We applied Fine and Gray’s competing risk regression model to determine the risk factors of a new contralateral, metachronous UTUC. The competing risk regression model demonstrated that older age (hazard ratio [HR] 0.75; 95% CI 0.67–0.85) and larger tumor size (HR 0.61; 95% CI 0.39–0.97) were associated with a significantly decreased risk of metachronous contralateral UTUC. However, bladder cancer presence was an independent risk factor for the development of contralateral tumors (HR 2.42; 95% CI 1.73–3.37). In addition, we demonstrated developing contralateral UTUC was not associated with poor prognosis by using Kaplan–Meier and multivariable analysis. Our findings suggest that metachronous contralateral UTUC is comparatively rare, and has not impact on survival. Importantly, patients with younger age, small tumours, and the presence of bladder cancer were more likely to develop a contralateral tumor, which may provide a rationale for lifelong surveillance in high-risk patients.

Development and Validation of the Chronic Disease Population Risk Tool (CDPoRT) to Predict Incidence of Adult Chronic Disease

Predicting chronic disease incidence for the population provides a comprehensive picture to health policy makers of their jurisdictions' overall future chronic disease burden. However, no population-based risk algorithm exists for estimating the risk of first major chronic disease. To develop and validate the Chronic Disease Population Risk Tool (CDPoRT), a population risk algorithm that predicts the 10-year incidence of the first major chronic disease in the adult population. In this cohort study, CDPoRT was developed and validated with 6 cycles of the Canadian Community Health Survey, linked to administrative data from January 2000 to December 2014. Development and internal validation (bootstrap and split sample) of CDPoRT occurred in Ontario, Canada, from June 2018 to April 2019 followed by external validation in Manitoba from May 2019 to July 2019. The study cohorts included 133 991 adults (≥20 years) representative of the Ontario and Manitoba populations who did not have a history of major chronic disease. Predictors were routinely collected risk factors from the Canadian Community Health Survey, such as sociodemographic factors (eg, age), modifiable lifestyle risk factors (ie, alcohol consumption, cigarette smoking, unhealthy diet, and physical inactivity), and other health-related factors (eg, body mass index). Six major chronic diseases were considered, as follows: congestive heart failure, chronic obstructive pulmonary disease, diabetes, myocardial infarction, lung cancer, and stroke. Sex-specific CDPoRT algorithms were developed with a Weibull model. Model performance was evaluated with measures of overall predictive performance (eg, Brier score), discrimination (eg, Harrell C index), and calibration (eg, calibration curves). The Ontario cohort (n = 118 747) was younger (mean [SD] age, 45.6 [16.1] vs 46.3 [16.4] years), had more immigrants (23 808 [20.0%] vs 1417 [10.7%]), and had a lower mean (SD) body mass index (26.9 [5.1] vs 27.7 [5.4]) than the Manitoba cohort (n = 13 244). During development, the full and parsimonious CDPoRT models had similar Brier scores (women, 0.087; men, 0.091), Harrell C index values (women, 0.779; men, 0.783), and calibration curves. A simple version consisting of cigarette smoking, age, and body mass index performed slightly worse than the other versions (eg, Brier score for women, 0.088; for men, 0.092). Internal validation showed consistent performance across models, and CDPoRT performed well during external validation. For example, the female parsimonious version had C index values for bootstrap, split sample, and external validation of 0.778, 0.776, and 0.752, respectively. In this study, CDPoRT provided accurate, population-based risk estimates for the first major chronic disease.

