Referral strategies based on risk scores and medical tests are commonly proposed. Direct assessment of their clinical utility requires implementing the strategy and is not possible in the early ...phases of biomarker research. Prior to late‐phase studies, net benefit measures can be used to assess the potential clinical impact of a proposed strategy. Validation studies, in which the biomarker defines a prespecified referral strategy, are a gold standard approach to evaluating biomarker potential. Uncertainty, quantified by a confidence interval, is important to consider when deciding whether a biomarker warrants an impact study, does not demonstrate clinical potential, or that more data are needed. We establish distribution theory for empirical estimators of net benefit and propose empirical estimators of variance. The primary results are for the most commonly employed estimators of net benefit: from cohort and unmatched case‐control samples, and for point estimates and net benefit curves. Novel estimators of net benefit under stratified two‐phase and categorically matched case‐control sampling are proposed and distribution theory developed. Results for common variants of net benefit and for estimation from right‐censored outcomes are also presented. We motivate and demonstrate the methodology with examples from lung cancer research and highlight its application to study design.
To investigate whether a panel of circulating protein biomarkers would improve risk assessment for lung cancer screening in combination with a risk model on the basis of participant characteristics.
...A blinded validation study was performed using prostate lung colorectal ovarian (PLCO) Cancer Screening Trial data and biospecimens to evaluate the performance of a four-marker protein panel (4MP) consisting of the precursor form of surfactant protein B, cancer antigen 125, carcinoembryonic antigen, and cytokeratin-19 fragment in combination with a lung cancer risk prediction model (PLCO
) compared with current US Preventive Services Task Force (USPSTF) screening criteria. The 4MP was assayed in 1,299 sera collected preceding lung cancer diagnosis and 8,709 noncase sera.
The 4MP alone yielded an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.77 to 0.82) for case sera collected within 1-year preceding diagnosis and 0.74 (95% CI, 0.72 to 0.76) among the entire specimen set. The combined 4MP + PLCO
model yielded an area under the receiver operating characteristic curve of 0.85 (95% CI, 0.82 to 0.88) for case sera collected within 1 year preceding diagnosis. The benefit of the 4MP in the combined model resulted from improvement in sensitivity at high specificity. Compared with the USPSTF2021 criteria, the combined 4MP + PLCO
model exhibited statistically significant improvements in sensitivity and specificity. Among PLCO participants with ≥ 10 smoking pack-years, the 4MP + PLCO
model would have identified for annual screening 9.2% more lung cancer cases and would have reduced referral by 13.7% among noncases compared with USPSTF2021 criteria.
A blood-based biomarker panel in combination with PLCO
significantly improves lung cancer risk assessment for lung cancer screening.
Decision curves are a tool for evaluating the population impact of using a risk model for deciding whether to undergo some intervention, which might be a treatment to help prevent an unwanted ...clinical event or invasive diagnostic testing such as biopsy. The common formulation of decision curves is based on an opt-in framework. That is, a risk model is evaluated based on the population impact of using the model to opt high-risk patients into treatment in a setting where the standard of care is not to treat. Opt-in decision curves display the population net benefit of the risk model in comparison to the reference policy of treating no patients. In some contexts, however, the standard of care in the absence of a risk model is to treat everyone, and the potential use of the risk model would be to opt low-risk patients out of treatment. Although opt-out settings were discussed in the original decision curve paper, opt-out decision curves are underused. We review the formulation of opt-out decision curves and discuss their advantages for interpretation and inference when treat-all is the standard.
Background. Microsimulation models synthesize evidence about disease processes and interventions, providing a method for predicting long-term benefits and harms of prevention, screening, and ...treatment strategies. Because models often require assumptions about unobservable processes, assessing a model’s predictive accuracy is important. Methods. We validated 3 colorectal cancer (CRC) microsimulation models against outcomes from the United Kingdom Flexible Sigmoidoscopy Screening (UKFSS) Trial, a randomized controlled trial that examined the effectiveness of one-time flexible sigmoidoscopy screening to reduce CRC mortality. The models incorporate different assumptions about the time from adenoma initiation to development of preclinical and symptomatic CRC. Analyses compare model predictions to study estimates across a range of outcomes to provide insight into the accuracy of model assumptions. Results. All 3 models accurately predicted the relative reduction in CRC mortality 10 years after screening (predicted hazard ratios, with 95% percentile intervals: 0.56 0.44, 0.71, 0.63 0.51, 0.75, 0.68 0.53, 0.83; estimated with 95% confidence interval: 0.56 0.45, 0.69). Two models with longer average preclinical duration accurately predicted the relative reduction in 10-year CRC incidence. Two models with longer mean sojourn time accurately predicted the number of screen-detected cancers. All 3 models predicted too many proximal adenomas among patients referred to colonoscopy. Conclusion. Model accuracy can only be established through external validation. Analyses such as these are therefore essential for any decision model. Results supported the assumptions that the average time from adenoma initiation to development of preclinical cancer is long (up to 25 years), and mean sojourn time is close to 4 years, suggesting the window for early detection and intervention by screening is relatively long. Variation in dwell time remains uncertain and could have important clinical and policy implications.
We recently reported that circulating apolipoprotein AII (apoAII) isoforms apoAII-ATQ/AT (C-terminal truncations of the apoAII homo-dimer) decline significantly in pancreatic cancer and thus might ...serve as plasma biomarkers for the early detection of this disease. We report here the development of novel enzyme-linked immunosorbent assays (ELISAs) for measurement of apoAII-ATQ/AT and their clinical applicability for early detection of pancreatic cancer. Plasma and serum concentrations of apoAII-ATQ/AT were measured in three independent cohorts, which comprised healthy control subjects and patients with pancreatic cancer and gastroenterologic diseases (n = 1156). These cohorts included 151 cases of stage I/II pancreatic cancer. ApoAII-ATQ/AT not only distinguished the early stages of pancreatic cancer from healthy controls but also identified patients at high risk for pancreatic malignancy. AUC values of apoAII-ATQ/AT to detect early stage pancreatic cancer were higher than those of CA19-9 in all independent cohorts. ApoAII-ATQ/AT is a potential biomarker for screening patients for the early stage of pancreatic cancer and identifying patients at risk for pancreatic malignancy (161 words).
Colorectal cancer (CRC) screening is underutilized despite evidence that screening improves survival. Since healthcare provider recommendation is a strong predictor of CRC screening completion, ...providers are encouraged to engage eligible patients in collaborative decision-making that attends to patients' values, needs, and preferences for guideline-concordant screening modalities.
This three-arm randomized controlled trial is testing the effectiveness of an evidence-based video intervention informing patients of screening choices delivered in a clinic prior to a healthcare appointment. We hypothesize that participants randomized to watch a basic video describing CRC and screening in addition to an informed choice video showing the advantages and disadvantages of fecal immunochemical test (FIT), stool DNA FIT (s-DNA FIT), and colonoscopy (Arm 3) will exhibit a greater proportion of time adherent to CRC screening guidelines after 1, 3 and 6 years than those who only watch the basic video (Arm 2) or no video at all (Arm 1). Primary care and Obstetrician/Gynecology clinics across the United States are recruiting 5280 patients, half who have never been screened and half who previously screened but are currently not guideline adherent. Participants complete surveys prior to and following an index appointment to self-report personal, cognitive, and environmental factors potentially associated with screening. Proportion of time adherent to screening guidelines will be assessed using medical record data and supplemented with annual surveys self-reporting screening.
Results will provide evidence on the effectiveness of informational and motivational videos to encourage CRC screening that can be easily integrated into clinical practice.
Clinicaltrials.gov #NCT05246839
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