Divergent Long-Term Detection Rates of Proximal and Distal Advanced Neoplasia in Fecal Immunochemical Test Screening Programs: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 169, No 9

Background: Short-term studies have reported that the fecal immunochemical test (FIT) is less accurate in detecting proximal than distal colorectal neoplasia. Objective: To assess the long-term detection rates for advanced adenoma and colorectal cancer (CRC), according to anatomical location. Design: Retrospective study. Setting: Population-based, organized screening program in the Veneto region of Italy. Participants: Persons aged 50 to 69 years who completed 6 rounds of FIT screening. Measurements: At each screening round, the detection rates for advanced adenoma and cancer, as well as the proportional interval cancer rate (PICR), were calculated by anatomical location (proximal colon, distal colon, or rectum). Results: Between 2002 and 2014, a total of 123 347 participants had 441 647 FITs. The numbers of advanced adenomas and cancer cases detected, respectively, were 1704 and 200 in the proximal colon, 3703 and 324 in the distal colon, and 1220 and 209 in the rectum. Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed. The PICR was higher in the proximal colon (25.2% [95% CI, 19.9% to 31.5%]) than the distal colon (6.0% [CI, 3.9% to 8.9%]) or rectum (9.9% [CI, 6.9% to 13.7%]). Limitations: Participants with irregular attendance were censored. Those who had a false-positive result on a previous FIT but negative colonoscopy results were included in subsequent rounds. Conclusion: This FIT-based, multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round. This was related to a higher PICR in the proximal colon and suboptimal efficacy in preventing the age-related proximal shifting of CRC. Primary Funding Source: None.

Precision Medicine in Internal Medicine

Medicine has long sought to match diagnostic and treatment approaches to the particular needs and risks of individual patients. The decreasing cost and increasing ease of genetic sequencing have propelled the rise of precision medicine. Precision medicine aims to use genetic and other information to provide care tailored to the individual patient, with the goal of improving clinical outcomes and minimizing unnecessary diagnostic and therapeutic interventions. Although developments in genetic sequencing have the potential to transform clinical care, there are important limitations, including uncertainty in the clinical interpretation of many genetic variants and concerns about privacy, discrimination, and cost. To help clinicians understand the basics of genetic sequencing and how to apply it in clinical practice, Annals of Internal Medicine is launching a new “Precision Medicine” series. This introduction provides a general overview of clinical sequencing, with a focus on germline variation. Subsequent articles will use a case-based format to provide concise summaries of specific clinical precision medicine scenarios that are relevant to the practice of internal medicine. These cases will highlight specific clinical indications; interpretation of genetic test results; and ethical, legal, cost, and privacy issues related to genetic testing. The goal is to provide practical information on the appropriate application and interpretation of genomics in routine clinical practice.

Does Using an iPad Make an Intervention Innovative?

Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota: A Systematic Review: Annals of Internal Medicine: Vol 169, No 4

Background: Probiotics, prebiotics, and synbiotics are used increasingly, although the safety and potential harms of these interventions are poorly understood. Purpose: To examine how harms-related information is reported in publications of randomized controlled trials (RCTs) of probiotics, prebiotics, and synbiotics. Data Sources: Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and Web of Science (without language restrictions) from 1 January 2015 to 20 March 2018. Study Selection: RCTs assessing the safety or efficacy of at least 1 intervention involving probiotics, prebiotics, or synbiotics alone or in combination with another intervention compared with any control (such as a placebo or an antibiotic) for any clinical condition. Data Extraction: 4 reviewers independently assessed study characteristics, the reporting of harms, and the presentation of safety results. Data Synthesis: Of 384 trials conducted in healthy volunteers (n = 136) or patients with any of several medical conditions (n = 248), 339 (88%) were published in specialty journals. Trials most often evaluated probiotics (n = 265 [69%]). Studies in persons with medical conditions enrolled outpatients (n = 195) and high-risk patients (n = 53). No harms-related data were reported for 106 trials (28%), safety results were not reported for 142 (37%), and the number of serious adverse events (SAEs) per study group was not given for 309 (80%). Of 242 studies mentioning harms-related results, 37% (n = 89) used only generic statements to describe AEs and 16% (n = 38) used inadequate metrics. Overall, 375 trials (98%) did not give a definition for AEs or SAEs, the number of participant withdrawals due to harms, or the number of AEs and SAEs per study group with denominators. Limitation: Journal publication processes may have affected the completeness of reporting; only English-language publications were examined. Conclusion: Harms reporting in published reports of RCTs assessing probiotics, prebiotics, and synbiotics often is lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data. Primary Funding Source: No specific funding.

