Elizabeth Liles

Screening for Colorectal Cancer: A Targeted, Updated Systematic Review for the U.S. Preventive Services Task Force

Colorectal cancer ranks third in incidence and second in cause of cancer death for both men and women (1). Most cases of colorectal cancer occur in average-risk individuals (those without a family or predisposing medical history), and increasing age, male sex, and black race are associated with increased incidence (2). Black persons have the highest incidence of and mortality rates from colorectal cancer among all racial and ethnic subgroups (37) and nearly double the colorectal cancerrelated mortality rate compared with other ethnic minorities (8). Colorectal cancer screening has been recommended by the U.S. Preventive Services Task Force (USPSTF) and many other organizations for more than 10 years (9). On the basis of evidence from multiple randomized, controlled trials (RCTs), a screening program with repeated annual or biennial guaiac fecal occult blood tests (FOBTs) and endoscopic follow-up of positive test results reduces colorectal cancer mortality; according to a recent update, colorectal cancer mortality was reduced 16% (CI, 10% to 22%) after 12 to 18 years (10). Extrapolating from trial evidence, clinical studies of test accuracy, and other supporting evidence, the USPSTF recognized flexible sigmoidoscopy (with or without FOBTs), colonoscopy, and double-contrast barium enema as other colorectal cancer screening options in 2002 (11, 12). However, because colorectal cancer screening tests have potential harms, limited accessibility, or imperfect acceptability to patients, and no tests could be identified as superior in cost-effectiveness analysis (13), the USPSTF also recommended that choice among recommended methods for colorectal cancer screening to be individualized to patients or practice settings (14). Despite strong recommendations from the USPSTF and many others, serial national surveys document inadequate, slowly improving rates of colorectal cancer screening in the United States (1520). In 2006, 60.8% of adults 50 years of age or older reported recent colorectal screening (20). Disparities in colorectal cancer screening exist, with lower rates of colorectal cancer screening in nonwhite and Hispanic populations (16, 21, 22) and in areas with higher poverty rates (23). To increase the uptake of and benefits from recommended colorectal cancer screening, researchers have sought to improve the accuracy, acceptability, or accessibility of screening by introducing new tests or enhancing existing tests. However, the availability of additional options for colorectal cancer screeningincluding highly sensitive guaiac FOBT; fecal immunochemical testing; fecal DNA testing; and virtual colonoscopy approaches, such as computed tomographic (CT) colonographyhas created uncertainty about what methods should be used for colorectal cancer screening in the general population. To assist the USPSTF in updating its 2002 recommendation for colorectal cancer screening in average-risk adults age 50 years or older, we conducted a targeted systematic review primarily focused on evidence gaps or new evidence since the previous review. This approach updated what the USPSTF judged was the most important evidence for newer colorectal cancer screening tests and community-performed endoscopies, and it was supplemented by a companion decision analysis examining screening program performance and life-years gained by using different colorectal cancer screening tests, test intervals, and starting and stopping ages (24). Methods Under guidance from the USPSTF, this targeted review addressed only the first 3 questions of the full evidence chain in the analytic framework (Figure 1). From our larger report (25), we report here the accuracy (one-time test performance characteristics) and potential harms of newer colorectal cancer screening tests (high-sensitivity FOBTs, fecal immunochemical tests, fecal DNA testing, and CT colonography) in screening populations (key questions 2b and 3b) and the accuracy and harms of screening colonoscopy and flexible sigmoidoscopy in the community setting (key questions 2a and 3a). In the full report, we discuss lack of new data on the mortality benefits of colorectal cancer screening beyond FOBT programs (key question 1); race-, sex-, and age-related issues in colorectal cancer screening; considerations of targeted screening recommendations; and suggested future research. Detailed methods are provided in the Appendix and Appendix Tables 1, 2, and 3 and in the full report (25). Figure 1. Analytic framework and key questions ( KQs ). KQ1: What is the effectiveness of the following screening methods (alone or in combination) in reducing mortality from colorectal cancer? a. Flexible sigmoidoscopy, b. Colonoscopy, c. Computed tomographic (CT) colonography, d. Fecal screening tests: i. High-sensitivity guaiac fecal occult blood test (FOBTs); ii. Fecal immunochemical test; iii. Fecal DNA test. KQ2a: What are the sensitivity and specificity