Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Sample size estimation for time-dependent receiver operating characteristic.

In contrast to the usual ROC analysis with a contemporaneous reference standard, the time-dependent setting introduces the possibility that the reference standard refers to an event at a future time and may not be known for every patient due to censoring. The goal of this research is to determine the sample size required for a study design to address the question of the accuracy of a diagnostic test using the area under the curve in time-dependent ROC analysis. We adapt a previously published estimator of the time-dependent area under the ROC curve, which is a function of the expected conditional survival functions. This estimator accommodates censored data. The estimation of the required sample size is based on approximations of the expected conditional survival functions and their variances, derived under parametric assumptions of an exponential failure time and an exponential censoring time. We also consider different patient enrollment strategies. The proposed method can provide an adequate sample size to ensure that the test's accuracy is estimated to a prespecified precision. We present results of a simulation study to assess the accuracy of the method and its robustness to departures from the parametric assumptions. We apply the proposed method to design of a study of positron emission tomography as predictor of disease free survival in women undergoing therapy for cervical cancer.

Validation of novel imaging methodologies for use as cancer clinical trial end-points.

The success or failure of a clinical trial, of any phase, depends critically on the choice of an appropriate primary end-point. In the setting of phases II and III cancer clinical trials, imaging end-points have historically, and continue presently to play a major role in determining therapeutic efficacy. The primary goal of this paper is to discuss the validation of imaging-based markers as end-points for phase II clinical trials of cancer therapy. Specifically, we outline the issues that must be considered, and the criteria that would need to be satisfied, for an imaging end-point to supplement or potentially replace RECIST- defined tumour status as a phase II clinical trial end-point. The key criteria proposed to judge the utility of a new end-point primarily relate to its ability to accurately and reproducibly predict the eventual phase III end-point for treatment effect, which is usually assessed by a difference between two arms on progression free or overall survival, both at the patient and more importantly at the trial level. As will be demonstrated, the level of evidence required to formally and fully validate a new imaging marker as an appropriate end-point for phase II trials is substantial. In many cases, this level of evidence will only become available by conducting a series of coordinated prospectively designed multicentre clinical trials culminating in a formal meta-analysis. We also include a discussion of situations where flexibility may be required, relative to the ideal rigorous evaluation, to accommodate inevitable real-world feasibility constraints.

Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative.

AIM: To improve the accuracy and completeness of reporting of studies of diagnostic accuracy in order to allow readers to assess the potential for bias in a study and to evaluate the general isability of its results. METHODS: The standards for reporting of diagnostic accuracy (STARD) steering committee searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies and extracted potential items into an extensive list. Researchers, editors, and members of professional organisations shortened this list during a 2 day consensus meeting with the goal of developing a checklist and a generic flow diagram for studies of diagnostic accuracy. RESULTS: The search for published guidelines about diagnostic research yielded 33 previously published checklists, from which we extracted a list of 75 potential items. At the consensus meeting, participants shortened the list to a 25-item checklist, by using evidence whenever available. A prototype of a flow diagram provides information about the method of recruitment of patients, the order of test execution and the numbers of patients undergoing the test under evaluation, the reference standard, or both. CONCLUSIONS: Evaluation of research depends on complete and accurate reporting. If medical journals adopt the checklist and the flow diagram, the quality of reporting of studies of diagnostic accuracy should improve to the advantage of clinicians, researchers, reviewers, journals, and the public.

[Reporting studies of diagnostic accuracy according to a standard method; the Standards for Reporting of Diagnostic Accuracy (STARD)]. / Verslaglegging van diagnostisch evaluatieonderzoek volgens een standaardmethode; de 'standards for reporting of diagnostic accuracy' (STARD).