Abstract PD3-01: Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study

Abstract Germline mutations in several cancer predisposition genes included in hereditary multigene testing panels have been associated with increased breast cancer risk. However, estimates of breast cancer risks for each gene have in large part been derived from studies of high-risk populations enriched for family history of breast and ovarian cancer, young age of breast cancer diagnosis, or founder mutations. The breast cancer risks associated with mutations in many of these genes in the general population remain to be clearly defined. As clinical hereditary cancer genetic testing is already provided to many women at increased risk and may soon be offered to all breast cancer patients, population-based risk estimates associated with predisposition gene mutations will be needed for appropriate clinical management of mutation carriers. The “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) consortium of 17 cohort-based case-control, population-based case-control, and family studies focused on estimation of population-based breast cancer risks and penetrance analysis for mutations in known and candidate breast cancer predisposition genes. Germline DNA from 39486 breast cancer cases and 35868 matched controls was subjected to dual bar-coded QIAseq multiplex amplification of 1733 target regions in 37 predisposition genes. Products from sets of 768 samples were pooled and sequenced in each lane of a HiSeq 4000 system. Mutations were called by GATK Haplotype Caller and Verdict. High quality sequence data was obtained for 99.3% of target regions. Here we report on results from 34741 population-based breast cancer cases and 32728 matched unaffected controls. The mean age of breast cancer diagnosis for cases was 61.2 years and mean age for controls was 61.1 years. Overall, 20.9% of cases and 14.3% of controls had a family history of breast cancer. Furthermore, 74.3% of cases and 75.8% of controls were non-Hispanic white, whereas 13.3% of cases and 15.3% of controls were African American. Among cases with tumor information available, 81.7% were ER-positive and 7.7% were triple negative breast cancers (TNBC). We assessed mutation frequencies in 24 genes including 12 established breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, andTP53). The overall mutation frequency was 6.2% in cases and 2.7% in controls. Case-control association analysis after adjusting for study, age, family history of breast cancer, and race/ethnicity showed that BRCA1(OR=7.45; 95%CI:5.24-10.95) and BRCA2(OR=5.31; 95%CI:4.15-6.88) were associated with high risks of breast cancer in the general population. However, PALB2mutations were only associated with moderate risks (OR=3.63; 95%CI:2.57-5.26). ATMmutations conferred attenuated risks (OR=1.83; 95%CI:1.47-2.28) relative to studies of high-risk families or young onset breast cancers. NBNmutations were not associated with increased breast cancer risk. Mutations in BARD1, RAD51C, RAD51Dand XRCC2were specifically significantly associated with moderate risks of ER-negative breast cancer and TNBC, whereas mutations in ATM, CDH1and CHEK2were specifically significantly associated with ER-positive disease. On the basis of these findings age-related absolute breast cancer risks for commonly mutated genes were estimated. Overall, results from the CARRIERS study establish that mutations in predisposition genes are associated with lower risks of breast cancer in the general population than in enriched populations including high-risk families and young onset, bilateral, or multiple primary cases. We anticipate that the results from this study will inform cancer screening and other risk management strategies for women in the general population with mutations in predisposition genes. Citation Format: Fergus J Couch, Chunling Hu, Steven N Hart, Rohan Gnanaolivu, Kun Y Lee, Jie Na, Chi Gao, Nicholas J Boddicker, Bruce Eckloff, Raed Samara, Josh Klebba, Christine B Ambrosone, Hoda Anton-Culver, Paul Auer, Leslie Bernstein, Mia M Gaudet, Christopher Haiman, Esther M John, Susan Neuhausen, Janet E Olson, Tuya Pal, Julie R Palmer, Dale P Sandler, Jack A Taylor, Amy Trentham-Dietz, Celine M Vachon, Clarice Weinberg, Song Yao, Jeffrey N Weitzel, David E Goldgar, Susan M Domchek, Katherine L Nathanson, Peter Kraft, Eric C Polley. Population-based breast cancer risk estimates for predisposition gene mutations: Results from the CARRIERS study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-01.

Timing of Pregnancy After Kidney Transplantation and Risk of Allograft Failure.

The optimal timing of pregnancy after kidney transplantation remains uncertain. We determined the risk of allograft failure among women who became pregnant within the first 3 posttransplant years. Among 21 814 women aged 15-45 years who received a first kidney-only transplant between 1990 and 2010 captured in the United States Renal Data System, n = 729 pregnancies were identified using Medicare claims. The probability of allograft failure from any cause including death (ACGL) at 1, 3, and 5 years after pregnancy was 9.6%, 25.9%, and 36.6%. In multivariate analyses, pregnancy in the first posttransplant year was associated with an increased risk of ACGL (hazard ratio [HR]: 1.18; 95% confidence interval [CI] 1.00, 1.40) and death censored graft loss (DCGL) (HR:1.25; 95% CI 1.04, 1.50), while pregnancy in the second posttransplant year was associated with an increased risk of DCGL (HR: 1.26; 95% CI 1.06, 1.50). Pregnancy in the third posttransplant year was not associated with an increased risk of ACGL or DCGL. These findings demonstrate a higher incidence of allograft failure after pregnancy than previously reported and that the increased risk of allograft failure extends to pregnancies in the second posttransplant year.

