Biomedical subjects

Philip W Lavori

Publications and source records attributed to Philip W Lavori.

At least 19 recordsLinked to original sources

PubMed2006

Adaptive strategies for treating childhood mania.

The conduct of trials in children is beset with special difficulties associated with the dearth of treatment data, the considerable heterogeneity of pediatric patient populations connected with (for example) developmental stage, and the strong desire of parents to see that children are provided with the best possible care at all times. To address these issues, we propose the adaptive treatment strategy (ATS) study in which medication changes are adaptively determined according to the evolving treatment response of the individual child. To formalize this methodological approach, we parameterize an ATS as a "threshold" decision rule that monitors whether the patient's response trajectory crosses some threshold of failure. In this formulation, the threshold represents a priori judgments about when to give up on response to medication, and the goal is to find the right response thresholds for continuation, augmentation, or switching. Our exposition is developed in the specific clinical context of childhood mania to maximize accessibility of the ideas but applies more generally to other chronic mental and physical health disorders that are difficult to treat.

Adolescent↗

PubMed2006

Plasma osteopontin is an independent prognostic marker for head and neck cancers.

PURPOSE: To confirm the relationship between plasma osteopontin (OPN) levels and treatment outcomes in head and neck squamous cell carcinoma (HNSCC) patients in an expanded study. PATIENTS AND METHODS: One hundred forty patients with newly diagnosed HNSCC were enrolled onto this study, 54 previously reported and 86 new patients. Pretreatment plasma OPN levels were assessed in all patients by an enzyme-linked immunosorbent assay method. OPN levels were correlated to treatment outcomes in the new group of patients. Detailed analyses were also performed on the relationship between OPN and tumor control rate, event-free survival (EFS), and postrelapse survival for the entire group. RESULTS: Using a previously defined cut off point of 450 ng/mL, there was a significant correlation between OPN and freedom-from-relapse (P = .047), overall survival (P = .019), and EFS (P = .023) in the new, independent patient cohort (n = 86). Sequence of event analyses using the entire group (N = 140) revealed that OPN was an independent prognostic factor for initial tumor control, EFS in those who have achieved tumor control, and postrelapse survival. CONCLUSION: In this expanded study, we were able to replicate the prognostic significance of OPN using a predefined cut off point in an independent patient group and demonstrated that plasma OPN is an independent prognostic marker for HNSCC.

Aged↗

PubMed2006

The cognitive effects of electroconvulsive therapy in community settings.

Despite ongoing controversy, there has never been a large-scale, prospective study of the cognitive effects of electroconvulsive therapy (ECT). We conducted a prospective, naturalistic, longitudinal study of clinical and cognitive outcomes in patients with major depression treated at seven facilities in the New York City metropolitan area. Of 751 patients referred for ECT with a provisional diagnosis of a depressive disorder, 347 patients were eligible and participated in at least one post-ECT outcome evaluation. The primary outcome measures, Modified Mini-Mental State exam scores, delayed recall scores from the Buschke Selective Reminding Test, and retrograde amnesia scores from the Columbia University Autobiographical Memory Interview-SF (AMI-SF), were evaluated shortly following the ECT course and 6 months later. A substantial number of secondary cognitive measures were also administered. The seven sites differed significantly in cognitive outcomes both immediately and 6 months following ECT, even when controlling for patient characteristics. Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.

Adult↗

PubMed2006

A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure.

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.

Adrenergic beta-Antagonists↗

PubMed2006

Determining the duration of antidepressant treatment: application of signal detection methodology and the need for duration adaptive designs (DAD).

BACKGROUND: With remission now the treatment goal, antidepressant trial duration has increased. However, most patients do not remit and are exposed to prolonged, ineffective treatment. METHODS: Conditional probabilities and signal detection methodology were contrasted in early detection of nonremitters in three comparator, 12-week antidepressant trials conducted in late- or mid-life depression. RESULTS: The mid- and late-life samples did not differ in rates or time-to-onset of remission or accuracy of early identification of nonremission. Using conditional probabilities, there were marked differences in predictive power depending on the remission criterion. With signal detection methods, sensitivity and specificity of early identification were uniform across the differing medication conditions, remission criteria, and the three studies. By week 6, > or = 60% of ultimate nonremitters were identified, while maintaining a false positive rate < or = 20%. CONCLUSIONS: The goals of providing maximal opportunity to achieve remission, while minimizing exposure to ineffective treatment can be satisfied by use of duration adaptive designs (DAD). While use of conditional probabilities has been the traditional method for early detection of nonremitters, this approach is inferior to use of signal detection methods. The findings also contradicted the widely held view that patients with late-life depression require longer treatment duration.

Antidepressive Agents, Second-Generation↗

PubMed2006

Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report.