The objective of the 'Standards for Reporting of Diagnostic Accuracy' (STARD) initiative is to improve the reporting of studies of diagnostic accuracy, so as to allow readers to assess the potential for bias in a study and to evaluate the generalibility of its results. The group searched the literature to identify publications on the appropriate conduct and reporting of diagnostic studies. This was used to draw up a list of potential items. During a consensus meeting, a group of researchers, medical journal editors, and members of professional organisations reduced this list to a usable checklist. Wherever possible, evidence from the literature was used to justify the decisions made. The search for published guidelines about diagnostic research yielded 33 previously published checklists, from which a list of 75 potential items was extracted. At the consensus meeting, participants shortened the list to a 25-item checklist. A generic flow diagram was drawn up to provide guidance on the method for including patients, the order in which tests were to be conducted and the number of patients to undergo the test being evaluated, the reference standard, or both. A scientific publication can only be assessed when the reporting is both correct and complete. Use of the checklist and flow diagram will improve the quality of reports produced, to the advantage of clinicians, researchers, reviewers, journal editors and other interested parties.

Meta-analysis of diagnostic test accuracy assessment studies with varying number of thresholds.

Current meta-analytic methods for diagnostic test accuracy are generally applicable to a selection of studies reporting only estimates of sensitivity and specificity, or at most, to studies whose results are reported using an equal number of ordered categories. In this article, we propose a new meta-analytic method to evaluate test accuracy and arrive at a summary receiver operating characteristic (ROC) curve for a collection of studies evaluating diagnostic tests, even when test results are reported in an unequal number of nonnested ordered categories. We discuss both non-Bayesian and Bayesian formulations of the approach. In the Bayesian setting, we propose several ways to construct summary ROC curves and their credible bands. We illustrate our approach with data from a recently published meta-analysis evaluating a single serum progesterone test for diagnosing pregnancy failure.

Racial differences in cardiac revascularization rates: does "overuse" explain higher rates among white patients?

BACKGROUND: Coronary artery bypass graft (CABG) surgery and percutaneous transluminal coronary angioplasty (PTCA) are well-established treatments for symptomatic coronary artery disease. Previous studies have documented racial differences in rates of use of these cardiac revascularization procedures. Other studies suggest that these procedures are overused: that is, they are done for patients with clinically inappropriate indications. OBJECTIVE: To test the hypothesis that the higher rate of cardiac revascularization among white patients is associated with a higher prevalence of overuse (revascularization for clinically inappropriate indications) among white patients than among African-American patients. DESIGN: Observational cohort study using Medicare claims and medical record review. SETTING: 173 hospitals in five U.S. states. PARTICIPANTS: A stratified, weighted, random sample of 3960 Medicare beneficiaries who underwent coronary angiography during 1991 and 1992; 1692 of these patients underwent 1711 revascularization procedures within 90 days. MEASUREMENTS: The proportion of CABG and PTCA procedures rated appropriate, uncertain, and inappropriate according to RAND criteria, and the multivariate odds of undergoing inappropriate revascularization among African-American patients and white patients. RESULTS: After angiography, rates of PTCA (23% vs. 19%) and CABG surgery (29% vs. 17%) were significantly higher among white patients than among African-American patients. The respective rates of inappropriate PTCA and CABG surgery were 14% and 10%. Among the study states, rates of inappropriate use ranged from 4% to 24% for PTCA and 0% to 14% for CABG surgery. White patients were more likely than African-American patients to receive inappropriate PTCA (15% vs. 9%; difference, 6 percentage points [95% CI, -0.4 to 12.7 percentage points]), and difference by race was statistically significant among men (20% vs. 8%; difference, 12 percentage points [CI, 1.2 to 21.7 percentage points]). Rates of inappropriate CABG surgery did not differ by race (10% in both groups). CONCLUSIONS: Among a large and diverse sample of Medicare beneficiaries in five U.S. states, overuse of PTCA was greater among white men than among other groups, but this difference did not fully account for racial disparities in revascularization. Overuse of cardiac revascularization varied significantly by geographic region.

A hierarchical regression approach to meta-analysis of diagnostic test accuracy evaluations.

