Elizabeth M Webber

Screening for Colorectal Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

IMPORTANCE Colorectal cancer (CRC) remains a significant cause of morbidity and mortality in the United States. OBJECTIVE To systematically review the effectiveness, diagnostic accuracy, and harms of screening for CRC. DATA SOURCES Searches of MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant studies published from January 1, 2008, through December 31, 2014, with surveillance through February 23, 2016. STUDY SELECTION English-language studies conducted in asymptomatic populations at general risk of CRC. DATA EXTRACTION AND SYNTHESIS Two reviewers independently appraised the articles and extracted relevant study data from fair- or good-quality studies. Random-effects meta-analyses were conducted. MAIN OUTCOMES AND MEASURES Colorectal cancer incidence and mortality, test accuracy in detecting CRC or adenomas, and serious adverse events. RESULTS Four pragmatic randomized clinical trials (RCTs) evaluating 1-time or 2-time flexible sigmoidoscopy (n = 458,002) were associated with decreased CRC-specific mortality compared with no screening (incidence rate ratio, 0.73; 95% CI, 0.66-0.82). Five RCTs with multiple rounds of biennial screening with guaiac-based fecal occult blood testing (n = 419,966) showed reduced CRC-specific mortality (relative risk [RR], 0.91; 95% CI, 0.84-0.98, at 19.5 years to RR, 0.78; 95% CI, 0.65-0.93, at 30 years). Seven studies of computed tomographic colonography (CTC) with bowel preparation demonstrated per-person sensitivity and specificity to detect adenomas 6 mm and larger comparable with colonoscopy (sensitivity from 73% [95% CI, 58%-84%] to 98% [95% CI, 91%-100%]; specificity from 89% [95% CI, 84%-93%] to 91% [95% CI, 88%-93%]); variability and imprecision may be due to differences in study designs or CTC protocols. Sensitivity of colonoscopy to detect adenomas 6 mm or larger ranged from 75% (95% CI, 63%-84%) to 93% (95% CI, 88%-96%). On the basis of a single stool specimen, the most commonly evaluated families of fecal immunochemical tests (FITs) demonstrated good sensitivity (range, 73%-88%) and specificity (range, 90%-96%). One study (n = 9989) found that FIT plus stool DNA test had better sensitivity in detecting CRC than FIT alone (92%) but lower specificity (84%). Serious adverse events from colonoscopy in asymptomatic persons included perforations (4/10,000 procedures, 95% CI, 2-5 in 10,000) and major bleeds (8/10,000 procedures, 95% CI, 5-14 in 10,000). Computed tomographic colonography may have harms resulting from low-dose ionizing radiation exposure or identification of extracolonic findings. CONCLUSIONS AND RELEVANCE Colonoscopy, flexible sigmoidoscopy, CTC, and stool tests have differing levels of evidence to support their use, ability to detect cancer and precursor lesions, and risk of serious adverse events in average-risk adults. Although CRC screening has a large body of supporting evidence, additional research is still needed.

Oncotype DX tumor gene expression profiling in stage II colon cancer. Application: prognostic, risk prediction.

Overall five-year survival for patients with stage-II colon cancer averages 75% after surgery alone. However, some of these patients have poorer outcomes, similar to patients with stage-III disease. The proposed use of the Oncotype DX assay is to improve risk stratification for recurrence in stage-II colon cancer.

Description and pilot results from a novel method for evaluating return of incidental findings from next-generation sequencing technologies

Purpose:The aim of this study was to develop, operationalize, and pilot test a transparent, reproducible, and evidence-informed method to determine when to report incidental findings from next-generation sequencing technologies.Methods:Using evidence-based principles, we proposed a three-stage process. Stage I “rules out” incidental findings below a minimal threshold of evidence and is evaluated using inter-rater agreement and comparison with an expert-based approach. Stage II documents criteria for clinical actionability using a standardized approach to allow experts to consistently consider and recommend whether results should be routinely reported (stage III). We used expert opinion to determine the face validity of stages II and III using three case studies. We evaluated the time and effort for stages I and II.Results:For stage I, we assessed 99 conditions and found high inter-rater agreement (89%), and strong agreement with a separate expert-based method. Case studies for familial adenomatous polyposis, hereditary hemochromatosis, and α1-antitrypsin deficiency were all recommended for routine reporting as incidental findings. The method requires <3 days per topic.Conclusion:We establish an operational definition of clinically actionable incidental findings and provide documentation and pilot testing of a feasible method that is scalable to the whole genome.Genet Med 15 9, 721–728.Genetics in Medicine (2013); 15 9, 721–728. doi:10.1038/gim.2013.37

Systematic review of the predictive effect of MSI status in colorectal cancer patients undergoing 5FU-based chemotherapy

