Counting Advanced Precancerous Lesions as True Positives When Determining Colorectal Cancer Screening Test Specificity.

The landmark Centers for Medicare & Medicaid Services (CMS) decision memo on blood-based biomarkers to screen for colorectal cancer (CRC) sets thresholds of 74% or higher for sensitivity and 90% or higher for specificity for CRC. This approach does not consider detection of advanced precancerous lesions as true positives. We contrasted the impact of counting advanced precancerous lesions as true vs false positives and projected CRC outcomes under contrasting tests in a validated model. A test with the threshold performance set by CMS decreased CRC incidence by 30% and CRC mortality by 48% in individuals aged 45 years. If this test also detected advanced precancerous lesions with 30% sensitivity, CRC incidence decreased by 45% and mortality by 58%, but the CRC specificity of the test of only 88% would not satisfy the CMS threshold. CMS should reconsider its definition of threshold specificity for CRC screening biomarkers. Future coverage determinations on biomarkers to screen for cancer should consider detection of relevant precursor lesions and projected outcomes.

Risk of Advanced Neoplasia Using the National Cancer Institute's Colorectal Cancer Risk Assessment Tool.

Background: There is no validated, discriminating, and easy-to-apply tool for estimating risk of colorectal neoplasia. We studied whether the National Cancer Institute's (NCI's) Colorectal Cancer (CRC) Risk Assessment Tool, which estimates future CRC risk, could estimate current risk for advanced colorectal neoplasia among average-risk persons. Methods: This cross-sectional study involved individuals age 50 to 80 years undergoing first-time screening colonoscopy. We measured medical and family history, lifestyle information, and physical measures and calculated each person's future CRC risk using the NCI tool's logistic regression equation. We related quintiles of future CRC risk to the current risk of advanced neoplasia (sessile serrated polyp or tubular adenoma ≥ 1 cm, a polyp with villous histology or high-grade dysplasia, or CRC). All statistical tests were two-sided. Results: For 4457 (98.5%) with complete data (mean age = 57.2 years, SD = 6.6 years, 51.7% women), advanced neoplasia prevalence was 8.26%. Based on quintiles of five-year estimated absolute CRC risk, current risks of advanced neoplasia were 2.1% (95% confidence interval [CI] = 1.3% to 3.3%), 4.8% (95% CI = 3.5% to 6.4%), 6.4% (95% CI = 4.9% to 8.2%), 10.0% (95% CI = 8.1% to 12.1%), and 17.6% (95% CI = 15.5% to 20.6%; P < .001). For quintiles of estimated 10-year CRC risk, corresponding current risks for advanced neoplasia were 2.2% (95% CI = 1.4% to 3.5%), 4.8% (95% CI = 3.5% to 6.4%), 6.5% (95% CI = 5.0% to 8.3%), 9.3% (95% CI = 7.5% to 11.4%), and 18.4% (95% CI = 15.9% to 21.1%; P < .001). Among persons with an estimated five-year CRC risk above the median, current risk for advanced neoplasia was 12.8%, compared with 3.7% among those below the median (relative risk = 3.4, 95 CI = 2.7 to 4.4). Conclusions: The NCI's Risk Assessment Tool, which estimates future CRC risk, may be used to estimate current risk for advanced neoplasia, making it potentially useful for tailoring and improving CRC screening efficiency among average-risk persons.

Breaking a vicious cycle.

Despite prodigious advances in tumor biology research, few tumor-biomarker tests have been adopted as standard clinical practice. This lack of reliable tests stems from a vicious cycle of undervaluation, resulting from inconsistent regulatory standards and reimbursement, as well as insufficient investment in research and development, scrutiny of biomarker publications by journals, and evidence of analytical validity and clinical utility. We offer recommendations designed to serve as a roadmap to break this vicious cycle and call for a national dialogue, as changes in regulation, reimbursement, investment, peer review, and guidelines development require the participation of all stakeholders.

Protein-based multiplex assays: mock presubmissions to the US Food and Drug Administration.