of 1) colonoscopy and 2) flexible sigmoidoscopy when used to screen for colorectal cancer in the community practice setting? KQ2b: What are the test performance characteristics of 1) CT colonography and 2) fecal screening tests (as listed in KQ1d) for colorectal cancer screening, as compared to an acceptable reference standard? KQ3a: What are age-specific rates of harm from colonoscopy and flexible sigmoidoscopy in the community practice setting? KQ3b: What are the adverse effects of newer tests, including 1) CT colonography and 2) fecal screening tests (as listed in KQ1d)? Appendix Table 1. Eligibility Criteria for Studies, by Key Question Appendix Table 2. U.S. Preventive Services Task Force Design-Specific Quality Rating Criteria Appendix Table 3. SAS Code for the Meta-Analysis of Serious Complications Searches and Selection Process In brief, we searched PubMed; Database of Abstracts of Reviews of Effects; Cochrane Database of Systematic Reviews; and the Institute of Medicine, National Institute for Health and Clinical Effectiveness, and Health Technology Assessment databases for recent systematic reviews (19992006) to support our review of all key questions (26). We found 11 existing systematic reviews for newer colorectal cancer screening tests (key question 2b). Using methods detailed in the Appendix, we selected 3 good-quality reviews of CT colonography (27, 28) or fecal DNA testing (29) to locate relevant primary studies; we supplemented these with additional MEDLINE and Cochrane Library searches from January 2006 through January 2008 to locate additional studies published after the end date of the searches. Because there were no good-quality relevant systematic reviews for reports on fecal immunochemical tests (key questions 2b and 3b), we searched MEDLINE and the Cochrane Library (19902008) and from 2000 to 2008 to locate studies of the harms of screening tests (key questions 3a and 3b) since the 2002 report. Abstracts and articles were dual-reviewed against inclusion criteria (Appendix) and required agreement of 2 reviewers. Eligible studies reported on the sensitivity and specificity of colorectal cancer screening tests or on health outcomes. We excluded studies that did not address average-risk populations for colorectal cancer screening, unless an average-risk subgroup was reported. We excluded casecontrol studies of screening accuracy because these may overestimate sensitivity as a design-related source of bias (30), as recently demonstrated for FOBTs (31). To avoid biases related to reference standards, we excluded studies of test accuracy that incompletely applied a valid reference standard or used an inadequate reference standard (32). For CT colonography, we considered only technologies that were compared with colonoscopy in average-risk populations, used a multidetector scanner (27), and reported per-patient sensitivity and specificity. In all, we evaluated 3948 abstracts and 490 full-text articles (Figure 2). Figure 2. Study selection. KQ= key question; SER= standardized evidence review. For list of key questions, see legend for Figure 1. Quality Assessment and Data Abstraction Two investigators critically appraised and quality-rated all eligible studies by using design-specific USPSTF criteria (33) supplemented by other criteria (Appendix). Poor-quality studies were excluded. One investigator abstracted key elements of included studies into standardized evidence tables. A second reviewer verified these data. We resolved disagreements about data abstraction or quality appraisal by consensus. Evidence tables and tables of excluded studies for each key question are available in the full report (25). Data Synthesis and Analysis We report qualitative synthesis of the results for most key questions because of study heterogeneity. The performance of screening tests is preferentially described per person (sensitivity and specificity), supplemented by per-polyp analyses (miss rates). Sensitivity for large adenomas from 2 similar studies of CT colonography screening was combined by using the inverse variance fixed-effects model because no heterogeneity was detected on the basis of the Cochran Q test and the I 2 statistic (34). Because of the stringency of our inclusion criteria for studies to estimate rates of endoscopy harms in the community practice setting (key question 3a), included studies were clinically homogeneous enough to pool. A random-effects logistic model was used to evaluate statistical heterogeneity, estimate pooled rates, and explore potential sources of variation for complications from study-level characteristics (35, 36). Model details and SAS PROC NLMIXED code are provided in the Appendix. Total serious adverse events required hospital admission (for example, perforation, major bleeding, severe abdominal symptoms, and cardiovascular events) or resulted in death. Results of exploratory analyses for potential sources of variation for pooled estimates are discussed in the full report, along with pooled estimates for individual complications, su