Development of an Individualized Surgical Risk Calculator for Abdominoplasty Procedures

INTRODUCTION: Individual surgical risk calculation is supplanting coarser, population-based risk estimates, helping surgeons better inform patients about risks and expectations of surgery.1,2 No risk calculators have been created for aesthetic surgical procedures like abdominoplasties. To this end, we used the Tracking Operations and Outcomes for Plastic Surgeons (TOPS) database to develop a risk calculator for abdominoplasties to predict the chance of complications. METHODS: Panniculectomies and abdominoplasties with and without liposuction were identified from the 2008-2011 TOPS database. Multiple-procedure cases, duplicate case-IDs, and revisions were excluded. Outlier ages (less than 18 or greater than 100) and BMIs (less than 10 or greater than 100) were also removed. Age, BMI, smoking history, diabetes, American Society of Anesthesiologists’ (ASA) Class, facility type, and admission status were examined as relevant clinical parameters. Seroma, dehiscence, surgical site infection (SSI), reoperation, and overall complications were the outcomes of interest. After extrapolating missing values with 5-iteration multiple imputation, we generated logistic regression models to predict the chance of complications based on the perioperative parameters. Model performance was assessed using p-value, c-statistic, Hosmer-Lemeshow (H-L), and Brier score. RESULTS: 4,597 cases met inclusion criteria. 9.4% suffered at least one surgical complication. Seroma, hematoma, dehiscence, SSI, and reoperation occurred in 3.9%, 1.0%, 3.6%, 1.7%, and 1.2% of cases respectively. Binary logistic regression modeled the risk of each complication, yielding beta values for each clinical parameter (Table 1). Each model performed satisfactorily based on the aforementioned metrics. The average predicted risk was 9.4%, ranging from 0.52% to 74%. The distribution of predicted risk of surgical complication was wide and positively skewed (Figure 1), highlighting the inadequacy of population-based risk estimates and therefore the importance of individualized risk assessment. The models were packaged and published online at AbdominoplastyRisk.org for public, user-friendly use.Table 1: Beta values for each predictive model and associated clinical parameters.Figure 1: Histogram of predicted probability of having any surgical complication, generated from one of five imputed datasets.CONCLUSION: With the advent of large surgical outcomes databases, we can leverage the abundance of data to develop risk calculators that evaluate absolute risk of complications based on individual patient information. Our risk calculator is based on regression models with good performance and can more accurately determine risk than traditional population-based estimates.

Time-to-Subsequent Head Injury From Sports and Recreation Activities

To provide population-based risk estimates for sustaining subsequent head injuries (HIs), which occur in sports and recreation (SR). Population-based, retrospective, cross-sectional study. Retrospective review of data from 2 tertiary care and 3 community care emergency departments (EDs) in Edmonton, Alberta, Canada. Individuals younger than 36 years presenting to an ED with an SR-related injury between April 1, 1997, and March 31, 2008. There were 9246 subsequent ED records identified for 8958 patients in the main analysis. Clinically diagnosed HI occurring in SR activities after an index presentation, and the number of days between ED presentations for diagnosed SR-HIs. Individuals with 1 and 2 previous SR-related HIs were 2.62 [95% confidence interval (CI), 2.23-3.07] and 5.94 times, respectively, more likely (95% CI, 3.43-10.29) to sustain a subsequent HI than those without a previous HI. The median time-to first HI was 758 days from an initial injury and decreased to 613 days and 303 days for those at risk of second and third SR-related HIs (P < 0.0001). Individuals aged 7 to 13 years were 4.29 times more likely (95% CI, 2.65-6.92) to sustain an HI when presenting with a subsequent SR injury, compared with those aged 30 to 35 years. The odds of sustaining a subsequent HI substantially increase with each successive HI. Time between SR-related HIs shortens as the number of HIs increases. Initial HI may be a key marker to institute high-risk injury prevention measures directed at young persons who present to EDs.

