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PURPOSE Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens. We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program. METHODS Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality. The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care. Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and flexible sigmoidoscopies. Men received serial chest radiographs, flexible sigmoidoscopies, digital rectal examinations, and serum prostate-specific antigen tests. Fourteen screening examinations for each sex were possible during the 3-year screening period. RESULTS After 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%–61.0%) for men, and 48.8% (95% CI, 48.1%–49.4%) for women. The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%–29.3%) for men and 22.1% (95% CI, 21.4%–22.7%) for women. CONCLUSIONS For an individual in a multimodal cancer screening trial, the risk of a false-positive finding is about 50% or greater by the 14th test. Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer screening.

Current medical training often does not include the formal study of trial design, forcing clinicians to acquire this knowledge independently. This article reviews the foundational elements of clinical trial design. An overarching hierarchy of clinical evidence is introduced, and the relative strengths and limitations of the major types of study designs are discussed. A corollary to the hierarchy of evidence in trial designs is proposed for trial outcomes: the ‘‘pyramid of endpoints.” This pyramid represents a spectrum of outcomes from tangible health events to intermediate markers with no direct physical impact on an individual. The potential advantages and difficulties inherent in the use of surrogate endpoints for final health outcomes are explored. Randomized controlled trials utilizing ‘‘hard” clinical endpoints are advocated as the most efficient and reliable way to directly assess the benefits and harms of a therapy; however, using a case study of treatments for hepatocellular carcinoma, we highlight the challenges that can complicate even the highest levels of evidence. All trials have a ‘‘signal-to-noise” ratio – this review emphasizes the need for careful and deliberate consideration of the potential limitations of every study, and provides basic tools to assist the practitioner in identifying common pitfalls of clinical trials. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.

The concept of early detection of cancer holds great promise and intuitive appeal. However, powerful biases can mislead clinicians when evaluating the efficacy of screening tests by clinical observation alone. Selection bias, lead-time bias, length-biased sampling, and overdiagnosis are counterintuitive concepts with critical implications for early-detection efforts. This article explains these biases and other common confounders in cancer screening. The most direct and reliable way to avoid being led astray by intuitions is through the use of randomized controlled trials.

Direct-to-consumer promotion of lung cancer screening has increased, especially low-dose computed tomography (CT). However, screening exposes healthy persons to potential harms, and cumulative false-positive rates for low-dose CT have never been formally reported.To quantify the cumulative risk that a person who participated in a 1- or 2-year lung cancer screening examination would receive at least 1 false-positive result, as well as rates of unnecessary diagnostic procedures.Randomized, controlled trial of low-dose CT versus chest radiography. (ClinicalTrials.gov registration number: NCT00006382)Feasibility study for the ongoing National Lung Screening Trial.Current or former smokers, aged 55 to 74 years, with a smoking history of 30 pack-years or more and no history of lung cancer (n = 3190).Random assignment to low-dose CT or chest radiography with baseline and 1 repeated annual screening; 1-year follow-up after the final screening. Randomization was centralized and stratified by age, sex, and study center.False-positive screenings, defined as a positive screening with a completed negative work-up or 12 months or more of follow-up with no lung cancer diagnosis.By using a Kaplan-Meier analysis, a person's cumulative probability of 1 or more false-positive low-dose CT examinations was 21% (95% CI, 19% to 23%) after 1 screening and 33% (CI, 31% to 35%) after 2. The rates for chest radiography were 9% (CI, 8% to 11%) and 15% (CI, 13% to 16%), respectively. A total of 7% of participants with a false-positive low-dose CT examination and 4% with a false-positive chest radiography had a resulting invasive procedure.Screening was limited to 2 rounds. Follow-up after the second screening was limited to 12 months. The false-negative rate is probably an underestimate.Risks for false-positive results on lung cancer screening tests are substantial after only 2 annual examinations, particularly for low-dose CT. Further study of resulting economic, psychosocial, and physical burdens of these methods is warranted.National Cancer Institute.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

CRA1502 Background: Screening with low-dose computed tomography (LDCT) has been promoted as the best hope for curing lung cancer. However, cumulative false-positive (FP) rates have never been formally reported. We quantified the cumulative risk of receiving ≥1 FP test for individuals in a lung cancer screening program with 2 annual screens. Methods: Prior to the ongoing National Lung Screening Trial (NLST), a definitive randomized controlled trial of LDCT versus single-view chest xray (CXR), a randomized controlled feasibility trial was conducted at six NLST centers. Participants (55–74 years at entry, current or former smokers, and ≥ 30 pack/year smoking history) were offered a baseline LDCT (N = 1,610) or CXR (N = 1,580), and one repeat annual screen, and were followed for 1 year after their final screen. Participants who received at least one screening exam were eligible for this analysis. Exclusion criteria included chest CT in the past 24 months or history of lung cancer. A positive screen was any no...