An important quality of meta-analytic models for research synthesis is their ability to account for both within- and between-study variability. Currently available meta-analytic approaches for studies of diagnostic test accuracy work primarily within a fixed-effects framework. In this paper we describe a hierarchical regression model for meta-analysis of studies reporting estimates of test sensitivity and specificity. The model allows more between- and within-study variability than fixed-effect approaches, by allowing both test stringency and test accuracy to vary across studies. It is also possible to examine the effects of study specific covariates. Estimates are computed using Markov Chain Monte Carlo simulation with publicly available software (BUGS). This estimation method allows flexibility in the choice of summary statistics. We demonstrate the advantages of this modelling approach using a recently published meta-analysis comparing three tests used to detect nodal metastasis of cervical cancer.

Fine-needle aspiration biopsy of nonpalpable breast lesions in a multicenter clinical trial: results from the radiologic diagnostic oncology group V.

PURPOSE: To determine the diagnostic accuracy of ultrasonographically (US) and stereotactically guided fine-needle aspiration biopsy (FNAB) in the diagnosis of nonpalpable breast lesions. MATERIALS AND METHODS: At 18 institutions, 442 women who underwent 22-25-gauge imaging-guided FNAB were enrolled. Definitive surgical, core-needle biopsy, and/or follow-up information was available for 423 (95.7%) of these women. The reference standard was established from additional clinical and imaging information for an additional six (1.4%) women who did not undergo further histopathologic evaluation. The FNAB protocol was standardized at all institutions, and all specimens were reread by one of two expert cytopathologists. RESULTS: When insufficient samples were included in the analysis and classified as positive, the sensitivity and specificity of FNAB were 85%-88% and 55.6%-90.5%, respectively; accuracy ranged from 62.2% to 89.2%. The diagnostic accuracy of FNAB was significantly better for detection of masses than for detection of calcifications (67.3% vs. 53.8%, P =.006) and with US guidance than with stereotactic guidance (77.2% vs. 58.9%; P =.002). CONCLUSION: FNAB of nonpalpable breast lesions has limited value given the high insufficient sample rate and greater diagnostic accuracy of other interventions, including core-needle biopsy and needle-localized open surgical biopsy.

Effects of angiotensin-converting enzyme inhibitors and digoxin on health outcomes of very old patients with heart failure. SAGE Study Group. Systematic Assessment of Geriatric drug use via Epidemiology.

BACKGROUND: Randomized trials have shown that angiotensin-converting enzyme (ACE) inhibitors reduce mortality and morbidity, and improve symptoms and exercise tolerance in selected patients with congestive heart failure (CHF). There is, however, no evidence on the effectiveness of ACE inhibitors in the typical, very old and frail patients with CHF. OBJECTIVE: To compare the effects of ACE inhibitors and digoxin on 1-year mortality, morbidity, and physical function among patients aged 85 years. METHODS: We conducted a retrospective cohort study using the SAGE database, a long-term care database linking patient information with drug utilization data. Among 64637 patients with CHF admitted to all nursing homes in 5 states between 1992 and 1995, we identified 19492 patients taking either an ACE inhibitor (n = 4911) or digoxin (n = 14890). Record of date of death was derived from Medicare enrollment files, and we used the part A Medicare files to identify hospital admissions and discharge diagnoses. As a measure of physical function, we used a scale for activities of daily living performance. The effect of ACE inhibitors was estimated using Cox proportional hazards models with digoxin users as the reference group. RESULTS: The overall mortality rate among ACE inhibitor recipients was more than 10% less than that of digoxin users (relative rate, 0.89; 95% confidence interval, 0.83-0.95). Mortality was equally reduced regardless of concomitant cardiovascular conditions and baseline physical function. Treatment with ACE inhibitors was associated with a tendency toward reduced hospital admissions that was more evident among patients with greater functional impairment. The adjusted relative rate for hospitalization for any reason was 0.96 (95% confidence interval, 0.91-1.01). The rate of functional decline was greatly reduced among ACE inhibitor recipients (relative rate, 0.74; 95% confidence interval, 0.69-0.80), and this effect was consistent and independent of background comorbidity and baseline physical function. CONCLUSIONS: These data suggest that survival and functional benefits of ACE inhibitor therapy extend to patients with CHF 85 years and older, and mostly women, both systematically underrepresented in randomized trials. Alternatively, digoxin has a detrimental effect in this population.