As a part of ongoing efforts of the NCI-FDA Interagency Oncology Task Force subcommittee on molecular diagnostics, members of the Clinical Proteomic Technology Assessment for Cancer program of the National Cancer Institute have submitted 2 protein-based multiplex assay descriptions to the Office of In Vitro Diagnostic Device Evaluation and Safety, US Food and Drug Administration. The objective was to evaluate the analytical measurement criteria and studies needed to validate protein-based multiplex assays. Each submission described a different protein-based platform: a multiplex immunoaffinity mass spectrometry platform for protein quantification, and an immunological array platform quantifying glycoprotein isoforms. Submissions provided a mutually beneficial way for members of the proteomics and regulatory communities to identify the analytical issues that the field should address when developing protein-based multiplex clinical assays.

Adverse events after outpatient colonoscopy in the Medicare population.

BACKGROUND: Although use of colonoscopy has increased substantially among elderly Medicare beneficiaries, no one has described colonoscopy-related adverse events in a representative sample of Medicare patients. OBJECTIVE: To determine risk for adverse events after outpatient colonoscopy in elderly patients. DESIGN: Population-based, matched cohort study. SETTING: Surveillance, Epidemiology, and End Results cancer registry areas. PATIENTS: Random 5% sample of Medicare beneficiaries, age 66 to 95 years, who underwent outpatient colonoscopy between 1 July 2001 and 31 October 2005 (n = 53 220), matched with beneficiaries who did not have colonoscopy. MEASUREMENTS: Medicare claims were used to measure the rate of serious gastrointestinal events (bleeding and perforation), other gastrointestinal events, and cardiovascular events resulting in a hospitalization or emergency department visit within 30 days after colonoscopy compared with matched beneficiaries who did not have colonoscopy. Logistic regression was used to estimate adjusted predictive risks for adverse events and to assess whether these events varied by age, comorbid conditions, or type of colonoscopy. RESULTS: Persons undergoing colonoscopy had a higher risk for adverse gastrointestinal events than their matched group. Rates of adverse events after colonoscopy increased with age. Patients having polypectomy had higher risk for all adverse events compared with their matched group and with the screening and diagnostic colonoscopy groups. Comorbid conditions increased the risk for adverse events. Patients with a history of stroke, chronic obstructive pulmonary disease, atrial fibrillation, or congestive heart failure had significantly higher risk for serious gastrointestinal events. LIMITATION: The analysis relied on the diagnosis and procedure codes recorded on the Medicare claims. CONCLUSION: Risks for adverse events after outpatient colonoscopy among elderly Medicare beneficiaries were low; however, they increased with age with specific comorbid conditions and depending on whether polypectomy was done. These data may inform decisions on whether to perform colonoscopy in persons of advanced age or those with comorbid conditions.

Multi-site assessment of the precision and reproducibility of multiple reaction monitoring-based measurements of proteins in plasma.

Verification of candidate biomarkers relies upon specific, quantitative assays optimized for selective detection of target proteins, and is increasingly viewed as a critical step in the discovery pipeline that bridges unbiased biomarker discovery to preclinical validation. Although individual laboratories have demonstrated that multiple reaction monitoring (MRM) coupled with isotope dilution mass spectrometry can quantify candidate protein biomarkers in plasma, reproducibility and transferability of these assays between laboratories have not been demonstrated. We describe a multilaboratory study to assess reproducibility, recovery, linear dynamic range and limits of detection and quantification of multiplexed, MRM-based assays, conducted by NCI-CPTAC. Using common materials and standardized protocols, we demonstrate that these assays can be highly reproducible within and across laboratories and instrument platforms, and are sensitive to low mug/ml protein concentrations in unfractionated plasma. We provide data and benchmarks against which individual laboratories can compare their performance and evaluate new technologies for biomarker verification in plasma.

Assessment of serum proteomics to detect large colon adenomas.

