Derivation and Validation of a Scoring System to Stratify Risk for Advanced Colorectal Neoplasia in Asymptomatic Adults

Context Many doctors and patients in the United States choose colonoscopy when screening for colorectal cancer, but there are not enough resources to provide colonoscopy for everyone. Contribution The authors developed a method that divides people with average risk for colorectal cancer into groups that have very low, low, intermediate, or high risk. Caution The method applies only to first-time screening. Implication Persons at lower risk might be screened using methods other than colonoscopy. In the United States, colorectal cancer is a significant cause of morbidity and mortality among men and women, accounting for nearly 140000 new cases and 55000 deaths per year (1). The natural history of colorectal neoplasia, which usually involves a slow progression from precancerous polyp to cancer, lends itself to screening. Screening for colorectal cancer with any of several tests and strategies has been found to be effective (2, 3) and cost-effective (47) and is supported by guidelines from several organizations (810). Foremost among them is the U.S. Preventive Services Task Force (10), which recommends any of several screening tests and strategies with no preference for any single strategy based on direct evidence and quantitative modeling (11, 12). Despite the favorable biology, test options, and evidence to support screening, it is underused, costly, and inefficient. Nearly 22 million U.S. residents aged 50 to 75 years have never been screened, and just 60% to 65% have had lower endoscopy of any kind for any reason within the past 10 years (13). Although screening is cost-effective, it is estimated to cost billions of dollars per year (14, 15). In addition to its high total cost, screening is conducted inefficiently; low-risk persons may receive colonoscopy with low yield and little benefit, and high-risk persons may receive noninvasive testing with missed opportunity for benefit. Tailoring of colorectal cancer screening based on risk could improve the overall uptake and efficiency of screening. Among average-risk persons not current with screening, knowledge of their personal risk for colorectal cancer or advanced neoplasia might affect how they choose to be screened. For lower-risk persons within the average-risk group, screening could be done with stool-based occult blood tests or sigmoidoscopy (or both), which are less invasive, less risky, and less costly than colonoscopy. For higher-risk persons, initial colonoscopy might be the preferred test. Several risk prediction models for either colorectal cancer (1618) or advanced neoplasia (1924) (colorectal cancer plus advanced, precancerous polyps) may not be clinically useful for several reasons. Models predicting risk for advanced neoplasia either show limited performance in risk stratification (that is, "high risk" and "low risk" are not far from average risk) or are based on populations with unclear generalizability to the U.S. population. Further, all models are limited in their degree of validation. In this study, we developed and validated a risk stratification tool for advanced neoplasia anywhere in the colon and rectum using the most commonly identified risk factors for colorectal cancer and advanced adenomas. We included advanced adenomas because they are believed to be immediate precursor lesions to most colorectal cancer (25), even though their natural history is unknown. Methods This study was conducted at the Indiana University Medical Center in Indianapolis, Indiana, and was approved by the Institutional Review Board of Indiana University at Indianapolis. We report methods and results in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) and TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) guidelines (26, 27). Between December 2004 and September 2011, we enrolled consecutive eligible and consenting persons aged 50 to 80 years who were scheduled to have their first screening colonoscopy. We initially recruited patients from endoscopy units participating in either of 2 company-based colorectal cancer prevention programs, one of which was based in central Indiana and the other in northeastern Ohio. Because of low uptake in these programs, we expanded recruitment to include general endoscopy practices and units within central Indiana, including those affiliated with Indiana University Medical Center. At all sites and throughout the study, we excluded persons with inflammatory bowel disease, those with a high-risk family history (polyposis or nonpolyposis colorectal cancer syndrome), and those reporting a history of polyps that required follow-up colonoscopy. Before having colonoscopy, enrolled participants were asked to complete a comprehensive survey that asked about candidate risk factors, including family history; sociodemographic factors; and lifestyle factors, including previous and current cigarette smoking. Participants were also asked to measure and record current height, weight, and waist and hip circumference; a tape measure was provided for the circumferential measurements. On the day of their screening colonoscopy, participants' physical measures were collected by medical personnel just before the procedure. In analysis, physical measures recorded by medical personnel were used unless they were unavailable, in which case self-reported measures were used. All surveys were reviewed for completeness by trained study personnel, who contacted participants by telephone for clarification or completion of survey items. Colonoscopy and pathology reports were reviewed and coded by trained personnel who were blinded to survey information. The most advanced findings in the colorectum were coded for both proximal (which includes the splenic flexure) and distal segments. Colonoscopies with no pathology report were assumed to show no neoplasia, provided that the colonoscopy report did not specify that a tissue specimen had been obtained (biopsy or polypectomy). After review, completion, and coding, all data were scanned into a deidentified database with unique identifier numbers. Statistical Analysis Study sample size was based on both prevalence of advanced neoplasia from a previous study of screening colonoscopy among average-risk persons (28) and a goal of ensuring an adequate number of persons with advanced neoplasia for derivation and split-sample validation. In analysis, a stratified random sample comprising two thirds of the original sample was obtained using PROC SURVEYSELECT in SAS, version 9.3 (SAS Institute). Strata were created using the following variables: advanced neoplasia, sex, family history of cancer, and body mass index (BMI). Participants in this data set were used as the derivation set, and the other one third of participants were used as a validation set. The data set was divided in this way to ensure a random but equal distribution of sex and most advanced findings. The goal of the analysis was to determine model performance using 5 factors that are most commonly associated with colorectal neoplasia in the published literature: age, sex, cigarette smoking, body fat, and a family history of colorectal cancer. For cigarette smoking, which was measured in pack-years, we considered different cutoffs to categorize exposure. For measures of body fat, we considered BMI, waist circumference, and waist-to-hip ratio. Categories for measures of body fat were determined a priori based on published literature that related each physical factor to risk for either colorectal cancer or advanced adenoma (2931). For family history of colorectal cancer, we considered first-degree relatives only and both first- and second-degree relatives, and we considered ages for both categories. For family history, cigarette smoking, and measures of body fat, we used age- and sex-adjusted logistic regression models to quantify the most discriminating variable (in the case of body fat) or to compare different ways of categorizing them, as determined by the Wald test and odds ratio for the variable itself and the omnibus likelihood ratio test for the model (32) (Appendix Table 1). The outcome (dependent) variable was advanced neoplasia, which included adenocarcinoma of the colon or rectum, a tubular adenoma or sessile serrated adenoma or polyp with a greatest dimension of at least 1 cm, or an adenomatous polyp with villous histology or high-grade dysplasia. Appendix Table 1. Comparison of Alternative Measures of Body Fat and Different Definitions for Cigarette Exposure and Family History of CRC* We used statistical metrics and clinical judgment to choose the optimal format for cigarette smoking, family history of colorectal cancer, and body fat measurement. We then included them in a model along with age and sex and determined performance of the full model in the derivation set by measuring calibration with the HosmerLemeshow test and discrimination with the c-statistic (32). The log-odds coefficients from each variable were subsequently incorporated into a points system, an approach described by Sullivan and colleagues (33). Coefficients were translated into risk categories for advanced neoplasia, with 0 points representing the lowest-risk group for each variable. Points were rounded to the nearest integer and were scaled such that a single point was equivalent to the increase in risk for advanced neoplasia associated with a 5-year increase in age (Appendix Table 2). On the basis of previous work (34), we planned to create risk categories by collapsing scores with clinically similar risk estimates. We used a chi-square test for trend for risk for (or prevalence of) advanced neoplasia across categories, and we tested performance of the model and the risk score classification table by using the same cutoffs and categories on the validation set, which contained the remaining one third of the study participants. SAS, version 9.3, was used for all analyses. For each r