Phase 3 Validation of Prognostic Liver Secretome Signature With α-Fetoprotein Plus Age, Male Sex, Albumin-Bilirubin, and Platelets for Hepatocellular Carcinoma Risk Stratification in Cirrhosis.

Background & Aims: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis.

Methods: Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events.

A Phase 3 Biomarker Validation of GALAD for the Detection of Hepatocellular Carcinoma in Cirrhosis.

Background & Aims: Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des-γ carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC.

Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study.

Background & Aims: Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S.

Multicenter Validation of Abbreviated MRI for Detecting Early-Stage Hepatocellular Carcinoma.

Background Abbreviated MRI is a proposed paradigm shift for hepatocellular carcinoma (HCC) surveillance, but data on its performance are lacking for histopathologically confirmed early-stage HCC. Purpose To evaluate the sensitivity and specificity of dynamic contrast-enhanced abbreviated MRI for early-stage HCC detection, using surgical pathologic findings as the reference standard. Materials and Methods This retrospective study was conducted at three U.

Blood-Based Biomarker Panel for Personalized Lung Cancer Risk Assessment.

Purpose: 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.

Methods: 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.

Statistical inference for net benefit measures in biomarker validation studies.

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.

Applying sequential surveillance methods that use regression adjustment or weighting to control confounding in a multisite, rare-event, distributed setting: Part 2 in-depth example of a reanalysis of the measles-mumps-rubella-varicella combination vaccine and seizure risk.

Objective: In-depth example of two new group sequential methods for postmarket safety monitoring of new medical products.

Study Design And Setting: Existing trial-based group sequential approaches have been extended to adjust for confounders, accommodate rare events, and address privacy-related constraints on data sharing. Most adaptations have involved design-based confounder strategies, for example, self-controlled or exposure matching, while analysis-based approaches like regression and weighting have received less attention.

Assessing the Clinical Impact of Risk Models for Opting Out of Treatment.

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.

A Plasma Biomarker Panel to Identify Surgically Resectable Early-Stage Pancreatic Cancer.

Background: Blood-based biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are urgently needed. Current biomarkers lack high sensitivity and specificity for population screening. The gold-standard biomarker, CA 19-9, also fails to demonstrate the predictive value necessary for early detection.

Validation of Models Used to Inform Colorectal Cancer Screening Guidelines: Accuracy and Implications.

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.

Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic malignancy using antibodies for apolipoprotein-AII isoforms.

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).

Validation sampling can reduce bias in health care database studies: an illustration using influenza vaccination effectiveness.

Objectives: Estimates of treatment effectiveness in epidemiologic studies using large observational health care databases may be biased owing to inaccurate or incomplete information on important confounders. Study methods that collect and incorporate more comprehensive confounder data on a validation cohort may reduce confounding bias.

Study Design And Setting: We applied two such methods, namely imputation and reweighting, to Group Health administrative data (full sample) supplemented by more detailed confounder data from the Adult Changes in Thought study (validation sample).

Vaccination site and risk of local reactions in children 1 through 6 years of age.

Objective: Our objective was to assess whether the occurrence of medically attended local reactions to intramuscularly administered vaccines varies by injection site (arm versus thigh) in children 1 to 6 years of age.

Methods: This is a retrospective cohort study of children in the Vaccine Safety Datalink population from 2002 to 2009. Site of injection and the outcome of medically attended local reactions were identified from administrative data.

Statistical approaches to group sequential monitoring of postmarket safety surveillance data: current state of the art for use in the Mini-Sentinel pilot.

Purpose: This manuscript describes the current statistical methodology available for active postmarket surveillance of pre-specified safety outcomes using a prospective incident user concurrent control cohort design with existing electronic healthcare data.

Methods: Motivation of the active postmarket surveillance setting is provided using the Food and Drug Administration's Mini-Sentinel Pilot as an example. Four sequential monitoring statistical methods are presented including the Lan-Demets error spending approach, a matched likelihood ratio test statistic approach with the binomial MaxSPRT as a special case, the conditional sequential sampling procedure with stratification, and a generalized estimating equation regression approach using permutation.