Accuracy of Fecal Immunochemical Tests for Colorectal Cancer: Systematic Review and Meta-analysis

Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States (1). Randomized, controlled trials have shown that annual or biennial fecal occult blood tests (FOBTs) are associated with a 15% to 33% decrease in CRC mortality rates (24). However, FOBTs only detect approximately 13% to 50% of cancer with 1 round of screening in asymptomatic patients (5, 6). In addition, adherence to repeated rounds of FOBTs in real-world screening programs is low, raising concern about their effectiveness as screening tests (7, 8). Fecal immunochemical tests (FITs) are more sensitive at detecting both CRC and adenomas than FOBTs (9, 10). Many FITs require only 1 or 2 stool samples, and none require dietary or medication restrictions, increasing ease of use. In 2008, several U.S. professional societies endorsed the use of FITs to replace FOBTs because of the formers improved performance characteristics and potential for higher participation rates (10, 11). Countries in Europe and Asia have also adopted widespread CRC screening programs using FITs (12, 13). However, the diagnostic characteristics of these tests have been difficult to estimate, with reported sensitivities ranging from 25% to 100% for CRC and specificities usually exceeding 90% (9, 14, 15). The lack of a precise estimate of sensitivity has resulted in confusion among health care providers about the sources of this variation, how best to apply FITs for CRC screening, the optimal number of stool samples for testing, optimal cutoff value for a positive test result, and whether any brand of FIT is superior to others. Our analysis provides a quantitative meta-analysis of the diagnostic accuracy (sensitivity and specificity) of FITs for CRC. In addition, we explored potential sources of heterogeneity by analyzing subgroups classified by FIT sample number, cutoff value for a positive test result, FIT brand, and the reference standard. Methods We developed a protocol on the basis of standard guidelines for the systematic review of diagnostic studies (16, 17) and the strategy used for the U.S. Preventive Services Task Force review in 2008 (9). We followed the STARD (Standards for the Reporting of Diagnostic Accuracy Studies) (18) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (19) statements for reporting our systematic review. This study was conducted as part of the National Cancer Institutefunded consortium, Population-Based Research Optimizing Screening through Personalized Regimens. The overall aim of this consortium is to conduct multisite, coordinated, transdisciplinary research to evaluate and improve cancer screening processes. Data Sources and Searches We included all studies identified in the previous USPSTF report (9) plus other studies identified by a search of FIT for CRC between 1 January 2008 and 31 August 2013 using MEDLINE (via Ovid), EMBASE, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We also searched bibliographies and reference lists of eligible papers and related reviews, consulted experts in the field, and contacted several authors from the included studies to locate additional studies. The Appendix Table 1 provides further details of our search strategy. Appendix Table 1. Search Strategy Study Selection Two persons independently reviewed the pertinent studies to determine eligibility. We included studies if they met all of the following criteria: evaluated the diagnostic accuracy of FITs for CRC; reported absolute numbers of true-positive, false-negative, true-negative, and false-positive observations, or if these same variables could be obtained from personal communication; used a randomized trial or cohort study design; evaluated adult participants who were asymptomatic and older than 18 years with a mean age greater than 40 years; and reported an appropriate reference standard (colonoscopy or 2-year longitudinal follow-up of controls with medical records or cancer registry). Given that only a subset of studies reported data on adenomatous polyps and that there is variability in definitions of polyps, we limited the scope of this analysis to test performance characteristics for detecting CRC; we excluded studies reporting test performance estimates for detection of adenomas only. We did not include conference abstracts and casecontrol studies, which, by creating spectrum bias, can overestimate the accuracy of a test (20). To avoid duplicate reporting of the same population for studies reporting several cutoff values or numbers of samples, we used the cutoff value or sample number most commonly used in current practice in the United States, used in national recommendations, or recommended by expert opinion in the main analyses. In addition, we selected the sample number or cutoff value a priori that was most similar to those in other studies for our subgroup analyses. Data Extraction and Quality Assessment Two reviewers independently evaluated and extracted relevant information from each included study and assessed study quality via the Quality Assessment of Diagnostic Accuracy Studies 2 instrument (21). For studies with incomplete or unavailable information, we contacted the corresponding authors or coauthors to complete missing information. Of the 15 contacted authors, 12 provided additional data. We converted units for cutoff thresholds for a positive test result in each study to micrograms of hemoglobin per gram of stool, as recommended by leading experts (22). Data Synthesis and Analysis We calculated the sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio (LR), and negative LR with 95% CI of each study. A positive LR greater than 5 and a negative LR less than 0.2 provide strong diagnostic evidence to rule in or rule out diagnoses, respectively (23). The overall pooled sensitivity and specificity of FIT for CRC were estimated using a bivariate random-effects model (24). We calculated the pooled positive LR and negative LR along with the respective CI using the bivariate model (24) according to the method used by Zwinderman and colleagues (25). We also generated a hierarchical summary receiver-operating characteristic curve that plots the individual and summary estimates of sensitivities and specificities along with a 95% confidence and prediction region (26). Last, we calculated the area under the hierarchical summary receiver-operating characteristic curve. An area under the curve between 0.9 and 1.0 indicates that the test in question is highly accurate (27). The Q value and the inconsistency index (I 2) test were used to estimate the heterogeneity between each study (28). We regarded values of 25%, 50%, and 75% for the I 2 as indicative of low, moderate, and high statistical heterogeneity, respectively (28). In addition, we calculated the between-study variance of logit sensitivity and logit specificity (24, 29). In diagnostic accuracy studies, 1 of the primary causes of heterogeneity is the threshold effect, which occurs when different cutoff values are used between studies to define a positive (or negative) test result. We searched for evidence of a threshold effect by calculating the squared correlation coefficient estimated from the between-study covariance variable in the bivariate model (30). We stratified studies into 4 subgroups on the basis of the number of FIT samples (1, 2, or 3 samples), prespecified cutoff values of fecal hemoglobin concentration for a positive test result (<20 g/g, 20 to 50 g/g, and >50 g/g), brand, and reference standard used to follow up on patients with negative FIT results. Cutoff values were grouped to ensure an adequate number of data sets for each analysis. To determine whether studies using older (discontinued) FITs were causing heterogeneity in our summary estimates, we did sensitivity analyses by removing these studies and recalculating the I 2 test for the remaining group. In addition to threshold effect and subgroup analyses, we did a bivariate random-effects meta-regression analysis to identify additional sources of heterogeneity that may have influenced our overall summary estimates (30). We used the following prespecified variables for our meta-regression: type of FIT (qualitative, point-of-care tests or quantitative, automated tests), geographic region (Asian or non-Asian countries), and enrollment of patients younger than 40 years. We used Stata, version 12.0 (StataCorp, College Station, Texas), for all statistical analyses. All tests were 2-sided, and we considered P values less than 0.05 to be statistically significant. Role of the Funding Source The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute. The funding source had no role in the conception, design, analysis, or conduct of the review. Results Study Selection The 2008 USPSTF report (9) included 9 studies in its systematic review (3139); our literature search identified 1771 additional new potential sources (Figure 1). After abstract review, we identified 53 articles for full-text review; of these, 18 unique articles satisfied all inclusion criteria and were included in our analysis (14, 15, 3146). Because 1 article (46) evaluated more than 1 FIT brand in a head-to-head comparison, the final analysis included 19 studies or data sets. Figure 1. Summary of evidence search and selection. USPSTF = U.S. Preventive Services Task Force. Characteristics of Included Studies Table 1 and the Supplement show the main characteristics of the included studies. Eighteen articles described 19 cohort studies of FIT sensitivity and specificity for CRC in average-risk asymptomatic patients; sample sizes ranged from 80 to 27860. Twelve studies (14, 3336, 4042, 4446) used colonoscopy in all patients, regardless of FIT results, as the re

