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.

Childhood-onset dysthymic disorder. Clinical features and prospective naturalistic outcome.

OBJECTIVES: To characterize the clinical presentation, course, and outcome of childhood-onset dysthymic disorder and assess the predictive validity of this diagnosis. DESIGN: As part of a longitudinal prospective study, school-age, clinically referred youngsters (n = 55) whose first depression was dysthymic disorder and a comparison group of youngsters (n = 60) whose first affective episode was major depressive disorder (MDD) were repeatedly examined during a 3- to 12-year interval. The diagnoses were based on DSM-III criteria. RESULTS: Dysthymic disorder was associated with earlier age at onset than MDD, similarly frequent symptoms of affective dysregulation, but low rates of anhedonia and neurovegetative symptoms and greater overall risk of any subsequent affective disorder. The affective disorders that dysthymic children developed, including first-episode MDD (76%) and bipolar disorder (13%), far outnumbered nonaffective conditions. After the first episode of MDD, the clinical course of the initially dysthymic youths was similar to the course of the comparison patients with regard to rates of recurrent major depression, bipolar disorder, and certain nonaffective disorders. CONCLUSIONS: Childhood-onset dysthymic disorder is an early marker of recurrent affective illness. Although on long-term follow-up, dysthymic disorder and MDD are associated with similar rates of certain outcomes, there exist sufficient differences to warrant diagnosis of each disorder. Dysthymic children who have subsequent mood disorders are most likely first to have an episode of MDD, and that episode appears to be the "gateway" to recurrent affective illness. The interval between the onset of dysthymia and the first major depression provides a window of opportunity for intervention and possible prevention of later episodes.

A controlled prospective study of DSM-III adjustment disorder in childhood. Short-term prognosis and long-term predictive validity.

OBJECTIVES: Using DSM-III criteria for adjustment disorder (AD), further operationalized by requiring at least three clinically significant symptoms, we sought to characterize this diagnosis in terms of presenting features, recovery, and predictive validity among juveniles. DESIGN: The samples included clinically referred, 8- to 13-year-old patients with the research diagnosis of AD (N = 30) and a high rate of comorbid disorders and age-and comorbid disorder-matched psychopathologic controls (N = 26). As part of a naturalistic, longitudinal, nosologic study, patients were repeatedly examined during an average follow-up interval of 7 to 8 years. RESULTS: Adjustment disorder was associated with six symptoms, on average, and 60% of the patients had other, specific psychiatric disorders. Adjustment disorder had a median episode length of 7 months and a 97% recovery rate. Comorbidity had no appreciable effect on recovery. Patients with adjustment disorder and controls had similar rates of new psychiatric disorders and other dysfunctional outcomes during the follow-up. CONCLUSIONS: Among psychiatrically referred youths, the diagnosis of AD has clinical information value and identifies a syndromatic presentation that can be the focus of concern or treatment. It has a reasonably good short-term prognosis, in spite of the fact that patients with this diagnosis typically present with comorbid specific psychiatric disorders. Controlling for the effects of comorbidity, AD does not predict later dysfunction. To achieve a convergence of findings from research and clinical practice, it would be important to ensure a uniform application of specific, operational diagnostic criteria for AD.

Depressive disorders in childhood. IV. A longitudinal study of comorbidity with and risk for anxiety disorders.

As part of a longitudinal nosologic study of major depressive disorder (MDD), dysthymic disorder (DD), and adjustment disorder with depressed mood (ADDM) in a school-age cohort, we examined the prevalence and clinical consequences of comorbid anxiety disorders. We also estimated the risk of a first anxiety disorder and examined its predictors. Of 104 cases, 41% had anxiety disorders in conjunction with their index depression, which was more likely with MDD and DD than with ADDM. The age-corrected risk of a first anxiety disorder was 0.47 up to age 18 years. Separation-anxiety disorder was the most frequent diagnosis of anxiety, followed by overanxious disorder of childhood. Among the MDD cases with comorbidity, the anxiety disorder preceded the depression about two thirds of the time and often persisted after the depression remitted. The effect of comorbid anxiety disorder on the length of index MDD depended on the presence of other clinical features, but it did not seem to affect the risk of subsequent MDD or the course of DD or ADDM. Concurrent maternal psychopathology and poor physical health increased the risk of anxiety disorder in the children, but a history of prior separation from parental figures did not seem to have an effect.