Ambulatory blood pressure responses and the circumplex model of mood: a 4-day study.

BACKGROUND: The relation between mood or emotions and concurrent ambulatory blood pressure responses holds both fundamental and clinical interest. METHODS: The primary sample consisted of 69 normotensive or borderline hypertensive but otherwise healthy adult males. The validation sample consisted of 85 healthy male undergraduate college students. Both samples underwent half-hourly 24-hour ambulatory blood pressure measurements on four separate workdays, 1 week apart. At each ambulatory measurement, subjects recorded their behavior, environment, and mood. The circular mood scale, a circular visual analogue scale based on the circumplex model of mood, was used to reflect the totality of a participant's affective state space. Longitudinal random effects regression models were applied in the data analysis. RESULTS: The results for both samples were quite similar. Sleep and posture had the greatest influence on ambulatory blood pressure and heart rate. The effects of the environmental setting, social setting, and consumption were modest but statistically significant. Independent of these covariates, mood exerted a significant effect on blood pressure and heart rate. Relative to the "mellow" default category, blood pressure increased both for "anxious/annoyed" and "elated/happy" and decreased during "disengaged/sleepy" mood. The range of mood-related blood pressure estimates was 6.0/3.7 mm Hg. CONCLUSIONS: The pattern of blood pressure responses suggests that they were related to the degree of engagement of a mood rather than the degree of unpleasantness. The hypothesis that posits that negative affect-related cardiovascular reactivity mediates the observed correlation between negative affect and disease risk should be reconsidered.

Characteristics of the SAGE database: a new resource for research on outcomes in long-term care. SAGE (Systematic Assessment of Geriatric drug use via Epidemiology) Study Group.

BACKGROUND: Because there is a lack of databases specific to long-term care, standardized assessments of nursing home residents are seen as a potential new resource for studying an important but neglected population. We describe the design and principal population characteristics of the first integrated database combining detailed clinical information and administrative claims data. METHODS: We studied nearly 300,000 residents admitted between 1992 and 1994 to all Medicare/Medicaid certified nursing homes of five U.S. states (Kansas, Maine, Mississippi, New York, and South Dakota). The database crosslinks: (a) Resident Data: over 350 items (demographic, diagnostic, clinical, and treatments) collected with the Minimum Data Set; (b) Drug Data: brand name, dosage route, and frequency of administration for all drugs consumed by each resident; (c) Medicare Data: eligibility and inpatient hospital claims; (d) Facilities Data: structural and staffing information on nursing homes; and (e) Country Data: information on population, health professions and facility data, and economic parameters. RESULTS: Ninety-two percent of the residents were aged 65 years and older. Residents were predominantly white (85%) and female (72%). The average number of medical diagnoses was above three, and residents were receiving an average of six medications. Sixty-five percent of residents had at least one hospital claim following the initial assessment, most commonly related to cardiovascular diseases and metabolic disorders. Fifty-five percent of the facilities were for-profit and 33% were of small size. Quality indicators and staffing level varied significantly by state. CONCLUSIONS: The SAGE (Systematic Assessment of Geriatric drug use via Epidemiology) database provides a unique resource to study the relation between treatments received and outcomes experienced, particularly functional and health services outcomes, that have not been possible before in very old, frail people.

The stability of preferences for life-sustaining care among persons with AIDS in the Boston Health Study.

