Risk scoring for time to end-stage knee osteoarthritis: data from the Osteoarthritis Initiative.

OBJECTIVE: This study constructs a risk score for patients' progression to end-stage knee osteoarthritis (OA) within 4 years. DESIGN: The Osteoarthritis Initiative (OAI) was a longitudinal study of the onset and progression of knee OA. Using a recent definition of end-stage knee OA, we implement interval-censored survival forests to select predictors of this endpoint. We fit an interval-censored Cox model for time to end-stage knee OA, using the selected predictors. The risk score is the Cox model's fitted linear combination of the nine selected baseline structural and symptomatic knee OA variables. RESULTS: We fit our models on a training set of 2,701 patients, and we evaluate on an independent test set of 1,436 patients. On the test sample, we observe a concordance index of 0.86 between risk score and time to end-stage, AUC of 0.87 for predicting end-stage within 24, 36, and 48 months, and positive predictive values that increase with the risk score. This risk stratification algorithm could enrich clinical trial patient enrollment. By enrolling test sample patients with scores above a threshold, a trial could have included 91% of test set patients who reach end-stage within 4 years while only enrolling 45% of the test sample. CONCLUSION: Using statistical methods, we construct and validate an interpretable risk score for time to end-stage knee OA. This score can help disease-modifying OA treatment developers to select candidates with the highest risk of fast-progressing knee OA.

Preventive intervention for living donor psychosocial outcomes: feasibility and efficacy in a randomized controlled trial.

There are no evidence-based interventions to prevent adverse psychosocial consequences after living donation. We conducted a single-site randomized controlled trial to examine the postdonation impact of a preventive intervention utilizing motivational interviewing (MI) to target a major risk factor for poor psychosocial outcomes, residual ambivalence (i.e. lingering hesitation and uncertainty) about donating. Of 184 prospective kidney or liver donors, 131 screened positive for ambivalence; 113 were randomized to (a) the MI intervention, (b) an active comparison condition (health education) or (c) standard care only before donation. Ambivalence was reassessed postintervention (before donation). Primary trial outcomes-psychosocial variables in somatic, psychological and family interpersonal relationship domains-were assessed at 6 weeks and 3 months postdonation. MI subjects showed the greatest decline in ambivalence (p = 0.050). On somatic outcomes, by 3 months postdonation MI subjects reported fewer physical symptoms (p = 0.038), lower rates of fatigue (p = 0.021) and pain (p = 0.016), shorter recovery times (p = 0.041) and fewer unexpected medical problems (p = 0.023). Among psychological and interpersonal outcomes, they had a lower rate of anxiety symptoms (p = 0.046) and fewer unexpected family-related problems (p = 0.045). They did not differ on depression, feelings about donation or family relationship quality. The findings suggest that the intervention merits testing in a larger, multisite trial.

Improved resolution of ambient flow through fractured rock with temperature logs.

In contaminant hydrogeology, investigations at fractured rock sites are typically undertaken to improve understanding of the fracture networks and associated groundwater flow that govern past and/or future contaminant transport. Conventional hydrogeologic, geophysical, and hydrophysical techniques used to develop a conceptual model are often implemented in open boreholes under conditions of cross-connected flow. A new approach using high-resolution temperature (+/-0.001 degrees C) profiles measured within static water columns of boreholes sealed using continuous, water-inflated, flexible liners (FLUTe) identifies hydraulically active fractures under ambient (natural) groundwater flow conditions. The value of this approach is assessed by comparisons of temperature profiles from holes (100 to 200 m deep) with and without liners at four contaminated sites with distinctly different hydrogeologic conditions. The results from the lined holes consistently show many more hydraulically active fractures than the open-hole profiles, in which the influence of vertical flow through the borehole between a few fractures masks important intermediary flow zones. Temperature measurements in temporarily sealed boreholes not only improve the sensitivity and accuracy of identifying hydraulically active fractures under ambient conditions but also offer new insights regarding previously unresolvable flow distributions in fractured rock systems, while leaving the borehole available for other forms of testing and monitoring device installation.

Protection of rhesus macaques against disease progression from pathogenic SHIV-89.6PD by vaccination with phage-displayed HIV-1 epitopes.