Long-term exposure to air pollution and the incidence of asthma: meta-analysis of cohort studies

We quantified the association between long-term exposure to air pollution and the incidence of asthma by conducting a systematic review and meta-analysis of cohort studies. Incidence was defined as the incidence of diagnosed asthma or of new wheeze symptom between two assessments or, in birth cohorts followed up to 10 years of age, a lifetime prevalence estimate of asthma or wheeze symptom. We identified 17 cohorts (eight birth cohorts and nine child/adult cohorts) with a total of 99 population-based risk estimates. The studies were heterogeneous in their design and methods of measurement. Follow-up ranged from 3 to 23 years. Most studies were based on within-community exposure contrasts dominated by traffic pollution. Twelve of the cohorts reported at least one positive statistically significant association between air pollution and a measure of incidence. Of the total of 99 estimates, only a minority (29) were positive and statistically significant. Estimates for meta-analysis were chosen a priori using a protocol. For the 13 studies with estimates for nitrogen dioxide (NO2), the random effects odds ratio was 1.07 (95% CI 1.02 to 1.13) per 10 μg/m3. For five studies with estimates for particulate matter with aerodynamic diameter <2.5 μm (PM2.5), the random effects estimate was 1.16 (95% CI 0.98 to 1.37) per 10 μg/m3. These estimates were reduced in size and statistical significance by adjustment for publication bias but remained positive. The results are consistent with an effect of outdoor air pollution on asthma incidence. Future meta-analyses would benefit from greater standardisation of cohort methods.

Time to Check CHEK2 in Families With Breast Cancer?

Time to Check <i>CHEK2</i> in Families With Breast Cancer?

Interactions among Smoking, Obesity, and Symptoms of Acid Reflux in Barrett's Esophagus

Barrett's esophagus, a metaplastic precursor to esophageal adenocarcinoma, is becoming increasingly prevalent in many populations. Clinical studies suggest acid reflux causes Barrett's esophagus; however, no population-based estimates of risk have been reported, and the role of other health factors in modifying risk is unclear. We conducted a population-based case-control study in Brisbane, Australia. Cases were 167 patients with histologically confirmed Barrett's esophagus diagnosed between February and December 2003. Age-matched and sex-matched controls (n = 261) were randomly selected from a population register. Data on exposure to self-reported symptoms of acid reflux, smoking, obesity, and other factors were collected through self-completed questionnaires followed by telephone interview. Risks of Barrett's esophagus and Barrett's esophagus with dysplasia associated with these exposures were estimated by the odds ratio (OR) and 95% confidence interval (95% CI), both crude and adjusted for other factors. Self-reported weekly episodes of acid reflux were associated with greatly increased risks of Barrett's esophagus (adjusted OR, 29.7; 95% CI, 12.2-72.6) and Barrett's esophagus with dysplasia (OR, 59.7; 95% CI, 18.5-193). Smoking was also associated with risk of Barrett's esophagus. We found evidence of interactions between symptoms of acid reflux and smoking and obesity. Obese people with self-reported symptoms of acid reflux had markedly higher risks of Barrett's esophagus (OR, 34.4; 95% CI, 6.3-188) than people with reflux alone (OR, 9.3; 95% CI, 1.4-62.2) or obesity alone (OR, 0.7; 95% CI, 0.2-2.4). Similarly, those reporting both acid reflux symptoms and smoking were at substantially higher risks of Barrett's esophagus (OR, 51.4; 95% CI, 14.1-188) than those reporting acid reflux or smoking alone. Although history of symptoms of acid reflux is the principle factor associated with Barrett's esophagus, risks are substantially increased by obesity and smoking.

Portrayal of Genetic Risk for Breast Cancer in Ethnic and Non-Ethnic Newspapers

ABSTRACT There has been enormous attention paid to the genetics of breast cancer in this era of genomic medicine. A great deal of the interest has been generated through discourse in the public mass media. However, genetic risk is a probabilistic concept and one that requires adequate numeracy skills. The purpose of this qualitative content analysis, was to describe and evaluate the portrayal of genetic risk for breast cancer in mass print media. Mass print newspapers targeting high (Ashke-nazi Jews) and low (general Canadian population) genetic risk audiences and published at least monthly, available in English and accessible through public archives at the National Library of Canada, were identified and hand searched for articles on breast cancer. Approximately 47% of breast cancer articles in 6 Jewish newspapers and published between 1996–2000 identified genetics in the title, first or last paragraph compared with 17% of 145 articles in 6 provincial newspapers published in 2000. The description of breast cancer risk was equally problematic in print media targeting high- and low-risk audiences. Statistics were presented in complex and contradictory ways, with, for example, the confounding of individual and population based risk estimates. Inconsistent messages about the value of genetic screening for breast cancer characterized articles in both ethnic and non-ethnic newspapers. Deciphering the information into a comprehensible form is likely challenging, particularly in light of widespread numeric-literacy limitations. The publication of discrepant research findings and the perplexing statistical information consequently brought into question the credibility of the scientific process and the recommendations of health care professionals.

