Data Sharing, Clinical Trials, and Biomarkers in Precision Oncology: Challenges, Opportunities, and Programs at the Department of Veterans Affairs.

Cancer genomic research reveals that a similar cancer clinical phenotype (e.g., non-small cell lung cancer) can arise from various mutations in tumor DNA. Thus, organ of origin is not a definitive classification. Further, targeted therapy for cancer patients (precision oncology) capitalizes on knowledge of individual patient mutational status to deliver treatment directed against the protein products of these mutations with the goal of reducing toxicity and enhancing efficacy relative to traditional nontargeted chemotherapy.

Two-year weight-loss maintenance in primary care-based Diabetes Prevention Program lifestyle interventions.

OBJECTIVE: To investigate whether the effects on weight loss and cardiometabolic risk factor reduction of two technology-mediated lifestyle interventions for 15 months in a primary care-based translation trial sustained at 24 months (that is, 9 months after the end of intervention). DESIGN: This study analyzed data from an extended follow-up of participants in the original 'E-LITE' (Evaluation of Lifestyle Interventions to Treat Elevated Cardiometabolic Risk in Primary Care)-randomized controlled trial, which demonstrated the effectiveness of two adapted Diabetes Prevention Program (DPP) lifestyle interventions compared with usual primary care. SUBJECTS: E-LITE randomized 241 overweight or obese participants with pre-diabetes and/or metabolic syndrome to receive usual care alone (n=81) or usual care plus a coach-led (n=79) or self-directed intervention (n=81). The interventions provided coach-led group behavioral weight-loss treatment or a take-home, self-directed DVD using the same 12-week curriculum, followed by 12 additional months of technology-mediated coach contact and self-monitoring support. Participants received no further intervention after month 15. A blinded assessor conducted 24-month visits by following the measurement protocols of the original trial. Measurements include weight and cardiometabolic risk factors (waist circumference, fasting plasma glucose, resting blood pressure, triglycerides, high- and low-density lipoprotein cholesterol, total cholesterol and triglyceride to high-density lipoprotein cholesterol ratio). RESULTS: At month 24, mean±s.e. changes in body mass index (trial primary outcome) and weight (kg) from baseline were -1.9±0.3 (P=0.001) and -5.4±0.9 (P<0.001) in the coach-led intervention, and -1.6±0.3 (P=0.03) and -4.5±0.9 (P=0.001) in the self-directed intervention, compared with -0.9±0.3 and 2.4±0.9 in the usual care group. In addition, both interventions led to a greater percentage of participants maintaining 7% weight loss and sustained improvements in waist circumference and fasting plasma glucose levels than usual care. CONCLUSION: This study shows sustained benefits of the two primary care-based, technology-mediated DPP lifestyle interventions. The findings warrant replication in long-term studies involving diverse populations.

Eating attitudes in high school students in the Philippines: a preliminary study.

PURPOSE: The purpose of this study was to examine the prevalence of abnormal eating attitudes among high school students from Pasig Catholic College in the Philippines. METHODS: Two survey questionnaires, the Eating Attitudes Test (EAT) and Beck's Depression Inventory (BDI), were administered to 932 high school students. The height and weight of the subjects were measured, and their body mass indices (BMI) calculated. RESULTS: The prevalence of abnormal eating attitudes according to the EAT scores was 14.5 +/- 3.2% among males and 15.0 +/- 3.5% among females, comparable to the 7-22% found in Western countries. There was a weak correlation between the EAT scores and BMI (r=0.180, p=0.01), and between the EAT scores and Beck's Depression Inventory (r=0.187, p=0.01). CONCLUSIONS: The results indicate the presence of abnormal eating attitudes among Filipino high school students from Pasig Catholic College, which suggests that further study of eating disorders and their associated risks is warranted.

Strengthening clinical effectiveness trials: equipoise-stratified randomization.

As psychiatric practice patterns evolve to take advantage of the growing list of treatments with proven efficacy, research studies with broader aims will become increasingly important. Randomized trials may need to accommodate multiple treatment options. In completely randomized designs, patients are assigned at random to one of the options, requiring that patients and clinicians find each of the options acceptable. In "clinician's choice" designs, patients are randomized to a small number of broad strategies and the choice of specific option within the broad strategy is left up to the clinician. The clinician's choice design permits some scope to patient and clinician preferences, but sacrifices the ability to make randomization-based comparisons of specific options. We describe a new approach, which we call the "equipoise stratified" design, that merges the advantages and avoids the disadvantages of the other two designs for clinical trials. The three designs are contrasted, using the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression trial as an example.