The antigenic polymorphism of HIV-1 is a major obstacle in developing an effective vaccine. Accordingly, we screened random peptide libraries (RPLs) displayed on phage with antibodies from HIV-infected individuals and identified an array of HIV-specific epitopes that behave as antigenic mimics of conformational epitopes of gp120 and gp41 proteins. We report that the selected epitopes are shared by a collection of HIV-1 isolates of clades A-F. The phage-borne epitopes are immunogenic in rhesus macaques, where they elicit envelope-specific antibody responses. Upon intravenous challenge with 60 MID50 of pathogenic SHIV-89.6PD, all monkeys became infected; however, in contrast to the naive and mock-immunized monkeys, four of five mimotope-immunized monkeys experienced lower levels of peak viremia, followed by viral set points of undetectable or transient levels of viremia and a mild decline of CD4+ T cells, and were protected from progression to AIDS-like illness. These results provide a new approach to the design of broadly protective HIV-1 vaccines.

Bayesian model selection: analysis of a survival model with a surviving fraction.

We describe a methodology for model comparison in a Bayesian framework as applied to survival with a surviving fraction. This is illustrated using a case study of a randomized and controlled clinical trial investigating time until recurrence of depression. Posterior distributions are simulated using Metropolis-within-Gibbs Markov chain methods. Models reflecting the effects of covariates on the log odds of being in the surviving fraction, the log of the hazard rate, as well as both and neither are compared. Bayes factors for comparing the models are obtained by using the bridge sampling method of calculating normalizing constants.

Control of SIV rebound through structured treatment interruptions during early infection.

In a randomized controlled trial with acute simian immunodeficiency virus (SIV)-infected macaques, both highly active antiretroviral therapy (HAART) and HAART with fixed-schedule structured treatment interruption (STI-HAART; alternating 3 weeks on and 3 weeks off therapy) suppressed viral load. In the STI-HAART group, T cell virus-specific immune response (VIR) and control of viral rebound increased concurrently during subsequent interruptions. In contrast, VIR did not increase and SIV rebounded after permanent treatment withdrawal in all animals on continuous HAART. Fixed-schedule STI-HAART appears to be an effective alternative to continuous HAART for the early treatment of retroviral infection.

Effect of PMPA and PMEA on the kinetics of viral load in simian immunodeficiency virus-infected macaques.

In this study we compared the effect of postexposure treatment of the acyclic nucleoside analogs 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) and 9-(2-phosphonylmethoxypropyl)-adenine (PMPA) on the kinetics of viral load in the blood and lymph nodes of rhesus macaques chronically infected with SIVmac251 for 18 weeks. Two of the four macaques treated with PMPA (20 mg/kg per day) for 28 consecutive days had demonstrable reductions in viral loads of 1.5 and 3 logs. Three of four macaques given the same dosing regimen of PMEA had viral load reductions ranging from 1.25 to 2.8 logs. Furthermore, treatment with either drug caused a reduction in virus burden in the lymph nodes by 2 weeks posttreatment. However, in both PMEA- and PMPA-treated animals, viral loads rebounded to day of treatment levels by 2 weeks after termination of treatment. The extent to which viral load was suppressed was similar for both drugs. In contrast, viral loads in three of four mock-treated animals remained persistently high throughout the study. This study has demonstrated that postexposure treatment with these acyclic nucleoside analogs could modulate the kinetics of viral load reduction in some animals.

Limited protection from a pathogenic chimeric simian-human immunodeficiency virus challenge following immunization with attenuated simian immunodeficiency virus.

Two live attenuated single-deletion mutant simian immunodeficiency virus (SIV) constructs, SIV239Deltanef and SIVPBj6.6Deltanef, were tested for their abilities to stimulate protective immunity in macaques. During the immunization period the animals were examined for specific immune responses and virus growth. Each construct generated high levels of specific immunity in all of the immunized animals. The SIV239Deltanef construct was found to grow to high levels in all immunized animals, with some animals remaining positive for virus isolation and plasma RNA throughout the immunization period. The SIVPBj6.6Deltanef was effectively controlled by all of the immunized animals, with virus mostly isolated only during the first few months following immunization and plasma RNA never detected. Following an extended period of immunization of over 80 weeks, the animals were challenged with a pathogenic simian-human immunodeficiency virus (SHIV) isolate, SIV89. 6PD, by intravenous injection. All of the SIV239Deltanef-immunized animals became infected with the SHIV isolate; two of five animals eventually controlled the challenge and three of five animals, which failed to check the immunizing virus, progressed to disease state before the unvaccinated controls. One of five animals immunized with SIVPBj6.6Deltanef totally resisted infection by the challenge virus, while three others limited its growth and the remaining animal became persistently infected and eventually died of a pulmonary thrombus. These data indicate that vaccination with attenuated SIV can protect macaques from disease and in some cases from infection by a divergent SHIV. However, if animals are unable to control the immunizing virus, potential damage that can accelerate the disease course of a pathogenic challenge virus may occur.

Assessing placebo response using Bayesian hierarchical survival models.

