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.

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.

Screening for Urinary Incontinence in Women: A Systematic Review for the Women's Preventive Services Initiative

Background: Urinary incontinence is infrequently addressed during routine health care despite its high prevalence and adverse effects on health. Purpose: To evaluate whether screening for urinary incontinence in women not previously diagnosed improves outcomes (symptoms, quality of life, and function) and to evaluate the accuracy of screening methods and potential harms of screening. Data Sources: English-language searches of Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (1 January 1996 to 30 March 2018); ClinicalTrials.gov (April 2018); and reference lists of studies and reviews. Study Selection: Randomized trials, cohort studies, systematic reviews of studies that enrolled nonpregnant women without previously diagnosed urinary incontinence and compared clinical outcomes and adverse effects between women who were and were not screened, and diagnostic accuracy studies that reported performance measures of screening tests. Data Extraction: Dual extraction and quality assessment of individual studies. Data Synthesis: No studies evaluated the overall effectiveness or harms of screening. Seventeen studies evaluated the diagnostic accuracy of 18 screening questionnaires against a clinical diagnosis or results of diagnostic tests. Of these, 14 poor-quality studies were based in referral clinics, enrolled only symptomatic women, or had other limitations. One good-quality and 2 fair-quality studies (evaluating 4 methods) enrolled women not recruited on the basis of symptoms. Areas under the receiver-operating characteristic curve for stress, urge, and any type of incontinence in these studies were 0.79, 0.88, and 0.88 for the Michigan Incontinence Symptom Index; 0.85, 0.83, and 0.87 for the Bladder Control Self-Assessment Questionnaire; and 0.68, 0.82, and 0.75 for the Overactive Bladder Awareness Tool. The Incontinence Screening Questionnaire had a sensitivity of 66% and specificity of 80% for any type of incontinence. Limitation: Studies enrolled few participants, often from symptomatic referral populations; used various reference standards; and infrequently reported CIs. Conclusion: Evidence is insufficient on the overall effectiveness and harms of screening for urinary incontinence in women. Limited evidence in general populations suggests fairly high accuracy for some screening methods. Primary Funding Source: Health Resources and Services Administration.

Prognostic Implications of Single-Sample Confirmatory Testing for Undiagnosed Diabetes: A Prospective Cohort Study: Annals of Internal Medicine: Vol 169, No 3

Background: Current clinical definitions of diabetes require repeated blood work to confirm elevated levels of glucose or hemoglobin A1c (HbA1c) to reduce the possibility of a false-positive diagnosis. Whether 2 different tests from a single blood sample provide adequate confirmation is uncertain. Objective: To examine the prognostic performance of a single-sample confirmatory definition of undiagnosed diabetes. Design: Prospective cohort study. Setting: The ARIC (Atherosclerosis Risk in Communities) study. Participants: 13 346 ARIC participants (12 268 without diagnosed diabetes) with 25 years of follow-up for incident diabetes, cardiovascular outcomes, kidney disease, and mortality. Measurements: Confirmed undiagnosed diabetes was defined as elevated levels of fasting glucose (≥7.0 mmol/L [≥126 mg/dL]) and HbA1c (≥6.5%) from a single blood sample. Results: Among 12 268 participants without diagnosed diabetes, 978 had elevated levels of fasting glucose or HbA1c at baseline (1990 to 1992). Among these, 39% had both (confirmed undiagnosed diabetes), whereas 61% had only 1 elevated measure (unconfirmed undiagnosed diabetes). The confirmatory definition had moderate sensitivity (54.9%) but high specificity (98.1%) for identification of diabetes cases diagnosed during the first 5 years of follow-up, with specificity increasing to 99.6% by 15 years. The 15-year positive predictive value was 88.7% compared with 71.1% for unconfirmed cases. Confirmed undiagnosed diabetes was significantly associated with cardiovascular and kidney disease and mortality, with stronger associations than unconfirmed diabetes. Limitation: Lack of repeated measurements of fasting glucose and HbA1c. Conclusion: A single-sample confirmatory definition of diabetes had a high positive predictive value for subsequent diagnosis and was strongly associated with clinical end points. Our results support the clinical utility of using a combination of elevated fasting glucose and HbA1c levels from a single blood sample to identify undiagnosed diabetes in the population. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute.