BackgroundWe systematically reviewed the evidence for the interaction of microsatellite instability status (MSI) and treatment with 5FU in colorectal cancer to determine how well MSI status predicts health outcomes in patients undergoing 5FU-based chemotherapy.MethodsWe conducted a search of four electronic databases through June 2013. We considered studies that included both colorectal cancer patients treated with 5FU-based chemotherapy and untreated patients with survival outcomes presented by MSI status.ResultsWe identified 16 studies for qualitative analysis (9,212 patients) with 14 studies eligible for meta-analysis. The microsatellite stable (MSS) group showed an effect of 5FU treatment on disease-free survival (HR of 0.62 [95% CI: 0.54, 0.71]) and overall survival (HR of 0.65 [95% CI: 0.54, 0.79]), indicating that MSS patients who received 5FU treatment had longer survival than MSS patients who were untreated. The effect of 5FU treatment was not statistically significant for microsatellite high (MSI-H) patients for disease-free survival (HR of 0.84 [95% CI: 0.53, 1.32]) or overall survival (HR 0.66 [95% CI: 0.43, 1.03]). However, the summarized point estimates of the effects of 5FU treatment for the MSS and MSI-H groups were not different at a statistically significant level.ConclusionsOur analyses indicate that treatment with 5FU-based chemotherapy improves disease-free and overall survival in CRC patients, but that there is no difference in the effect of treatment based on MSI status. Therefore, the use of MSI status to guide treatment decisions about the use of 5FU treatment for CRC has no significant benefits for patients.

Screening for Chronic Obstructive Pulmonary Disease: Evidence Report and Systematic Review for the US Preventive Services Task Force

IMPORTANCE Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. OBJECTIVE To systematically review literature on the accuracy of screening questionnaires and office-based screening pulmonary function testing and the efficacy and harms of treatment of screen-detected COPD. DATA SOURCES MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials for relevant English-language studies published through January 2015. STUDY SELECTION Two reviewers independently screened abstracts and studies. The search yielded 13,141 unique citations; 465 full-text articles were reviewed, and 33 studies met the inclusion criteria. DATA EXTRACTION AND SYNTHESIS Two reviewers rated the quality of each study using USPSTF criteria. MAIN OUTCOMES AND MEASURES Diagnostic accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]; treatment efficacy (COPD exacerbations, all-cause mortality, quality of life, and dyspnea); and treatment harms. RESULTS All screening questionnaires were based on symptoms as well as risk factors such as age and smoking history. The COPD Diagnostic Questionnaire was the most extensively studied (5 studies, n = 3048), with moderate overall performance for COPD detection: area under the receiver operating characteristic curve (AUC), 0.65 to 0.72; sensitivity, 80% to 93%; and specificity, 24% to 49%, at a threshold of greater than 16.5. Positive predictive value and NPV ranged from 17% to 45% and 76% to 98%, respectively. For pulmonary function-based screening tools, FEV1/FEV6 was the best studied (3 studies, n = 1587), with AUC ranging from 0.84 to 0.85. Sensitivity ranged from 51% to 80%. Specificity (range, 90%-95%) and PPV (range, 63%-75%) appeared better than questionnaires. There was not strong evidence to support that screening and supplying smokers with spirometry results improves smoking cessation rates. Treatment trials were unavailable for screen-detected patients. Trials that reported outcomes in patients with mild to moderate COPD included 2 trials of long-acting β-agonists (LABAs) (n = 3174), 1 RCT of LABAs and inhaled corticosteroids (ICS) (n = 1097), 5 RCTs of the long-acting muscarinic antagonist tiotropium (n = 4592), and 6 RCTs of ICS (n = 3983). They suggested no benefit in all-cause mortality, but a decrease in annual rates of exacerbations with pharmacologic treatments. Few trials reported harms for any individual drug class. Adverse effects were generally mild (eg, dry mouth and cough). CONCLUSIONS AND RELEVANCE There was no direct evidence available to determine the benefits and harms of screening asymptomatic adults for COPD using questionnaires or office-based screening pulmonary function testing or to determine the benefits of treatment in screen-detected populations. Indirect evidence suggests that the COPD Diagnostic Questionnaire has moderate overall performance for COPD detection. Among patients with mild to moderate COPD, the benefit of pharmacotherapy for reducing exacerbations was modest.

A standardized, evidence-based protocol to assess clinical actionability of genetic disorders associated with genomic variation.

Purpose:Genome and exome sequencing can identify variants unrelated to the primary goal of sequencing. Detecting pathogenic variants associated with an increased risk of a medical disorder enables clinical interventions to improve future health outcomes in patients and their at-risk relatives. The Clinical Genome Resource, or ClinGen, aims to assess clinical actionability of genes and associated disorders as part of a larger effort to build a central resource of information regarding the clinical relevance of genomic variation for use in precision medicine and research.Methods:We developed a practical, standardized protocol to identify available evidence and generate qualitative summary reports of actionability for disorders and associated genes. We applied a semiquantitative metric to score actionability.Results:We generated summary reports and actionability scores for the 56 genes and associated disorders recommended by the American College of Medical Genetics and Genomics for return as secondary findings from clinical genome-scale sequencing. We also describe the challenges that arose during the development of the protocol that highlight important issues in characterizing actionability across a range of disorders.Conclusion:The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.Genet Med 18 12, 1258–1268.