The National Institute of Mental Health (NIMH) Collaborative Study of Long-Term Maintenance Drug Therapy in Recurrent Affective Illness was a multicenter randomized controlled clinical trial designed to determine the efficacy of a pharmacotherapy for the prevention of the recurrence of unipolar affective disorders. The outcome of interest in this study was the time until the recurrence of a depressive episode. The data show much heterogeneity between centers for the placebo group. The aim of this paper is to use Bayesian hierarchical survival models to investigate the heterogeneity of placebo effects among centers in the NIMH study. This heterogeneity is explored in terms of the marginal posterior distributions of parameters of interest and predictive distributions of future observations. The Gibbs sampling algorithm is used to approximate posterior and predictive distributions. Sensitivity of results to the assumption of a constant hazard survival distribution at the first stage of the hierarchy is examined by comparing results derived from a two component exponential mixture and a two component exponential changepoint model to the results derived from an exponential model. The second component of the mixture and changepoint models is assumed to be a surviving fraction. For each of these first stage parametric models sensitivity of results to second stage prior distributions is also examined.

Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations.

BACKGROUND: Few reliable correlates of treatment response in depression have emerged despite nearly 40 years of research. We examined the correlates of recovery in a "mega-analysis," or meta-analysis of original data, of 595 patients with major depressive disorder enrolled in 6 standardized treatment protocols. METHODS: All patients (mean age, 44 years; 31% male and 69% female) met criteria for nonbipolar, nonpsychotic primary major depressive disorder and were treated for 16 weeks with either cognitive behavior therapy or interpersonal psychotherapy alone (psychotherapy alone; n = 243) or interpersonal psychotherapy plus antidepressant pharmacotherapy (combined therapy; n = 352). The impact of treatment type, severity, study, and other covariates on recovery rates or time to recovery were examined by means of chi 2, log-rank tests, the Cox proportional hazards model, and sensitivity analyses. RESULTS: Whereas combined therapy was not significantly more effective than psychotherapy alone in milder depressions, a highly significant advantage was observed in more severe recurrent depressions. Poorer outcomes were also observed in women and older patients, although these effects were dependent on inclusion of particular studies. CONCLUSIONS: Mega-analysis is a powerful method for comparing the efficacy of treatments and examining correlates of response. Using this method, we found new evidence in support of the widespread clinical impression that combined therapy is superior to psychotherapy alone for treatment of more severe, recurrent depressions.

Characteristics of the CD8+ lymphocytosis during primary simian immunodeficiency virus infections.

OBJECTIVE: To investigate the source of the expanded blood CD8+ subsets during an acute primary simian immunodeficiency virus (SIV) infection of macaques and the potential role of these cells in disease progression. DESIGN AND METHODS: The primary CD8+ lymphocytosis, which occurs at 1-2 weeks following infection with SIVsmm/PBj-14, was examined in rhesus and cynomolgus macaques. Extensive subset analysis of the expanded blood CD8+ cell pool in a rhesus macaque was compared phenotypically with those in thymus, lymph nodes, spleen, ileum and lung washouts obtained at necropsy during blood lymphocytosis. The influence of the primary CD8+ cells expansion on disease progression was assessed at days 175-679 post-infection in long-term PBj-14 survivors staged according to immunological, virological and histopathological changes in their lymphoid organs. RESULT: The very rapid and transient blood lymphocytosis following infection consisted of two distinct CD45RA(low), CD8+ and CD28-, lymphocyte function-associated antigen (LFA)-1(high), CD45RA(high), CD8+ populations. These populations were present in low levels in thymus, lymph and spleen but were highly represented in mucosal tissues, such as long washout, in which CD28- LFA-1(high) CD45RA(high) CD8+ cells comprised 86% of CD8+ cells, and gut, which was predominantly CD45RA(low) CD28- CD8+ cells. A comparison of progressor and non-progressor PBj-14-infected rhesus and cynomolgus macaques also indicated that the existence or magnitude of a blood CD8+ lymphocytosis during the acute phase of infection did not by itself appear to influence or be predictive of disease progression. CONCLUSION: The marked blood CD8+ lymphocytosis observed during acute SIV infection did not result from expansion of virus-specific precursors in peripheral lymph node and did not appear to influence the rate of disease progression. The findings provide a novel explanation for the primary CD8+ cell lymphocytosis and invoke a mechanism whereby virus-induced cytokine/chemokine production in mucosal sites initiate the transient migration of a pre-existing CD8+ population into the blood from compartments such as lung and gut. Such results suggest that the magnitude of lymphocytosis may depend on the level of viral replication in mucosal tissues and the presence of other infections, for example, cytomegalovirus.