BACKGROUND: Clinicians recognize the importance of eliciting patient preferences for life-sustaining care, yet little is known about the stability of those preferences for patients with serious disease. OBJECTIVES: To examine the stability of preferences for life-sustaining care among persons with AIDS and to assess factors associated with changes in preferences. DESIGN: Two patient surveys and medical record reviews, administered four months apart in 1990-1991. SETTING: Three health care settings in Boston. PATIENTS: 252 of 505 eligible persons with AIDS who participated in both baseline and follow-up surveys. MAIN OUTCOME MEASURES: A single question assessing desire for cardiac resuscitation and a scale of preferences for life-extending treatment conditional on hypothetical health states. RESULTS: Approximately one-fourth of the respondents changed their minds about life-sustaining care during a four-month period. Of patients who initially desired cardiac resuscitation, 23% decided to forego it four months later, and of those who initially said they would decline care, 34% later said they would accept it. Of those who initially desired any of the life-extending treatments, 25% decided to forego them four months later, and of those who initially said they would decline life-extending care, 24% later said they would accept some treatment. Patients reporting changes in physical function, pain, or suicide ideation were more likely to modify their desires to be resuscitated (all p< or =0.05). Patients lacking an advance directive, not completing high school, or becoming more severely ill were more likely to change their preferences on the Life Extension scale (p< or =0.05). Patients who discussed their preferences with at least one physician were just as likely as others to change desires for cardiac resuscitation. Age, gender, race, emotional health, clinical severity, social support, and site of care were not significant correlates of change for either measure. CONCLUSIONS: Health care providers should periodically reassess preferences for life-sustaining care, particularly for patients with progressive disease, given the instability in patient preferences. However, predictors of instability may vary with how preferences are measured. In particular, changes in health status may be related to instability of preferences for certain types of treatments.

Generalized estimating equations for ordinal categorical data: arbitrary patterns of missing responses and missingness in a key covariate.

We propose methods for regression analysis of repeatedly measured ordinal categorical data when there is nonmonotone missingness in these responses and when a key covariate is missing depending on observables. The methods use ordinal regression models in conjunction with generalized estimating equations (GEEs). We extend the GEE methodology to accommodate arbitrary patterns of missingness in the responses when this missingness is independent of the unobserved responses. We further extend the methodology to provide correction for possible bias when missingness in knowledge of a key covariate may depend on observables. The approach is illustrated with the analysis of data from a study in diagnostic oncology in which multiple correlated receiver operating characteristic curves are estimated and corrected for possible verification bias when the true disease status is missing depending on observables.

Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology.

CONTEXT: Cancer pain can be relieved with pharmacological agents as indicated by the World Health Organization (WHO). All too frequently pain management is reported to be poor. OBJECTIVE: To evaluate the adequacy of pain management in elderly and minority cancer patients admitted to nursing homes. DESIGN: Retrospective, cross-sectional study. SETTING: A total of 1492 Medicare-certified and/or Medicaid-certified nursing homes in 5 states participating in the Health Care Financing Administration's demonstration project, which evaluated the implementation of the Resident Assessment Instrument and its Minimum Data Set. STUDY POPULATION: A group of 13 625 cancer patients aged 65 years and older discharged from the hospital to any of the facilities from 1992 to 1995. Data were from the multilinked Systematic Assessment of Geriatric Drug Use via Epidemiology (SAGE) database. MAIN OUTCOME MEASURES: Prevalence and predictors of daily pain and of analgesic treatment. Pain assessment was based on patients' report and was completed by a multidisciplinary team of nursing home personnel that observed, over a 7-day period, whether each resident complained or showed evidence of pain daily. RESULTS: A total of 4003 patients (24%, 29%, and 38% of those aged > or =85 years, 75 to 84 years, and 65 to 74 years, respectively) reported daily pain. Age, gender, race, marital status, physical function, depression, and cognitive status were all independently associated with the presence of pain. Of patients with daily pain, 16% received a WHO level 1 drug, 32% a WHO level 2 drug, and only 26% received morphine. Patients aged 85 years and older were less likely to receive morphine or other strong opiates [corrected] than those aged 65 to 74 years (13% vs 38%, respectively). More than a quarter of patients (26%) in daily pain did not receive any analgesic agent. Patients older than 85 years in daily pain were also more likely to receive no analgesia (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13-1.73). Other independent predictors of failing to receive any analgesic agent were minority race (OR, 1.63; 95% CI, 1.18-2.26 for African Americans), low cognitive performance (OR, 1.23; 95% CI, 1.05-1.44), and the number of other medications received (OR, 0.65; 95% CI, 0.5-0.84 for 11 or more medications). CONCLUSIONS: Daily pain is prevalent among nursing home residents with cancer and is often untreated, particularly among older and minority patients.