Implementation challenges and successes of a population-based colorectal cancer screening program: a qualitative study of stakeholder perspectives

BackgroundFew studies describe system-level challenges or facilitators to implementing population-based colorectal cancer (CRC) screening outreach programs. Our qualitative study explored viewpoints of multilevel stakeholders before, during, and after implementation of a centralized outreach program. Program implementation was part of a broader quality-improvement initiative.MethodsDuring 2008–2010, we conducted semi-structured, open-ended individual interviews and focus groups at Kaiser Permanente Northwest (KPNW), a not-for-profit group model health maintenance organization using the practical robust implementation and sustainability model to explore external and internal barriers to CRC screening. We interviewed 55 stakeholders: 8 health plan leaders, 20 primary care providers, 4 program managers, and 23 endoscopy specialists (15 gastroenterologists, 8 general surgeons), and analyzed interview transcripts to identify common as well as divergent opinions expressed by stakeholders.ResultsThe majority of stakeholders at various levels consistently reported that an automated telephone-reminder system to contact patients and coordinate mailing fecal tests alleviated organizational constraints on staff’s time and resources. Changing to a single-sample fecal immunochemical test (FIT) lessened patient and provider concerns about feasibility and accuracy of fecal testing. The centralized telephonic outreach program did, however, result in some screening duplication and overuse. Higher rates of FIT completion and a higher proportion of positive results with FIT required more colonoscopies.ConclusionsAddressing barriers at multiple levels of a health system by changing the delivery system design to add a centralized outreach program, switching to a more accurate and easier-to-use fecal test, and providing educational and electronic support had both benefits and problematic consequences. Other health care organizations can use our results to understand the complexities of implementing centralized screening programs.