Methods for Evaluating Natural Experiments in Obesity: A Systematic Review: Annals of Internal Medicine: Vol 168, No 11

Background: Given the obesity pandemic, rigorous methodological approaches, including natural experiments, are needed. Purpose: To identify studies that report effects of programs, policies, or built environment changes on obesity prevention and control and to describe their methods. Data Sources: PubMed, CINAHL, PsycINFO, and EconLit (January 2000 to August 2017). Study Selection: Natural experiments and experimental studies evaluating a program, policy, or built environment change in U.S. or non-U.S. populations by using measures of obesity or obesity-related health behaviors. Data Extraction: 2 reviewers serially extracted data on study design, population characteristics, data sources and linkages, measures, and analytic methods and independently evaluated risk of bias. Data Synthesis: 294 studies (188 U.S., 106 non-U.S.) were identified, including 156 natural experiments (53%), 118 experimental studies (40%), and 20 (7%) with unclear study design. Studies used 106 (71 U.S., 35 non-U.S.) data systems; 37% of the U.S. data systems were linked to another data source. For outcomes, 112 studies reported childhood weight and 32 adult weight; 152 had physical activity and 148 had dietary measures. For analysis, natural experiments most commonly used cross-sectional comparisons of exposed and unexposed groups (n = 55 [35%]). Most natural experiments had a high risk of bias, and 63% had weak handling of withdrawals and dropouts. Limitation: Outcomes restricted to obesity measures and health behaviors; inconsistent or unclear descriptions of natural experiment designs; and imperfect methods for assessing risk of bias in natural experiments. Conclusion: Many methodologically diverse natural experiments and experimental studies were identified that reported effects of U.S. and non-U.S. programs, policies, or built environment changes on obesity prevention and control. The findings reinforce the need for methodological and analytic advances that would strengthen evaluations of obesity prevention and control initiatives. Primary Funding Source: National Institutes of Health, Office of Disease Prevention, and Agency for Healthcare Research and Quality. (PROSPERO: CRD42017055750)

Influence of Varying Quantitative Fecal Immunochemical Test Positivity Thresholds on Colorectal Cancer Detection: A Community-Based Cohort Study: Annals of Internal Medicine: Vol 169, No 7

Background: The fecal immunochemical test (FIT) is commonly used for colorectal cancer (CRC) screening. Despite demographic variations in stool hemoglobin concentrations, few data exist regarding optimal positivity thresholds by age and sex. Objective: To identify programmatic (multitest) FIT performance characteristics and optimal FIT quantitative hemoglobin positivity thresholds in a large, population-based, screening program. Design: Retrospective cohort study. Setting: Kaiser Permanente Northern and Southern California. Participants: Adults aged 50 to 75 years who were eligible for screening and had baseline quantitative FIT results (2013 to 2014) and 2 years of follow-up. Nearly two thirds (411 241) had FIT screening in the previous 2 years. Measurements: FIT programmatic sensitivity for CRC and number of positive test results per cancer case detected, overall and by age and sex. Results: Of 640 859 persons who completed a baseline FIT and were followed for 2 years, 481 817 (75%) had at least 1 additional FIT and 1245 (0.19%) received a CRC diagnosis. Cancer detection (programmatic sensitivity) increased at lower positivity thresholds, from 822 in 1245 (66.0%) at 30 µg/g to 925 (74.3%) at 20 µg/g and 987 (79.3%) at 10 µg/g; the number of positive test results per cancer case detected increased from 43 at 30 µg/g to 52 at 20 µg/g and 85 at 10 µg/g. Reducing the positivity threshold from 20 to 15 µg/g would detect 3% more cancer cases and require 23% more colonoscopies. At the conventional FIT threshold of 20 µg/g, programmatic sensitivity decreased with increasing age (79.0%, 73.4%, and 68.9% for ages 50 to 59, 60 to 69, and 70 to 75 years, respectively; P = 0.009) and was higher in men than women (77.0% vs. 70.6%; P = 0.011). Limitation: Information on advanced adenoma was lacking. Conclusion: Increased cancer detection at lower positivity thresholds is counterbalanced by substantial increases in positive tests. Tailored thresholds may provide screening benefits that are more equal among different demographic groups, depending on local resources. Primary Funding Source: National Cancer Institute.