Rate of insufficient samples for fine-needle aspiration for nonpalpable breast lesions in a multicenter clinical trial: The Radiologic Diagnostic Oncology Group 5 Study. The RDOG5 investigators.

BACKGROUND: Radiologic Diagnostic Oncology Group 5 is a multicenter clinical trial designed to evaluate fine-needle aspiration (FNA) of nonpalpable breast lesions performed by multiple operators using the same protocol. METHODS: Four hundred and nineteen women with mammographically detected nonpalpable breast lesions were enrolled on the trial at 18 institutions. Group A institutions randomized women to stereotactically guided FNA (SFNA) followed by stereotactically guided core needle biopsy (SCNB), or SCNB only. Group B institutions randomized women to SFNA and SCNB, SCNB, or ultrasonographically guided FNA followed by ultrasonographically guided core needle biopsy (USCNB), or USCNB only. A total of 377 women were eligible for analysis. RESULTS: FNA yielded 128 insufficient samples for the 377 patients (33.95%; 95% confidence interval, 29.2-38.7%). The rate of insufficient samples varied by type of lesion with calcified lesions associated with a significantly higher rate of insufficient sampling than masses (P < 0.001). The radiologist's level of suspicion of the lesion was not a statistically significant predictor of insufficient samples for mass lesions, but was a predictor for calcified lesions. For the 336 lesions for which histologic information was available, insufficient samples occurred in significantly more benign than malignant lesions. CONCLUSIONS: The high rate of insufficient samples for FNA of nonpalpable breast lesions in this multicenter trial makes its use impractical in this setting. Because of this factor, the study was terminated early.

Hierarchical polytomous regression models with applications to health services research.

The analysis of variations is an important area of interest in health services and outcomes research and has two main goals: to identify and quantify variability across units, such as geographic regions or health care providers, in terms of procedure utilization and outcomes, and to explore the links between process, such as regional or hospital practice patterns, and outcomes, such as patient mortality and functional status. Hierarchical regression models are well suited for this type of analysis. In this paper we formulate a hierarchical polytomous regression model and apply it to the analysis of variations in the utilization of alternative cardiac procedures in a national cohort of elderly Medicare patients who had an acute myocardial infarction during 1987. The model is designed to accommodate clustered multinomial data with covariate vectors available on individual cases and on clusters. We present a Bayesian approach to fitting and checking the model using simulated values from the posterior distribution of the parameters. The simulation algorithms are based on Gibbs sampling in combination with Metropolis steps. Using the hierarchical polytomous regression model, we examine how the rates of cardiac procedures depend on patient-level characteristics, including age, gender and race, and whether there exist interstate differences and regional patterns in the use of these procedures.

First-episode major depressive and dysthymic disorder in childhood: clinical and sociodemographic factors in recovery.

OBJECTIVE: To characterize the temporal pattern of depressive disorder in childhood, the first episode of depression was examined, focusing on recovery and its baseline predictors. METHOD: The sample includes 112 clinically referred 8- to 13-year-olds with first-episode major depressive or dysthymic disorder participating in a naturalistic follow-up study. Psychiatric diagnoses were based on standardized interviews and operational criteria. Recovery was modeled by multivariate procedures using baseline clinical and demographic predictors. RESULTS: Recovery rates were 86% and 7% for major depression and dysthymia, respectively, 2 years after onset. Median duration of major depression was 9 months and was predicted only by underlying dysthymia. Median duration of dysthymic disorder was 3.9 years and was predicted only by comorbid externalizing disorder. In post hoc analyses, no positive treatment effects were detected. CONCLUSIONS: First-episode depression in youths is persistent, it generally appears to run its own course, and its naturalistic treatment requires scrutiny. However, because comorbid externalizing disorder apparently affects duration of dysthymia, intervention for behavior problems may shorten this type of depression.