Balancing Adherence and Expense: The Cost-Effectiveness of Two-Sample vs One-Sample Fecal Immunochemical Test

Colorectal cancer (CRC) causes more than 50,000 deaths each year in the United States but early detection through screening yields survival gains; those diagnosed with early stage disease have a 5-year survival greater than 90%, compared to 12% for those diagnosed with late stage disease. Using data from a large integrated health system, this study evaluates the cost-effectiveness of fecal immunochemical testing (FIT), a common CRC screening tool. A probabilistic decision-analytic model was used to examine the costs and outcomes of positive test results from a 1-FIT regimen compared with a 2-FIT regimen. The authors compared 5 diagnostic cutoffs of hemoglobin concentration for each test (for a total of 10 screening options). The principal outcome from the analysis was the cost per additional advanced neoplasia (AN) detected. The authors also estimated the number of cancers detected and life-years gained from detecting AN. The following costs were included: program management of the screening program, patient identification, FIT kits and their processing, and diagnostic colonoscopy following a positive FIT. Per-person costs ranged from

Pneumococcal Conjugate Vaccine Safety in Elderly Adults

33 (1-FIT at 150ng/ml) to

Correction to: Early Colorectal Cancer Detected by Machine Learning Model Using Gender, Age, and Complete Blood Count Data

92 (2-FIT at 50ng/ml) across screening options. Depending on willingness to pay, the 1-FIT 50 ng/ml and the 2-FIT 50 ng/ml are the dominant strategies with cost-effectiveness of

Screening for Colorectal Cancer: An Updated Systematic Review

11,198 and

Change to FIT increased CRC screening rates: evaluation of a US screening outreach program.

28,389, respectively, for an additional AN detected. The estimates of cancers avoided per 1000 screens ranged from 1.46 to 4.86, depending on the strategy and the assumptions of AN to cancer progression.

More Comprehensive Discussion of CRC Screening Associated With Higher Screening

Abstract Background The 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) were both recommended to adults aged ≥65 years. The study examines adults ≥65 years for risk of adverse events (AEs) requiring medical attention following vaccination with PCV13 as compared with vaccination with PPSV23, a long-standing vaccine with a satisfactory safety profile. Methods The cohort study included 6 Vaccine Safety Datalink sites. The exposed person-time included follow-up time of the first PCV13 received by subjects age ≥65 years from January 1 to August 15, 2015. The comparator person-time included follow-up time after the first PPSV23 received by subjects of the same age during Janaury 1 to August 15 of each year of 2011–2015. The prespecified AEs included cardiovascular events, Bell’s palsy, Guillain-Barré syndrome, syncope, erythema multiforme, thrombocytopenia, cellulitis and infection, allergic reaction, and anaphylaxis. Inverse probability of treatment weighting–adjusted Poisson regression models was used to estimate the relative risk (RR) of each AE. Results A total of 313 136 doses of PCV13 and 232 591 doses of PPSV23 were included. The adjusted RRs comparing the incidence of AEs following PCV13 vs PPSV23 were all <1, except for anaphylaxis, which was insignificant with an RR of 1.32 (95% confidence interval, 0.30–5.79). Only 1 patient who received PCV13 and 4 other vaccines concomitantly was confirmed by medical chart review as having experienced anaphylaxis after vaccination. Conclusions These data do not support an increased rate of adverse events following PCV13 administration in elders compared with PPSV23 and should provide reassurance regarding continued use of PCV13.

Automated telephone calls to enhance colorectal cancer screening: Economic analysis

The article Early Colorectal Cancer Detected by Machine Learning Model Using Gender, Age, and Complete Blood Count Data, written by Mark C. Hornbrook, Ran Goshen, Eran Choman, Maureen O’Keeffe-Rosetti, Yaron Kinar, Elizabeth G. Liles, and Kristal C. Rust, was originally published Online First without open access