Persistence and Drivers of High-Cost Status Among Dual-Eligible Medicare and Medicaid Beneficiaries: An Observational Study: Annals of Internal Medicine: Vol 169, No 8

Background: Little is known about the persistence of high-cost status among dual-eligible Medicare and Medicaid beneficiaries, who account for a substantial proportion of expenditures in both programs. Objective: To determine what proportion of this population has persistently high costs. Design: Observational study. Setting: Medicare–Medicaid Linked Enrollee Analytic Data Source data for 2008 to 2010. Participants: 1 928 340 dual-eligible Medicare and Medicaid beneficiaries who were alive all 3 years. Measurements: Medicare and Medicaid payments for these beneficiaries were calculated for each year. Beneficiaries were categorized as high-cost for a given year if their spending was in the top 10% for that year. Differences in spending were then examined for those who were persistently high-cost (all 3 years) versus those who were transiently high-cost (2008 but not 2009 or 2010) and those who were non–high-cost in all 3 years. Results: In the first year, 192 835 patients were high-cost. More than half (54.8%) remained high-cost across all 3 years. These patients were younger than transiently high-cost patients, with fewer medical comorbidities and greater intellectual impairment. Persistently high-cost patients spent $161 224 per year compared with $86 333 per year for transiently high-cost patients and $22 352 per year for non–high-cost patients. Most of the spending among persistently high-cost patients (68.8%) was related to long-term care, and very little (<1%) was related to potentially preventable hospitalizations for ambulatory care–sensitive conditions. Limitation: Potential misclassification of preventable spending and lack of detailed clinical data in administrative claims. Conclusion: A substantial majority of high-cost dual-eligible beneficiaries had persistently high costs over 3 years, with most of the cost related to long-term care and very little related to potentially preventable hospitalizations. Primary Funding Source: Peterson Center on Healthcare.

Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2018*

High-Deductible Insurance and Delay in Care for the Macrovascular Complications of Diabetes

Background: Little is known about the long-term effects of high-deductible insurance on care for chronic medical conditions. Objective: To determine whether a transition from low-deductible to high-deductible insurance is associated with delayed medical care for macrovascular complications of diabetes. Design: Observational longitudinal comparison of matched groups. Setting: A large national health insurer during 2003 to 2012. Participants: The intervention group comprised 33 957 persons with diabetes who were continuously enrolled in low-deductible (≤$500) insurance plans during a baseline year followed by up to 4 years in high-deductible (≥$1000) plans. The control group included 294 942 persons with diabetes who were enrolled in low-deductible plans contemporaneously with matched intervention group members. Intervention: Employer-mandated transition to a high-deductible plan. Measurements: The number of months it took for persons in each study group to seek care for their first major macrovascular symptom, have their first major diagnostic test for macrovascular disease, and have their first major procedure-based treatment was determined. Between-group differences in time to reach a midpoint event rate were then calculated. Results: No baseline differences were found between groups. During follow-up, the delay for the high-deductible group was 1.5 months (95% CI, 0.8 to 2.3 months) for seeking care for the first major symptom, 1.9 months (CI, 1.4 to 2.3 months) for the first diagnostic test, and 3.1 months (CI, 0.5 to 5.8 months) for the first procedure-based treatment. Limitation: Health outcomes were not examined. Conclusion: Among persons with diabetes, mandated enrollment in a high-deductible insurance plan was associated with delays in seeking care for the first major symptoms of macrovascular disease, the first diagnostic test, and the first procedure-based treatment. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases.

Model-Based Eligibility for Lung Cancer Screening: Where Theory Meets Practice

Long-Term Outcomes Among Patients Discharged From the Hospital With Moderate Anemia: A Retrospective Cohort Study: Annals of Internal Medicine: Vol 170, No 2

Background: Randomized clinical trial findings support decreased red blood cell (RBC) transfusion and short-term tolerance of in-hospital anemia. However, long-term outcomes related to changes in transfusion practice have not been described. Objective: To describe the prevalence of anemia at and after hospital discharge and associated morbidity and mortality events. Design: Retrospective cohort study. Setting: Integrated health care delivery system with 21 hospitals serving 4 million members. Participants: 445 371 surviving adults who had 801 261 hospitalizations between January 2010 and December 2014. Measurements: Hemoglobin levels and RBC transfusion, rehospitalization, and mortality events within 6 months of hospital discharge. Generalized estimating equations were used to examine trends over time, accounting for correlated observations and patient-level covariates. Results: From 2010 to 2014, the prevalence of moderate anemia (hemoglobin levels between 7 and 10 g/dL) at hospital discharge increased from 20% to 25% (P < 0.001) and RBC transfusion declined by 28% (39.8 to 28.5 RBC units per 1000 patients; P < 0.001). The proportion of patients whose moderate anemia had resolved within 6 months of hospital discharge decreased from 42% to 34% (P < 0.001), and RBC transfusion and rehospitalization within 6 months of hospital discharge decreased from 19% to 17% and 37% to 33%, respectively (P < 0.001 for both). During this period, the adjusted 6-month mortality rate decreased from 16.1% to 15.6% (P = 0.004) in patients with moderate anemia, in parallel with that of all others. Limitation: Possible unmeasured confounding. Conclusion: Anemia after hospitalization increased in parallel with decreased RBC transfusion. This increase was not accompanied by a rise in subsequent RBC use, rehospitalization, or mortality within 6 months of hospital discharge. Longitudinal analyses support the safety of practice recommendations to limit RBC transfusion and tolerate anemia during and after hospitalization. Primary Funding Source: National Heart, Lung, and Blood Institute.

The ACC/AHA 2017 Hypertension Guidelines: Both Too Much and Not Enough of a Good Thing?