Use of a simple symptom questionnaire to predict Barrett's esophagus in patients with symptoms of gastroesophageal reflux.

OBJECTIVE: Accurately predicting Barrett's esophagus (BE) in patients with gastroesophageal reflux disease (GERD) is difficult. Using logistic regression analysis of symptom questionnaire scores we created a model to predict the presence of BE. METHODS: We conducted a logistic regression analysis of symptom data collected prospectively on 517 GERD patients and created a prediction model based on patient gender, age, ethnicity, and symptom severity. RESULTS: There were 337 (65%) males and 180 (35%) females, of whom 99 (19%) had Barrett's esophagus (BE). Multiple logistic regression analysis was performed to determine the predictive ability of gender, age, and ethnicity along with symptoms of heartburn, nocturnal pain, odynophagia, presence of belching, dysphagia, relief of symptoms with food, and nausea. The only significant predictors (at the 0.05 level) were male gender, heartburn, nocturnal pain, and odynophagia (all with positive effects on the presence of BE) and dysphagia (which had a negative effect). A nomogram was produced to show the effect of a given predictor on the probability of having BE in the context of the effects of the other predictors, and to estimate the probability of having BE for a given individual. The mean score (+/-SD) for the BE patients in our sample was 397.4+/-46.2 with a range of 292-530. For the patients without BE, the mean score (+/-SD) was 351.3+/-60.3 with a range of 190 - 528 (p < 0.001). If screening for BE is performed at a score of 375 or more, our model would have a specificity of 63% with a sensitivity of 77% (95% CI 61-86% given the 63% specificity). CONCLUSIONS: By asking seven questions about symptom severity, clinicians may be able to assign a probability to the presence of BE, and thus, determine the need for endoscopy in GERD patients.

Design of Department of Veterans Affairs Cooperative Study no. 420: group treatment of posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a significant problem for a large number of veterans who receive treatment from the Department of Veterans Affairs (VA) health-care system. VA Cooperative Study 420 is a randomized clinical trial of group psychotherapy for treating PTSD among veterans who sought VA care. Participants at ten sites were randomly assigned to receive one of the two treatments: active treatment that embedded exposure therapy in a group context or comparison treatment that avoided trauma focus and instead addressed current interpersonal problems. Treatment was delivered weekly to groups of six participants for 30 weeks, followed by five monthly booster sessions. Follow-up assessments were conducted at the end of treatment (7 months) and the end of boosters (12 months) for all participants. Long-term follow-up data were collected for a subset of participants at 18 and 24 months. The primary outcome is PTSD severity; other symptoms, functional status, quality of life, physical health, and service utilization also were assessed. Data analysis will account for the clustering introduced by the group nature of the intervention. The pivotal comparison was at the end of treatment. Analyses of subsequent outcomes will concentrate on the question of the durability of effects. The study provides an example of how to address the unique challenges posed by multisite trials of group psychotherapy through attention to methodological and statistical issues. This article discusses these challenges and describes the design and methods of the study. Control Clin Trials 2001;22:74-88

Non-Q-wave myocardial infarction following thrombolytic therapy: a comparison of outcomes in patients randomized to invasive or conservative post-infarct assessment strategies in the Veterans Affairs non-Q-wave Infarction Strategies In-Hospital (VANQWISH) Trial.

OBJECTIVES: We wished to determine the effect of post-infarct management strategy on event rates (death or recurrent nonfatal myocardial infarction [MI]) in patients who evolved non-Q-wave MI (NQMI) following thrombolytic therapy. BACKGROUND: Patients who evolve NQMI following thrombolytic therapy are often considered to be at high risk and are frequently managed with routine early invasive testing despite a lack of data supporting improved outcome. METHODS: The Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study included 115 patients who evolved NQMI following thrombolytic therapy. We compared the event rates in patients randomized to routine early coronary angiography with those in patients randomized to a conservative strategy of noninvasive functional assessment, with angiography reserved for patients with spontaneous or induced ischemia. RESULTS: During an average follow-up of 23 months, 19 of 58 patients (33%) randomized to the invasive management strategy died or suffered recurrent nonfatal MI, compared with 11 of 57 patients (19%) randomized to the conservative strategy (p = 0.152). Equivalent numbers of patients were subjected to revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass graft). There were more deaths in the invasive management group than in the conservative management group (11 vs. 2). Excess deaths could not be attributed to periprocedural mortality. CONCLUSIONS: Overall event rates (death or recurrent nonfatal MI) are comparable with conservative and invasive strategies in patients who evolve NQMI following thrombolytic therapy. Mortality rate in patients managed conservatively is low (3.5%), and routine invasive management may be associated with an increased risk of death.