Family history and the natural history of colorectal cancer: Systematic review

Purpose:Family history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks.Methods:We conducted a systematic review to estimate the impact of family history on the natural history of CRC and adherence to screening.Results:We found high heterogeneity in family-history definitions, the most common definition being one or more first-degree relatives. The prevalence of family history may be lower than the commonly cited 10%, and confirms evidence for increasing levels of risk associated with increasing family-history burden. There is evidence for higher prevalence of adenomas and of multiple adenomas in people with family history of CRC but no evidence for differential adenoma location or adenoma progression by family history. Limited data regarding the natural history of CRC by family history suggest a differential age or stage at cancer diagnosis and mixed evidence with respect to tumor location. Adherence to recommended colonoscopy screening was higher in people with a family history of CRC.Conclusion:Stratification based on polygenic and/or multifactorial risk assessment may mature to the point of displacing family history–based approaches, but for the foreseeable future, family history may remain a valuable clinical tool for identifying individuals at increased risk for CRC.Genet Med 17 9, 702–712.

Behavioral and Pharmacotherapy Weight Loss Interventions to Prevent Obesity-Related Morbidity and Mortality in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Importance Overweight and obesity have been associated with adverse health effects. Objective To systematically review evidence on benefits and harms of behavioral and pharmacotherapy weight loss and weight loss maintenance interventions in adults to inform the US Preventive Services Task Force. Data Sources MEDLINE, PubMed Publisher-Supplied Records, PsycINFO, and the Cochrane Central Register of Controlled Trials for studies published through June 6, 2017; ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform for ongoing trials through August 2017; and ongoing surveillance in targeted publications through March 23, 2018. Studies from previous reviews were reevaluated for inclusion. Study Selection Randomized clinical trials (RCTs) focusing on weight loss or weight loss maintenance in adults. Data Extraction and Synthesis Data were abstracted by one reviewer and confirmed by another. Random-effects meta-analyses were conducted for weight loss outcomes in behavior-based interventions. Main Outcomes and Measures Health outcomes, weight loss or weight loss maintenance, reduction in obesity-related conditions, and adverse events. Results A total of 122 RCTs (N = 62 533) and 2 observational studies (N = 209 993) were identified. Compared with controls, participants in behavior-based interventions had greater mean weight loss at 12 to 18 months (−2.39 kg [95% CI, −2.86 to −1.93]; 67 studies [n = 22065]) and less weight regain (−1.59 kg [95% CI, −2.38 to −0.79]; 8 studies [n = 1408]). Studies of medication-based weight loss and maintenance interventions also reported greater weight loss or less weight regain in intervention compared with placebo groups at 12 to 18 months (range, −0.6 to −5.8 kg; no meta-analysis). Participants with prediabetes in weight loss interventions had a lower risk of developing diabetes compared with controls (relative risk, 0.67 [95% CI, 0.51 to 0.89]). There was no evidence of other benefits, but most health outcomes such as mortality, cardiovascular disease, and cancer were infrequently reported. Small improvements in quality of life in some medication trials were noted but were of unclear clinical significance. There was no evidence of harm such as cardiovascular disease from behavior-based interventions; higher rates of adverse events were associated with higher dropout rates in medication groups than in placebo groups. Conclusions and Relevance Behavior-based weight loss interventions with or without weight loss medications were associated with more weight loss and a lower risk of developing diabetes than control conditions. Weight loss medications, but not behavior-based interventions, were associated with higher rates of harms. Long-term weight and health outcomes data, as well as data on important subgroups, were limited.

Evidence-based assessments of clinical actionability in the context of secondary findings: Updates from ClinGen's Actionability Working Group

The use of genome‐scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Groups (AWG) protocol for evidence synthesis and semi‐quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up‐to‐date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome‐related domains (severity and likelihood), but not on intervention‐related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.

Estimating data from figures with a Web-based program: Considerations for a systematic review

BACKGROUND Systematic reviewers often encounter incomplete or missing data, and the information desired may be difficult to obtain from a study author. Thus, systematic reviewers may have to resort to estimating data from figures with little or no raw data in a studys corresponding text or tables. METHODS We discuss a case study in which participants used a publically available Web-based program, called webplotdigitizer, to estimate data from 2 figures. We evaluated and used the intraclass coefficient and the accuracy of the estimates to the true data to inform considerations when using estimated data from figures in systematic reviews. RESULTS The estimates for both figures were consistent, although the distribution of estimates in the figure of a continuous outcome was slightly higher. For the continuous outcome, the percent difference ranged from 0.23% to 30.35% while the percent difference of the event rate ranged from 0.22% to 8.92%. For both figures, the intraclass coefficient was excellent (>0.95). CONCLUSIONS Systematic reviewers should consider and be transparent when estimating data from figures when the information cannot be obtained from study authors and perform sensitivity analyses of pooled results to reduce bias.