OBJECTIVE: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHOD: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of or=11 (HRSD(17)>or=14) defined relapse. RESULTS: The QIDS-SR(16) remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. CONCLUSIONS: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.

Adolescent↗

PubMed2005

The impact of patient self-testing of prothrombin time for managing anticoagulation: rationale and design of VA Cooperative Study #481--the Home INR Study (THINRS).

BACKGROUND: Anticoagulation (AC) with warfarin reduces the risk of thromboembolism (TE) in a variety of applications, yet despite compelling evidence of the value and importance of high quality AC, warfarin remains underused, and dosing is often suboptimal. Approaches to improve AC quality include (1) an AC service (ACS), which allows the physician to delegate day-to-day details of AC management to another provider dedicated to AC care, and (2) incorporating into the treatment plan patient self-testing (PST) under which, after completing a training program, patients perform their own blood testing (typically, using a finger-stick blood analyzer), have dosage adjustments guided by a standard protocol, and forward test results, dosing and other information to the provider. Studies have suggested that PST can improve the quality of AC and perhaps lower TE and bleed rates. The purpose of Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) #481, "The Home INR Study" (THINRS) is to compare AC management with frequent PST using a home monitoring device to high quality AC management (HQACM) implemented by an ACS with conventional monitoring of prothrombin time by international normalized ratio (INR) on major health outcomes. PST in THINRS involves use of an INR monitoring device that is FDA approved for home use. STUDY DESIGN: Sites are VA Medical Centers where the ACS has an active roster of more than 400 patients. THINRS includes patients with atrial fibrillation (AF) and/or mechanical heart valve (MHV) expected to be anticoagulated indefinitely. THINRS has two parts. In Part 1, candidates for PST are evaluated for 2 to 4 weeks for their ability to use home monitoring devices. In Part 2, individuals capable of performing PST are randomized to (1) HQACM with testing every 4 weeks and as indicated for out of range values, medication/clinical changes, or (2) PST with testing every week and as indicated for out of range values, medication/clinical changes. The primary outcome measure is event rates, defined as the percent of patients who have a stroke, major bleed, or die. Secondary outcomes include total time in range (TTR), other events (myocardial infarction (MI), non-stroke TE, minor bleeds), competence and compliance with PST, satisfaction with AC, AC associated quality of life (QOL), and cost-effectiveness. To assess the effect of PST frequency on TTR and other outcomes, at selected sites patients randomized to perform PST are assigned one of three test frequencies (weekly, twice weekly, or once every four weeks).

Anticoagulants↗

PubMed2005

Improving treatment of depression in the elderly: two innovations in statistical design of clinical trials.

Depression in the elderly patient may present special challenges for the design of clinical treatment trials due to a complex antidepressant treatment history, individual contraindications to certain medications, medical comorbidity, as well as concurrent medications for other medical conditions. The chronic, relapsing, and remitting nature of depression calls for a dynamic, adaptive treatment strategy, matching treatment changes to patient responses. To market a drug successfully in a cost-conscious environment, it also may be necessary to define the unique contribution that a new drug makes to the treatment of patients, in addition to proving that it is efficacious (by comparison to placebo). These issues, although not unique to the elderly, take on greater importance and weight as patient populations age. This article describes 2 innovations in clinical trials design that may help deal with these issues.

Aged↗

PubMed2005

Evaluating the quality of informed consent.

CONTEXT: Although informed consent is a critical means of protecting the rights and interests of participants in clinical research, effective and efficient means of evaluating the quality of consent are needed. Having such means will be important to monitoring consent and testing potential improvements in the consent process. OBJECTIVE: To develop and test a practical and general means of evaluating the quality of informed consent for clinical research. Methods We developed and tested the Brief Informed Consent Evaluation Protocol (BICEP), a short telephone-based assessment of informed consent. As soon as patient-participants completed the informed consent process for a participating VA Cooperative Studies Program clinical trial they called an interviewer who administered the BICEP. RESULTS: 632 participants completed BICEP, representing eight ongoing studies from 14 VA and one non-VA medical centers across the country. Site coordinators reported little to no difficulty implementing BICEP. The average duration of BICEP was 8.8 minutes (SD 3.6). Overall, patient-participants evaluated the informed consent process positively. A reliable coding system was then developed to analyze the verbatim responses of the final 191 participants. An Informed Consent Aggregate Score (ICAS) had a mean score of 8.23 (SD 1.17) with a range of 0-10, with 10 a perfect score; and a Therapeutic Misconception Aggregate Score (TMAS) had a mean of 1.62 (SD 0.93) with a range of 0-5, with 5 a perfect score. CONCLUSIONS: The BICEP is an efficient means of evaluating informed consent that is acceptable to research participants and research personnel. While participants tend to be satisfied with the informed consent process, the BICEP indicates there is room for improvement in the informed consent process for research.