Early invasive versus ischaemia-guided strategies in the management of non-Q wave myocardial infarction patients with and without prior myocardial infarction; results of Veterans Affairs Non-Q Wave Infarction Strategies in Hospital (VANQWISH) trial.

AIMS: To compare the role of early invasive vs conservative management strategies in treating patients with non-Q wave myocardial infarction with or without a prior myocardial infarction. BACKGROUND: In patients recovering from non-Q wave myocardial infarction, the prognosis among patients with a first non-Q wave myocardial infarction is significantly better than in patients with a prior myocardial infarction, yet physicians often adopt an early invasive strategy to treat patients with a first non-Q wave myocardial infarction. METHODS: Non-Q wave myocardial infarction patients enrolled in the VANQWISH trial with a history of prior myocardial infarction were compared to those with a first non-Q wave myocardial infarction, for the trial primary end-point of death or myocardial infarction at 1 and 12 months, as well as for the initial randomized treatment strategy. RESULTS: Of the 920 non-Q wave myocardial infarction patients, 396 had a history of prior myocardial infarction and 524 did not. Patients with a history of prior myocardial infarction were older and had a higher incidence of multiple high-risk baseline characteristics than those with a first non-Q wave myocardial infarction. Compared to the group with a first myocardial infarction, the prior myocardial infarction group suffered more events at both 1 month (11% vs 6%, P=0.007) and at 12 months (29% vs 16%, P<0.001). This difference in outcome remained significant even after adjusting for confounding variables (P<0.0001 at 12 months). Among the non-Q wave myocardial infarction patients with a prior myocardial infarction, the frequency of death or recurrent myocardial infarction was similar in both invasive and conservative groups during the first year of follow-up. Among the first non-Q wave myocardial infarction group, those assigned to the conservative strategy had significantly fewer events (3% vs 9%, P=0.009 at 1 month; 12% vs 20%, P=0.016 at 12 months) and mortality (1% vs 5%, P=0.012 at one month; 5% vs 11%, P=0.009 at 12 months) than those assigned to early invasive strategy. CONCLUSION: A history of prior myocardial infarction identifies a moderately high-risk subset of non-Q wave myocardial infarction patients who display similar long-term outcomes regardless of the strategy assignment; however, patients with a first non-Q wave myocardial infarction may fare better with a conservative or ischaemia-guided approach during the first post infarction year.

Electronic trial banks: a complementary method for reporting randomized trials.

BACKGROUND: Randomized clinical trial (RCT) results are often difficult to find, interpret, or apply to clinical care. The authors propose that RCTs be reported into electronic knowledge bases-trial banks-in addition to being reported in text. What information should these trial-bank reports contain? METHODS: Using the competency decomposition method, the authors specified the ideal trial-bank contents as the information necessary and sufficient for completing the task of systematic reviewing. RESULTS: They decomposed the systematic reviewing task into four top-level tasks and 62 subtasks. 162 types of trial information were necessary and sufficient for completing these subtasks. These items relate to a trial's design, execution, administration, and results. CONCLUSION: Trial-bank publishing of these 162 items would capture into computer-understandable form all the trial information needed for critically appraising and synthesizing trial results. Decision-support systems that access shared, up-to-date trial banks could help clinicians manage, synthesize, and apply RCT evidence more effectively.

Flexible treatment strategies in chronic disease: clinical and research implications.

Multiple treatments are available for nearly all the mood disorders. This range of treatment options adds a new dimension of choice to clinical decision making. In addition to prescribing the best initial treatment, clinicians should have an algorithm for deciding if and when to make subsequent changes in treatment to take advantage of second-line treatment options when necessary. This article aims to 1) show that a wide variety of clinical decisions can be framed as choices among adaptive (within-patient) threshold-based strategies or algorithms, illustrating the generality of the concept; 2) illustrate two ways to design randomized clinical trials to compare treatment strategies with each other to decide which strategy is best; and 3) discuss some of the advantages offered by these designs, in terms of both patient acceptability and adherence to experimental protocols.