Transplanting Hepatitis C Virus–Infected Versus Uninfected Kidneys Into Hepatitis C Virus–Infected Recipients: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 169, No 4

Background: Direct-acting antiviral agents are now available to treat chronic hepatitis C virus (HCV) infection in patients with end-stage renal disease (ESRD). Objective: To examine whether it is more cost-effective to transplant HCV-infected or HCV-uninfected kidneys into HCV-infected patients. Design: Markov state-transition decision model. Data Sources: MEDLINE searches and bibliographies from relevant English-language articles. Target Population: HCV-infected patients with ESRD receiving hemodialysis in the United States. Time Horizon: Lifetime. Perspective: Health care system. Intervention: Transplant of an HCV-infected kidney followed by HCV treatment versus transplant of an HCV-uninfected kidney preceded by HCV treatment. Outcome Measures: Effectiveness, measured in quality-adjusted life-years (QALYs), and costs, measured in 2017 U.S. dollars. Results of Base-Case Analysis: Transplant of an HCV-infected kidney followed by HCV treatment was more effective and less costly than transplant of an HCV-uninfected kidney preceded by HCV treatment, largely because of longer wait times for uninfected kidneys. A typical 57.8-year-old patient receiving hemodialysis would gain an average of 0.50 QALY at a lifetime cost savings of $41 591. Results of Sensitivity Analysis: Transplant of an HCV-infected kidney followed by HCV treatment continued to be preferred in sensitivity analyses of many model parameters. Transplant of an HCV-uninfected kidney preceded by HCV treatment was not preferred unless the additional wait time for an uninfected kidney was less than 161 days. Limitation: The study did not consider the benefit of decreased HCV transmission from treating HCV-infected patients. Conclusion: Transplanting HCV-infected kidneys into HCV-infected patients increased quality-adjusted life expectancy and reduced costs compared with transplanting HCV-uninfected kidneys into HCV-infected patients. Primary Funding Source: Merck Sharp & Dohme and the National Center for Advancing Translational Sciences.

Terminal

The Role of Genetic Counseling in Familial and Sporadic Cancer: Considerations, Challenges, and Collaboration

Effect of a Digital Health Intervention on Receipt of Colorectal Cancer Screening in Vulnerable Patients: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 168, No 8

Background: Screening for colorectal cancer (CRC) reduces mortality, yet more than one third of age-eligible Americans are unscreened. Objective: To examine the effect of a digital health intervention, Mobile Patient Technology for Health–CRC (mPATH-CRC), on rates of CRC screening. Design: Randomized clinical trial. (ClinicalTrials.gov: NCT02088333) Setting: 6 community-based primary care practices. Participants: 450 patients (223 in the mPATH-CRC group and 227 in usual care) scheduled for a primary care visit and due for routine CRC screening. Intervention: An iPad application that displays a CRC screening decision aid, lets patients order their own screening tests, and sends automated follow-up electronic messages to support patients. Measurements: The primary outcome was chart-verified completion of CRC screening within 24 weeks. Secondary outcomes were ability to state a screening preference, intention to receive screening, screening discussions, and orders for screening tests. All outcome assessors were blinded to randomization. Results: Baseline characteristics were similar between groups; 37% of participants had limited health literacy, and 53% had annual incomes less than $20 000. Screening was completed by 30% of mPATH-CRC participants and 15% of those receiving usual care (logistic regression odds ratio, 2.5 [95% CI, 1.6 to 4.0]). Compared with usual care, more mPATH-CRC participants could state a screening preference, planned to be screened within 6 months, discussed screening with their provider, and had a screening test ordered. Half of mPATH-CRC participants (53%; 118 of 223) “self-ordered” a test via the program. Limitation: Participants were English speakers in a single health care system. Conclusion: A digital health intervention that allows patients to self-order tests can increase CRC screening. Future research should identify methods for implementing similar interventions in clinical care. Primary Funding Source: National Cancer Institute.