Consent Forms↗

PubMed2004

Placebo-free designs for evaluating new mental health treatments: the use of adaptive treatment strategies.

The dominant pre-marketing clinical trial in psychopharmacology is a non-equivalence design that randomizes patients to one of three treatments: an accepted standard, the innovation (new drug), or placebo, with the main efficacy comparison being innovation vs placebo. The reasons behind the choice of placebo control in new drug development include anticipated small effect size for active-controlled comparisons and the sufficiency of demonstrated treatment effect (new drug vs placebo) for regulatory approval. These reasons have led to great reliance on placebo control in drug evaluation studies, despite the ethical controversy over the use of placebo when there are known effective standard treatments. While the use of placebo controls has been widely debated, a less considered aspect of the usual placebo-controlled non-equivalence design is the disparity between the decisions that it supports and those that pervade clinical practice. We propose an alternative approach that randomizes one group of patients to an adaptive treatment strategy that exemplifies the adaptive nature of clinical decision-making in the treatment of ongoing mental health disorders. The basic idea is to compare the adaptive strategy, which uses a patient's outcomes to date to determine when to switch from an initial treatment (e.g. an accepted standard) to an alternative (e.g. the new) treatment, to fixed trials of either treatment option. We state the conditions under which the adaptive treatment RCT is attractive to implement and the requirements for doing so.

Antipsychotic Agents↗

PubMed2004

Translating research into practice: organizational issues in implementing automated decision support for hypertension in three medical centers.

Information technology can support the implementation of clinical research findings in practice settings. Technology can address the quality gap in health care by providing automated decision support to clinicians that integrates guideline knowledge with electronic patient data to present real-time, patient-specific recommendations. However, technical success in implementing decision support systems may not translate directly into system use by clinicians. Successful technology integration into clinical work settings requires explicit attention to the organizational context. We describe the application of a "sociotechnical" approach to integration of ATHENA DSS, a decision support system for the treatment of hypertension, into geographically dispersed primary care clinics. We applied an iterative technical design in response to organizational input and obtained ongoing endorsements of the project by the organization's administrative and clinical leadership. Conscious attention to organizational context at the time of development, deployment, and maintenance of the system was associated with extensive clinician use of the system.

Academic Medical Centers↗

PubMed2004

Implementation of an iron reduction protocol in patients with peripheral vascular disease: VA cooperative study no. 410: the Iron (Fe) and Atherosclerosis Study (FeAST).

BACKGROUND: Iron accumulates imperceptibly over time in adults because intake exceeds loss and because no physiologic mechanism exists for excreting levels that may be toxic. Levels of stored iron represented by the serum ferritin concentration have been implicated in the pathogenesis of vascular (and other) diseases, but the role of such stored iron remains controversial. Our hypothesis was that reduction in body iron stores to levels typical of children and premenopausal women (corresponding to ferritin levels of approximately 25 ng/mL) would alter morbidity and mortality rates in patients with advanced peripheral vascular disease. METHODS AND RESULTS: A randomized, single-blinded, clinical trial of graded reduction of iron stores by controlled phlebotomy was undertaken in patients with advanced peripheral vascular disease. Details of implementation of the protocol for testing this unusual experimental intervention are reported. CONCLUSIONS: A methodology is described for testing the concept that reduction of body iron stores (while avoiding iron deficiency) may alter disease outcomes. This methodology appears to be suitable for further testing to determine whether levels of iron stores presumed to be pathologic contribute to disease initiation or progression.

Aged↗

PubMed2004

Sequenced treatment alternatives to relieve depression (STAR*D): rationale and design.

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Adolescent↗

PubMed2004

Dynamic treatment regimes: practical design considerations.

BACKGROUND: Clinical management of chronic disease requires a dynamic treatment regime (DTR): rules for choosing the new treatment based on the history of response to past treatments. Estimating and comparing the effects of DTRs from a sample of observed trajectories of treatment and outcome depends on the untestable assumption that new treatments are assigned independently of potential future responses to treatment, conditional on the history of treatments and response to date ("sequential ignorability"). In longitudinal observational studies, sequential ignorability must be assumed, while randomization of dynamic regimes can guarantee it. METHODS: Using several clinical examples, we describe the simplest randomized experimental designs for comparing DTRs. We begin by considering an initial treatment A and a second treatment B, and discuss how a dynamic treatment regime that starts with A and leads (sometimes) to B, might be compared to either fixed treatment A or B. We also illustrate the problem of finding the optimal sequence of treatments in a DTR, when there are several choices. We describe and contrast two ways of incorporating randomization into studies to compare such regimes: baseline randomization among DTRs versus randomization at the decision points (sequentially randomized designs). CONCLUSIONS: We discuss estimation and inference from both baseline randomized and sequentially randomized designs and conclude with a discussion of the differences between the experimental and observational approaches to optimizing and comparing dynamic treatment regimes.