Placebo control groups in randomized treatment trials: a statistician's perspective.

Because a statistical tie between standard treatment and an innovation is uninterpretable, most trials intended to demonstrate efficacy of innovations in psychopharmacology employ a placebo control group, despite the existence of standard medications for many disorders. In this review I consider the statistical issues that inform the ethics of the decision to use a placebo condition and make the following points: 1) the investigator is relying on the assumption that the effects of delayed standard treatment are neither long-lasting nor harmful; 2) the usual practice of truncating follow-up when a patient ceases to adhere to a study treatment makes it difficult to empirically test that assumption; 3) placebo control trials often suffer from methodological weaknesses (including nonrandom truncation) that reduce their inferential power; 4) these subtleties place a substantial burden on the informed consent process; 5) alternative designs are available but not well explored, due to the dominant role of "regulatory" trial methodology; and 6) researchers should consider other goals besides helping to introduce another treatment that improves on placebos but not the standard treatment.

Multiple recurrences of major depressive disorder.

OBJECTIVE: The authors of this study examined multiple recurrences of unipolar major depressive disorder. METHOD: A total of 318 subjects with unipolar major depressive disorder were prospectively followed for 10 years within a multicenter naturalistic study. Survival analytic techniques were used to examine the probability of recurrence after recovery from the index episode. RESULTS: The mean number of episodes of major depression per year of follow-up was 0. 21, and nearly two-thirds of the subjects suffered at least one recurrence. The number of lifetime episodes of major depression was significantly associated with the probability of recurrence, such that the risk of recurrence increased by 16% with each successive recurrence. The risk of recurrence progressively decreased as the duration of recovery increased. Within subjects, there was very little consistency in the time to recurrence. CONCLUSIONS: Major depressive disorder is a highly recurrent illness. The risk of the recurrence of major depressive disorder progressively increases with each successive episode and decreases as the duration of recovery increases.

The iron (Fe) and atherosclerosis study (FeAST): a pilot study of reduction of body iron stores in atherosclerotic peripheral vascular disease.

BACKGROUND: Levels of body iron stores, represented by the serum ferritin concentration, rise with age after adolescence in men and menopause in women. This rise has been implicated mechanistically and epidemiologically in the pathogenesis of atherosclerosis through iron-induced oxygen free radical-mediated lipid oxidation. However, the precise contribution of iron stores to atherosclerosis and its complications are unknown because prospective randomized trials designed to test effects of reduction of iron stores on clinical outcomes in this disease have not been performed. METHODS AND RESULTS: In preparation for a prospective randomized trial, a randomized pilot study was conducted to evaluate the feasibility, safety, and methodologic accuracy of calibrated reduction in iron stores by phlebotomy in a cohort of patients with advanced peripheral vascular disease. Phlebotomy resulted in a significant reduction in serum ferritin concentration to near targeted levels. Thus the formula for calculating the volume of blood to be removed to achieve a predetermined decrement in serum ferritin concentration was accurate and phlebotomy was not associated with any adverse laboratory or clinical effects. CONCLUSIONS: Reduction of body iron stores to a predetermined level is feasible and can be achieved in a timely manner with excellent patient compliance. Prospective randomized trials of calibrated reduction of body iron stores may be undertaken to define their pathophysiologic significance in atherosclerosis and other diseases in which excessive iron-induced oxidative stress has been implicated.

Sample-size calculations for the Cox proportional hazards regression model with nonbinary covariates.

This paper derives a formula to calculate the number of deaths required for a proportional hazards regression model with a nonbinary covariate. The method does not require assumptions about the distributions of survival time and predictor variables other than proportional hazards. Simulations show that the censored observations do not contribute to the power of the test in the proportional hazards model, a fact that is well known for a binary covariate. This paper also provides a variance inflation factor together with simulations for adjustment of sample size when additional covariates are included in the model. Control Clin Trials 2000;21:552-560

Comparison based on age of baseline electrocardiographic abnormalities in non-Q-wave myocardial infarction. VANQWISH Trial Research Investigators. Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital.