A noninvasive blood test that could reliably detect early colorectal cancer or large adenomas would provide an important advance in colon cancer screening. The purpose of this study was to determine whether a serum proteomics assay could discriminate between persons with and without a large (> or =1 cm) colon adenoma. To avoid problems of "bias" that have affected many studies about molecular markers for diagnosis, specimens were obtained from a previously conducted study of colorectal cancer etiology in which bloods had been collected before the presence or absence of neoplasm had been determined by colonoscopy, helping to assure that biases related to differences in sample collection and handling would be avoided. Mass spectra of 65 unblinded serum samples were acquired using a nanoelectrospray ionization source on a QSTAR-XL mass spectrometer. Classification patterns were developed using the ProteomeQuest algorithm, performing measurements twice on each specimen, and then applied to a blinded validation set of 70 specimens. After removing 33 specimens that had discordant results, the "test group" comprised 37 specimens that had never been used in training. Although in the primary analysis, no discrimination was found, a single post hoc analysis, done after hemolyzed specimens had been removed, showed a sensitivity of 78%, a specificity of 53%, and an accuracy of 63% (95% confidence interval, 53-72%). The results of this study, although preliminary, suggest that further study of serum proteomics, in a larger number of appropriate specimens, could be useful. They also highlight the importance of understanding sources of "noise" and "bias" in studies of proteomics assays.

Evaluation of claims, medical records, and self-report for measuring fecal occult blood testing among medicare enrollees in fee for service.

BACKGROUND: There is no agreement on the best data source for measuring colorectal cancer (CRC) screening. Medicare claims have been used to measure CRC testing but the validity of using claims to measure fecal occult blood tests (FOBT) has not been established. METHODS: We compared ascertainment of FOBT among three data sources: self-reports, Medicare claims, and medical records. Data were collected on FOBT use during the study window (1/1/1998 - 12/31/2002). Our study was conducted with North Carolina Medicare enrollees (N = 561) who had previously responded to a telephone survey on CRC tests. FOBT information was abstracted from respondents' physician office medical records and compared with self-reported FOBT use and Medicare claims for FOBT. Data sources were assessed for accuracy and completeness of FOBT reporting using sensitivity, specificity, positive predictive value, negative predictive value, and agreement. RESULTS: Reporting of FOBT use in the prior year in medical records and Medicare claims agreed 82% of the time [95% confidence interval (95% CI), 79-85%]. FOBT 1-year use rates from self-report agreed with test use found in medical records 70% of the time (95% CI, 66-74%). The lowest agreement was between self-reported 1-year FOBT use and Medicare claims, which agreed 67% of the time (95% CI, 63-71%). CONCLUSIONS: No data source could be established as providing complete and valid information about FOBT use among Medicare enrollees, showing the difficulty of ascertaining test use rates for noninvasive, low-cost procedures conducted in multiple settings. Caution should be used when attempting to measure FOBT use with self-report, Medicare claims, or medical records.

Data sources for measuring colorectal endoscopy use among Medicare enrollees.

BACKGROUND: Estimates of colorectal cancer test use vary widely by data source. Medicare claims offer one source for monitoring test use, but their utility has not been validated. We compared ascertainment of sigmoidoscopy and colonoscopy between three data sources: self reports, Medicare claims, and medical records. MATERIALS AND METHODS: The study population included Medicare enrollees residing in North Carolina (n = 561) who had participated in a telephone survey on colorectal cancer tests. Medicare claims were obtained for the 5 years preceding the survey (January 1, 1998 to December 31, 2002). Information about sigmoidoscopy and colonoscopy procedures conducted in physician offices were abstracted from medical records. Sensitivity, specificity, positive predictive value, negative predictive value, agreement, and kappa statistics were calculated using the medical record as the gold standard. Agreement on specific procedure type and purpose was also assessed. RESULTS: Agreement between claim and medical record regarding whether an endoscopic procedure had been done was high (over 90%). Agreement between self report and medical record and between self report and claim was good (79% and 74%, respectively). All three data sources adequately distinguished the type of procedure done. None of the data sources showed reliable levels of agreement regarding procedure purpose (screening or diagnostic). CONCLUSION: Medicare claims can provide accurate information on whether a patient has undergone colorectal endoscopy and may be more complete than physician medical records. Medicare claims cannot be used to distinguish screening from diagnostic tests. Recognizing this limitation, researchers who use Medicare claims to assess rates of colorectal testing should include both screening and diagnostic endoscopy procedures in their analyses.