Chronic Disease↗

PubMed2003

Randomized trial of trauma-focused group therapy for posttraumatic stress disorder: results from a department of veterans affairs cooperative study.

BACKGROUND: Department of Veterans Affairs Cooperative Study 420 is a randomized clinical trial of 2 methods of group psychotherapy for treating posttraumatic stress disorder (PTSD) in male Vietnam veterans. METHODS: Vietnam veterans (360 men) were randomly assigned to receive trauma-focused group psychotherapy or a present-centered comparison treatment that avoided trauma focus. Treatment was provided weekly to groups of 6 members for 30 weeks, followed by 5 monthly booster sessions. Severity of PTSD was the primary outcome. Additional measures were other psychiatric symptoms, functional status, quality of life, physical health, and service utilization. Follow-up assessments were conducted at the end of treatment (7 months) and at the end of the booster sessions (12 months); 325 individuals participated in 1 or both assessments. Additional follow-up for PTSD severity was performed in a subset of participants at 18 and 24 months. RESULTS: Although posttreatment assessments of PTSD severity and other measures were significantly improved from baseline, intention-to-treat analyses found no overall differences between therapy groups on any outcome. Analyses of data from participants who received an adequate dose of treatment suggested that trauma-focused group therapy reduced avoidance and numbing and, possibly, PTSD symptoms. Dropout from treatment was higher in trauma-focused group treatment. Average improvement was modest in both treatments, although approximately 40% of participants showed clinically significant change. CONCLUSIONS: This study did not find a treatment effect for trauma-focused group therapy. The difference between the effectiveness and adequate dose findings suggests the possible value of methods to enhance the delivery of cognitive-behavioral treatments in clinical practice settings.

Ambulatory Care↗

PubMed2003

Recurrence of bipolar disorders and major depression. A life-long perspective.

OBJECTIVE: It is not known whether the risk of recurrence declines with time in bipolar disorders and in major depression. This study describes the life-long recurrence risk of bipolar I, bipolar II and major depressive disorders. METHOD: 160 bipolar-I, 60 bipolar-II and 186 depressive patients hospitalised between 1959 and 1963 were followed up every five years from 1965 to 1985. The course prior to the index hospitalisation was assessed in retrospect. The recurrence risk was computed by the multiplicative intensity model (Aalen et al. 1980). RESULTS: The cumulative intensity curves for the transition from states of remission to new episodes remained linear over 30 to 40 years after onset, indicating a constant risk of recurrence over the life-span up to the age of 70 or more. The recurrence risk of bipolar disorders (0.40 episodes per year) was about twice that of depression (0.20 episodes per year); BP-II disorders had only a slightly higher recurrence risk than BP-I disorders. There were no significant gender differences in the course of either bipolar or depressive disorders. CONCLUSION: If long-term trials confirm its efficacy, these results support lifelong prophylactic treatment of severe types of mood disorders.

Adult↗

PubMed2003

Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study.

Sequenced Treatment Alternatives to Relieve Depression (STAR*D) attempts to fill in major clinical information gaps and to evaluate the theoretical principles and clinical beliefs that currently guide pharmacotherapy of major depressive disorder. The study is conducted in representative participant groups and settings using clinical management tools that easily can be applied in daily practice. Outcomes include clinical outcomes and health care utilization and cost estimates. Research findings should be immediately applicable to, and easily implemented in, the daily primary and specialty care practices. This article provides the overall rationale for STAR*D and details the rationale for key design, measurement, and analytic features of the study.

Antidepressive Agents↗

PubMed2003

Correlates of sexual risk for HIV infection in female members of heterosexual California Latino couples: an application of a Bernoulli process model.

Individual HIV risk estimates were generated from reported sexual behavior for 1,146 California Latino Couples Study participants (573 couples). These Bernoulli process model-based estimates proved strongly associated with individual sexually transmitted disease history. Mean estimated background risk from sexual contacts other than with their primary partner was substantially lower for the females than the males (1.4 vs. 7.4 per 10,000). After including their chance of infection from each other, mean net estimated risk was higher for the females than the males (9.2 vs. 8.6 per 10,000). Individual background risk was predicted by individual demographic and psychosocial characteristics (females: coefficient of concordance C = 0.84 predicting any (nonzero) risk; adjusted R(2) = 36% predicting level of risk, given any risk; males: C = 0.78; R(2) = 24%). Characteristics of women with higher risk primary partners were also identifiable (C = 0.65; R(2) = 13%). There was no significant negative association between the male partner's background sexual risk and the aggregate infectivity of the woman from him (taking into account the total number of their condom-protected and unprotected acts of different types).

Adolescent↗