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.

Discussion of preferences for life-sustaining care by persons with AIDS. Predictors of failure in patient-physician communication.

OBJECTIVES: To assess the determinants of communication about resuscitation between persons with acquired immunodeficiency syndrome (AIDS) and their physician. DESIGN AND SETTING: Structured patient interview at a staff-model health maintenance organization (HMO), an internal medicine group practice at a private teaching hospital, and an AIDS clinic at a public hospital. PATIENTS: 289 persons with AIDS. MAIN RESULTS: Only 38% of patients had discussed their preferences for resuscitation with their physician. Using logistic regression, we found that patients were less likely to have discussed resuscitation with their physician if they were nonwhite (odds ratio [OR], 0.49; 95% confidence interval [CI], 0.24 to 0.99), had never been hospitalized (OR, 0.52; 95% CI, 0.27 to 0.99), or were cared for in the HMO (OR, 0.44 relative to the private teaching hospital; 95% CI, 0.23 to 0.82). Patients were more likely to have discussed their preferences if they were not currently taking zidovudine (OR, 1.76; 95% CI, 1.02 to 3.03) and if they had decided to defer life-sustaining therapy (OR, 2.30; 95% CI, 1.35 to 3.91). Among nonwhites, those with a nonwhite physician were more likely to have discussed resuscitation (OR, 4.38; 95% CI, 1.13 to 16.93). Of patients who had not discussed their preferences for life-sustaining care, 72% wanted to do so. Patient desire for discussion of this issue did not vary by race, severity of illness, hospitalization status, use of zidovudine, or site of care. CONCLUSIONS: A majority of persons with AIDS in this study had not discussed their preferences for life-sustaining care with their physician, despite the desire to do so. Interventions to improve patient-physician communication about resuscitation for nonwhites and other groups at risk of inadequate discussion might lead to clinical decisions that are more consistent with patient preferences.

Multiple correlation: exact power and sample size calculations.

This article discusses power and sample size calculations for observational studies in which the values of the independent variables cannot be fixed in advance but are themselves outcomes of the study. It reviews the mathematical framework applicable when a multivariate normal distribution can be assumed and describes a method for calculating exact power and sample sizes using a series expansion for the distribution of the multiple correlation coefficient. A table of exact sample sizes for level .05 tests is provided. Approximations to the exact power are discussed, most notably those of Cohen (1977). A rigorous justification of Cohen's approximations is given. Comparisons with exact answers show that the approximations are quite accurate in many situations of practical interest. More extensive tables and a computer program for exact calculations can be obtained from the authors.

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.

Secular trends in age at onset of major depressive disorder in a clinical sample of children.

Using a psychiatrically referred, depressed, school-age sample, we sought to cross-validate the clinically pertinent epidemiologic finding that the distribution of age at onset of first episode of major depressive disorder (MDD) is subject to birth-cohort and period effects. Demographic and historical variables also were considered in attempting to explain the variability in age-at-onset. The results indicated a birth-cohort effect, but no discernable period effect on age at onset of MDD; successive birth cohorts were younger when they first developed MDD even after stringent analyses were conducted that corrected for structural sampling biases in the sample. In view of the relatively small size and clinical nature of the sample and the restricted birth-year span that characterizes children, the results are presented to stimulate further discussion of this topical area.

Suicidal behaviors and childhood-onset depressive disorders: a longitudinal investigation.

In this longitudinal study, the rates and correlates of suicidal ideation and suicide attempts were determined among outpatient youths with depressive disorders and youths with other psychiatric disorders. At study entry, about 66% of the subjects evidenced suicidal ideation and 9% already attempted suicide. The rate of ideation remained fairly stable over time, whereas the rate of attempts reached 24% by the average age of 17 years. Major depressive and dysthymic disorders were associated with significantly higher rates of suicidal behaviors than were adjustment disorder with depressed mood and nondepressive disorders. In the presence of affective disorders, comorbid conduct and/or substance use disorders further increased the risk of suicide attempts.