Population-based risk estimates of Wilms tumor in sporadic aniridia. A comprehensive mutation screening procedure of PAX6 identifies 80% of mutations in aniridia.

Aniridia is a severe eye disease characterized by iris hypoplasia; both sporadic cases and familial cases with an autosomal dominant inheritance exist. Mutations in the PAX6 gene have been shown to be the genetic cause of the disease. Some of the sporadic cases are caused by large chromosomal deletions, some of which also include the Wilms tumor gene (WAGR syndrome), resulting in an increased risk of developing Wilms tumor. Based on the unique registration of both cancer and aniridia cases in Denmark, we have made the most accurate risk estimate to date for Wilms tumor in sporadic aniridia. We have found that patients with sporadic aniridia have a relative risk of 67 (confidence interval: 8.1-241) of developing Wilms tumor. Among patients investigated for mutations, Wilms tumor developed in only two patients out of 5 with the Wilms tumor gene (WT1) deleted. None of the patients with smaller chromosomal deletions or intragenic mutations were found to develop Wilms tumor. Our observations suggest a smaller risk for Wilms tumor than previous estimates, and that tumor development requires deletion of WT1. We report a strategy for the mutational analysis of aniridia cases resulting in the detection of mutations in 68% of sporadic cases and 89% of familial cases. We also report four novel mutations in PAX6, and furthermore, we have discovered a new alternatively spliced form of PAX6.

Putting risk in perspective: An evidence-based approach to selected risks associated with the use of oral contraception

Although use of oral contraceptives is an effective way to prevent unintended pregnancy, concerns exist about associated adverse health outcomes. The concept of risk and different approaches to describing risk are discussed, and studies of health risks associated with specific exposures are used to illustrate the differences between relative and absolute risk. Evidence about health risks associated with use of oral contraceptives is presented within the context of population-based risk estimates.

Incidence of colorectal cancer following adenomatous polyps of the large intestine.

An association between adenomatous polyps of the large bowel and colorectal cancer has been reported, in the absence, however, of population-based estimates of risk. Subjects with histologically confirmed first diagnosis of large-bowel polyps notified to the population-based Cancer Registry of the Swiss Canton of Vaud (about 600,000 inhabitants) during the calendar period 1979-1990 were actively followed up to the end of 1990 for the subsequent occurrence of malignant neoplasms. Among 2,496 individuals with intestinal polyps, followed for a total of 10,310 person-years at risk (6,201 among males and 4,109 among females), 150 malignant neoplasms were registered versus 152 expected. Thus, the standardized incidence ratio (SIR) for all cancers combined was 0.99. A significant excess was observed for colorectal cancer, with 35 cases observed (19 males, 16 females) versus 17.0 expected (SIR = 2.1; 95% CI: 1.5-3.0). There was also an excess, although not significant, for small-bowel cancer (2 cases observed vs. 0.4 expected; SIR = 5.4). In none of the other cancer sites was SIR significantly or appreciably elevated: in subjects with colorectal polyps the SIR was 1.6 for stomach, 1.0 for lung, 0.9 for breast and 1.2 for prostate. The SIR of colorectal cancer was 3.1 in the first year since polyp registration, and declined thereafter to 1.8, in the absence, however, of any further trend with time since diagnosis. The cumulative risk of colorectal cancer in subjects with colorectal polyps was 2% at 5 years and 3% at 10 years. The quantitative estimates of this study are of interest for their population-based nature, and are potentially useful for defining and targeting screening colonoscopy programmes.

Five Types of Ambiguity: Scientific Uncertainty in Risk Assessment

The application of risk assessment methodologies for developing scientifically based policies for risk reduction is limited by continuing uncertainties. However, too often these uncertainties are abused in the process of risk management by a too-rigid separation between scientific and managerial input into decisionmaking. This separation obscures the scientific origins of uncertainty, or incorrectly exaggerates the variance functions of statistics or confuses the epidemiological bases of individual and population based risk estimates. Decisionmaking which encourages the divorce between science and policy will result in further distortions and abuses of uncertainty.