Improving colorectal cancer screening in primary care practice: innovative strategies and future directions.

Colorectal cancer (CRC) screening has been supported by strong research evidence and recommended in clinical practice guidelines for more than a decade. Yet screening rates in the United States remain low, especially relative to other preventable diseases such as breast and cervical cancer. To understand the reasons, the National Cancer Institute and Agency for Healthcare Research and Quality sponsored a review of CRC screening implementation in primary care and a program of research funded by these organizations. The evidence base for improving CRC screening supports the value of a New Model of Primary Care Delivery: 1. a team approach, in which responsibility for screening tasks is shared among other members of the practice, would help address physicians' lack of time for preventive care; 2. information systems can identify eligible patients and remind them when screening is due; 3. involving patients in decisions about their own care may enhance screening participation; 4. monitoring practice performance, supported by information systems, can help target patients at increased risk because of family history or social disadvantage; 5. reimbursement for services outside the traditional provider-patient encounter, such as telephone and e-mail contacts, may foster enhanced screening delivery; 6. training opportunities in communication, cultural competence, and use of information technologies would improve provider competence in core elements of screening programs. Improvement in CRC screening rates largely depends on the efforts of primary care practices to implement effective systems and procedures for screening delivery. Active engagement and support of practices are essential for the enormous potential of CRC screening to be realized.

Interpretations of 'appropriate' minority inclusion in clinical research.

The range of possible interpretations of the phrase "appropriate representation" has left investigators struggling with the practical application of the National Institutes of Health guidelines on the inclusion of minorities in research. At least three goals might be reached by including minorities in clinical research: to test specific hypotheses about differences by race and ethnicity; to generate hypotheses about possible differences by race and ethnicity; and to ensure the just distribution of the benefits and burdens of participation in research, regardless of whether there are expected differences in outcome by race or ethnicity. In this paper, we describe possible interpretations of "appropriate representation," as well as provide a general approach that investigators might use to address this issue. To expand scientific knowledge about the health of minority populations, investigators should be expected to state which goal they have selected and why that goal is appropriate as compared with other possible goals.

Adequacy of reporting race/ethnicity in clinical trials in areas of health disparities.

Although federal initiatives have mandated broader inclusion of minorities in clinical research on diseases that have disparities in health by race and ethnicity, it is not clear whether these initiatives have affected reporting of trial results. The objective of this study was to examine the reporting of race/ethnicity in clinical trials reports in areas of known disparities in health (i.e., diabetes, cardiovascular disease, HIV/AIDS, and cancer) and to determine what factors were associated with reporting of race/ethnicity in results. We performed a Medline search covering the period January 1989 to Oct 2000 to identify clinical trials of diabetes, cardiovascular disease, HIV/AIDS, and cancer published in the Annals of Internal Medicine, JAMA, and New England Journal of Medicine. The main outcome measure was the reporting of participation and of results by race/ethnicity of trial participants. Of 253 eligible trials, 40% (n=102) were non race-focused yet did not report race, while 2% (n=4) were non gender-focused and did not report gender. Forty-six percent of trials that reported the race/ethnicity of the sample reported only one or two racial/ethnic categories, and in 43% of these trials the total number of individuals reported in each race/ethnicity category did not equal the total reported sample size. Analysis of results by race/ethnicity was reported in only two trials, and by gender in only three trials. In diseases with known racial and ethnic disparities, many clinical trials do not report the race/ethnicity of the study participants, and almost none report analyses by race/ethnicity. Although federal initiatives mandate inclusion of minority groups in research, that inclusion has not translated to reporting of results that might guide therapeutic decisions.

Screening colonoscopy in balance. Issues of implementation.

Although colonoscopy is currently considered an option for colon cancer screening, its choice as a preferred screening test is not supported by data, recommendations, or cost-effectiveness analysis. The use of colonoscopy in postpolypectomy surveillance constitutes a huge potential effort that should be appropriately anticipated and managed. Noninvasive methods for colon cancer screening may reduce the need for colonoscopy in the future.