Virus-induced cytokines regulate circulating lymphocyte levels during primary SIV infections.

Decline in blood CD4+ lymphocytes during primary symptomatic infections with HIV is usually attributed to viral killing, and has not been considered in terms of altered lymphocyte migration and sequestration. We therefore sought to examine whether CD4+ cell loss from blood of macaques undergoing an acute primary SIV infection might be due to increased synthesis of cytokines, known to profoundly affect lymphocyte trafficking, rather than to direct lymphocyte destruction by virus. The findings indicate that rapid lymphocyte depletion following acute infection is not selective for CD4+ cells, correlates precisely with increased plasma IFN-gamma and tumor necrosis factor-alpha levels, and is reversible. CD4/CD8 ratios in lymph nodes with high viral burdens remain relatively unchanged despite lymphocyte loss from blood. Levels of cytokine mRNA measured in lymphoid organs reflect neither cytokine plasma levels nor their potential to induce sequestration. These results support a model of cytokine-induced lymphocyte extravasation to account for the acute HIV/SIV-induced CD4+ cell lymphopenia and raise questions regarding the extent to which altered lymphocyte migration plays a role in the gradual CD4+ cell depletion throughout infection.

Enhanced follicular dendritic cell function in lymph nodes of simian immunodeficiency virus-infected macaques: consequences for pathogenesis.

HIV and simian immunodeficiency virus (SIV) infections are characterized by several abnormalities in B cell function. Pathogenesis is also associated with marked changes within germinal centers (GC) including hypertrophy and degeneration of follicular dendritic cells (FDC) and accumulation of both viral antigen and activated CD45RO+ CD8+ cells. Since FDC are critical to the generation of antibody-forming cells and specific B cell memory, the simplest assumption is that such B cell defects directly result from virus-induced changes in the GC environment. The present study examined FDC-enriched mesenteric lymph node lymphocyte preparations from early and late stage SIV-infected and uninfected macaques for their ability to support GC reactions in vitro. The results indicate that FDC function as measured by cluster formation, B cell proliferation and SIV-specific antibody production is enhanced in SIV-infected macaques suggesting that, despite FDC atrophy, virus accumulation induces increased FDC-B cell interactions resulting in B cell hyperactivity. The activation and proliferation of CD8+ cells in FDC-enriched cultures further suggest that the infiltrating CD8+ population observed in situ in GC of late-stage SIV/HIV-infected individuals may also benefit from FDC-derived growth signals. Thus, in addition to enhanced B cell proliferation and antibody production, hyperactivity of FDC may potentially promote their own self destruction via the infiltrating CD8+ cells. The increased B cell responsiveness may further exacerbate the disease process due to an overall decrease in the affinity of anti-HIV/SIV antibody, a loss of crucial protective antibodies to other infectious agents and the creation of an environment in which increased trapping of virions facilitates more extensive infection of CD4+ T cells.

Applications of a mixture survival model with covariates to the analysis of a depression prevention trial.

This paper presents a case study of model selection for survival analysis data. We use an approximate Bayesian method for model selection based on assessing the posterior probability of competing models given the data. We introduce the Schwarz criteria, an approximation to the logarithm of the Bayes factor, to provide an indication of evidence in favour of one model compared to another. Specifically, in the context of a depression prevention clinical trial we evaluate the efficacy of treatment in preventing or delaying the time to recurrence of depression, and evaluate how differences in the survival distributions between the two treatment groups depend on explanatory variables of interest. This investigation is based on a mixture survival model that explicitly incorporates the possibility of a surviving fraction.

Mixture models for eye-tracking data: a case study.

Heterogeneity in biomedical data is often a source of great scientific interest and mixture models provide a general framework for modelling the various types that arise in practice. Finite mixture models model discrete subgroups within populations while continuous mixture models inflate the variance to account for over-dispersed data. A potential problem with the application of finite mixture models in practice is that these models may drastically overestimate the number of component densities when there is a lack of model fit. This can have severe consequences, leading the data analyst to attach substantive interpretations to spurious subgroups. For this reason, we propose using the continuous mixture model as an alternative when fitting finite mixture models with an arbitrary number of components. In the context of an example examining a specific oculomotor component of eye-tracking dysfunction in schizophrenia, we demonstrate why the continuous mixture model provides a viable alternative to the finite mixture model for small sample sizes. We present methods for fitting and comparing both models using the parametric bootstrap and EM algorithm, and show that the distinction between the models decreases as the number of component densities in the finite mixture model increases.

Bone lead levels and delinquent behavior.