OBJECTIVE: To compare the incidence of electrocardiographic abnormalities between older (age > or = 70 years) and younger patients presenting with acute non-Q-wave myocardial infarction. DESIGN: Retrospective review of qualifying electrocardiograms in 918 patients enrolled in the multicenter Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study. SETTING: Seventeen Department of Veterans Affairs medical centers. PARTICIPANTS: A total of 918 patients (224 > or = 70 years old) with acute non-Q-wave myocardial infarction. MEASUREMENTS: Comparison of electrocardiograms in patients aged > or = 70 years and younger patients for presence of left ventriculary hypertrophy, widened QRS complex, ST and T wave abnormalities, rhythm other than sinus, heart rate > or = 80 beats/minute, and location of acute non-Q-wave myocardial infarction. RESULTS: Left ventricular hypertrophy and ST depression > or = 1 mm were significantly more frequent in older than in younger patients. CONCLUSIONS: Older patients presenting with non-Q-wave myocardial infarction have a greater incidence of left ventricular hypertrophy and ST depression on their electrocardiograms than younger patients. Both of these electrocardiographic findings have previously been associated with increased risk of death and recurrent myocardial infarction and may help account for the worse prognosis of non-Q-wave myocardial infarction in older patients.

Plans, designs, and analyses for clinical trials of anti-cocaine medications: where we are today. NIDA/VA/SU Working Group on Design and Analysis.

Increased interest in addiction psychopharmacology has raised unique methodologic issues in the design, conduct, and analysis of outcomes in clinical trials of therapeutic agents for drug dependence. This article summarizes issues raised at a meeting in Palo Alto, California, on November 4, 1996, that was sponsored by the Medication Development Division of the National Institute on Drug Abuse and the Department of Veterans Affairs Cooperative Studies Program to discuss the methodologic issues in clinical trials of cocaine pharmacotherapy.

Course of treatment received by depressed patients.

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one month's duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

Improving informed consent in clinical trials: a duty to experiment.

Practitioners of clinical trials have a responsibility to ensure that patients' participation in research be informed and voluntary. This responsibility implies that we should strive continuously to improve the effectiveness of methods for informing prospective research volunteers about experimental studies, thereby enhancing the protection of their interests. We should test innovations in informed consent in realistic contexts (i.e., in clinical trials) and with randomization, when it is appropriate, at the first opportunity. In this study, we develop a preliminary proposal to improve the quality of informed consent, based on experimentation with informed consent in ongoing clinical trials. We discuss the conceptual, ethical, organizational, and technical bases for such an effort.

Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators.

BACKGROUND: Non-Q-wave myocardial infarction is usually managed according to an "invasive" strategy (i.e., one of routine coronary angiography followed by myocardial revascularization). METHODS: We randomly assigned 920 patients to either "invasive" management (462 patients) or "conservative" management, defined as medical therapy and noninvasive testing, with subsequent invasive management if indicated by the development of spontaneous or inducible ischemia (458 patients), within 72 hours of the onset of a non-Q-wave infarction. Death or nonfatal infarction made up the combined primary end point. RESULTS: During an average follow-up of 23 months, 152 events (80 deaths and 72 nonfatal infarctions) occurred in 138 patients who had been randomly assigned to the invasive strategy, and 139 events (59 deaths and 80 nonfatal infarctions) in 123 patients assigned to the conservative strategy (P=0.35). Patients assigned to the invasive strategy had worse clinical outcomes during the first year of follow-up. The number of patients with one of the components of the primary end point (death or nonfatal myocardial infarction) and the number who died were significantly higher in the invasive-strategy group at hospital discharge (36 vs. 15 patients, P=0.004, for the primary end point; 21 vs. 6, P=0.007, for death), at one month (48 vs. 26, P=0.012; 23 vs. 9, P=0.021), and at one year (111 vs. 85, P=0.05; 58 vs. 36, P= 0.025). Overall mortality during follow-up did not differ significantly between patients assigned to the conservative-strategy group and those assigned to the invasive-strategy group (hazard ratio, 0.72; 95 percent confidence interval, 0.51 to 1.01). CONCLUSIONS: Most patients with non-Q-wave myocardial infarction do not benefit from routine, early invasive management consisting of coronary angiography and revascularization. A conservative, ischemia-guided initial approach is both safe and effective.