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.

Depressive disorders in childhood. III. A longitudinal study of comorbidity with and risk for conduct disorders.

As part of a longitudinal nosologic study of major depressive disorder (MDD), dysthymic disorder, and adjustment disorder with depressed mood in 104 school-aged probands, the prevalence and consequences of comorbid conduct disorders (CD) were examined. During the index depressive episodes, 16% of the patients had comorbid CD; during the full study observation 23% had CD; and the estimated time-dependent risk of conduct disorder developing was 36% by age 19. For most cases, comorbid CD developed as a complication of the depression and persisted after the depression remitted. Comorbid CD was not differentially associated with the type of depression at study entry, did not affect depressive symptom presentation, was similarly distributed among boys and girls, and was unrelated to demographic factors. Additionally, comorbid CD did not affect recovery from the index depressive episodes and did not influence the symptom-free interval before a recurrent depression among cases with MDD. The risk of CD developing was not altered by chronologically earlier family variables or demographic factors. But girls who had attention deficit disorder, compared to those who did not, seemed to be at higher risk for CD during study observation. Finally, in this depressed cohort, having CD any time was associated with an increased rate of long-term functional problems.

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.

Current issues in profiling quality of care.

Profiling provider performance for the assessment of quality involves a number of issues related to selection of appropriate quality measures, subsequent data collection and analysis, and selection of standards of comparison. This article emphasizes the limitations of current data systems for this purpose and discusses hierarchical modeling as the optimal analytic approach for analyzing resulting data. Mention is made of the difficulties of achieving large enough sample sizes for statistical significance at the individual provider level. Finally, the article discusses feasible options for profiling quality.

Costs of medical care and out-of-pocket expenditures for persons with AIDS in the Boston Health Study.

We examined the cost of health care and out-of-pocket medical expenditures for 189 persons with AIDS at three sites in Massachusetts: an HMO; a public hospital immunodeficiency clinic; and a group practice at a major teaching hospital. The mean cost of care during a four-month reference period was $9,093 +/- $12,683 (mean +/- standard deviation) per patient. Thirty-six percent of the cost was due to hospital care and 40% was due to home health care. Mean out-of-pocket expenditures were $429 +/- $991 (mean +/- standard deviation). Studies that focus on the cost of hospital care may seriously underestimate the medical costs of AIDS.

[Management of myocardial infarction in the Rhone-Alps area. Are there many variations in practice?]. / Prise en charge de l'infarctus du myocarde dans la région Rhône-Alpes. Existe-t-il une variation des pratiques?

The aim of this study was to determine the diagnostic and therapeutic strategies after myocardial infarction and to examine variations in medical and surgical practice with respect to the severity of disease, status of the hospital and patients' characteristics. The method used was a prospective study with follow-up at 30 days and 18 months. The subjects came from an exhaustive cohort of all patients admitted to hospital for myocardial infarction during the month of April 1991 in 57 public and private hospitals in the Rhone-Alps region (n = 311). The patients were identified after admission by consulting physicians of the Department of Social Security. The study included all patients with acute myocardial infarction with at least two of the three usual diagnostic criteria (prolonged, constrictive chest pain, enzyme increases and electrocardiographic changes). The study excluded patients who were dead before arrival at hospital. The parameters analysed included the clinical management, use of echocardiography, exercise stress testing, myocardial scintigraphy, coronary angiography, thrombolysis, angioplasty and coronary bypass surgery in the first 30 days after admission. The severity of infarction was assessed by seven clinical, enzymatic and electrocardiographic criteria by physicians from the Department of Social Security (pain, syncope, shock, left ventricular dysfunction, elevation of CPK > 1000 IU, anterior or extensive necrosis, arrhythmias). The mortality rate of this cohort was calculated from hospital statistics and then by enquiring in the town halls of the region. The demographic features of the cohort were marked by a predominance of men (69.5%) and a relatively high mean age (69 years; 23% over 80 years). Complementary investigations were used with the following frequencies: echocardiography, 61.1%; coronary angiography, 26.4%; exercise stress testing 22.8%; myocardial scintigraphy, 5.5%.(ABSTRACT TRUNCATED AT 250 WORDS)

[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.