OBJECTIVE: To evaluate the association between body lead burden and social adjustment. DESIGN: Retrospective cohort study. SETTING: Public school community. PARTICIPANTS: From a population of 850 boys in the first grade at public schools, 503 were selected on the basis of a risk scale for antisocial behavior. All of the 850 boys who scored in the upper 30th percentile of the distribution on a self-reported antisocial behavior scale were matched with an equal number drawn by lot from the lower 70% of the distribution. From this sample, 301 students accepted the invitation to participate. EXPOSURE MEASURE: K x-ray fluorescence spectroscopy of tibia at subjects' age of 12 years. MAIN OUTCOME MEASURES: Child Behavior Checklist (CBCL), teachers' and parents' reports, and subjects' self-report of antisocial behavior and delinquency at 7 and 11 years of age. RESULTS: Subjects, teachers, and parents were blind to the bone lead measurements. At 7 years of age, borderline associations between teachers' aggression, delinquency, and externalizing scores and lead levels were observed after adjustment for covariates. At 11 years of age, parents reported a significant lead-related association with the following CBCL cluster scores: somatic complaints and delinquent, aggressive, internalizing, and externalizing behavior. Teachers reported significant associations of lead with somatic complaints, anxious/depressed behavior, social problems, attention problems, and delinquent, aggressive, internalizing, and externalizing behavior. High-lead subjects reported higher scores in subjects' self-reports of delinquency at 11 years. High-lead subjects were more likely to obtain worse scores on all items of the CBCL during the 4-year period of observation. High bone lead levels were associated with an increased risk of exceeding the clinical score (T > 70) for attention, aggression, and delinquency. CONCLUSION: Lead exposure is associated with increased risk for antisocial and delinquent behavior, and the effect follows a developmental course.

An introduction to logistic regression with an application to the analysis of language recovery following a stroke.

The aim of a statistical model is to present a simplified representation of the underlying structure in a data set by separating systematic features from random variation. Sometimes the purpose of a statistical model is to provide a simple descriptive summary of the data and sometimes it is to use the data for comparative or inferential purposes. In practice, the specification of a statistical model requires a thorough understanding of the substantive area of application, an assessment of the validity of the assumptions of the model, and an evaluation of the fit of the model to the data. In this paper, as an illustration of these aspects of the statistical modeling of data, we consider the specification, application, and interpretation of a logistic regression model for the investigation of relationships between binary response data and a collection of explanatory variables. We illustrate applications of the methodology using data from a prospective study of spontaneous language recovery following a stroke (Holland, Greenhouse, Fromm, & Swindell, 1989).

Robust Bayesian methods for monitoring clinical trials.

Bayesian methods for the analysis of clinical trials data have received increasing attention recently as they offer an approach for dealing with difficult problems that arise in practice. A major criticism of the Bayesian approach, however, has focused on the need to specify a single, often subjective, prior distribution for the parameters of interest. In an attempt to address this criticism, we describe methods for assessing the robustness of the posterior distribution to the specification of the prior. The robust Bayesian approach to data analysis replaces the prior distribution with a class of prior distributions and investigates how the inferences might change as the prior varies over this class. The purpose of this paper is to illustrate the application of robust Bayesian methods to the analysis of clinical trials data. Using two examples of clinical trials taken from the literature, we illustrate how to use these methods to help a data monitoring committee decide whether or not to stop a trial early.

Cost utility analysis of maintenance treatment for recurrent depression.

This paper presents a cost-utility analysis of three maintenance treatments for recurrent depression: interpersonal therapy (IPT-M), imipramine drug therapy (Drug), and a combination of the two. We base our analysis on the results of the University of Pittsburgh's Controlled Clinical Trial of Maintenance Therapies for Recurrent Depression. We construct a Markovian state-transition model to incorporate clinical effectiveness into cost and quality-of-life impacts; we assign empirical values to the parameters of this model; and we then use Monte Carlo analysis to compare the relative cost effectiveness of the different maintenance treatments. For the patients who met the eligibility standards for the study, Drug maintenance treatment is cost-effective in the strongest sense of the term compared to either a placebo group or IPT-M: it both improves expected lifetime health (measured in quality-adjusted life years, or QALYs) and reduces direct medical costs. This is true even when relatively severe side effects of the drug are considered. Compared to the placebo group, IPT-M and the combination of IPT-M and Drug each improve expected lifetime health, although in neither case are expected direct medical costs reduced. Still, the cost of the resulting health improvements, under $5000/QALY, are very reasonable. A similar conclusion holds comparing Drug and IPT-M to IPT-M alone. All of the above conclusions are quite robust to sensitivity analyses.