Functional additive models for optimizing individualized treatment rules
Park, Hyung; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
A novel functional additive model is proposed, which is uniquely modified and constrained to model nonlinear interactions between a treatment indicator and a potentially large number of functional and/or scalar pretreatment covariates. The primary motivation for this approach is to optimize individualized treatment rules based on data from a randomized clinical trial. We generalize functional additive regression models by incorporating treatment-specific components into additive effect components. A structural constraint is imposed on the treatment-specific components in order to provide a class of additive models with main effects and interaction effects that are orthogonal to each other. If primary interest is in the interaction between treatment and the covariates, as is generally the case when optimizing individualized treatment rules, we can thereby circumvent the need to estimate the main effects of the covariates, obviating the need to specify their form and thus avoiding the issue of model misspecification. The methods are illustrated with data from a depression clinical trial with electroencephalogram functional data as patients' pretreatmentÂ covariates.
Developing a Bayesian hierarchical model for a prospective individual patient data meta-analysis with continuous monitoring
Wu, Danni; Goldfeld, Keith S; Petkova, Eva
BACKGROUND:Numerous clinical trials have been initiated to find effective treatments for COVID-19. These trials have often been initiated in regions where the pandemic has already peaked. Consequently, achieving full enrollment in a single trial might require additional COVID-19 surges in the same location over several years. This has inspired us to pool individual patient data (IPD) from ongoing, paused, prematurely-terminated, or completed randomized controlled trials (RCTs) in real-time, to find an effective treatment as quickly as possible in light of the pandemic crisis. However, pooling across trials introduces enormous uncertainties in study design (e.g., the number of RCTs and sample sizes might be unknown in advance). We sought to develop a versatile treatment efficacy assessment model that accounts for these uncertainties while allowing for continuous monitoring throughout the study using Bayesian monitoring techniques. METHODS:We provide a detailed look at the challenges and solutions for model development, describing the process that used extensive simulations to enable us to finalize the analysis plan. This includes establishing prior distribution assumptions, assessing and improving model convergence under different study composition scenarios, and assessing whether we can extend the model to accommodate multi-site RCTs and evaluate heterogeneous treatment effects. In addition, we recognized that we would need to assess our model for goodness-of-fit, so we explored an approach that used posterior predictive checking. Lastly, given the urgency of the research in the context of evolving pandemic, we were committed to frequent monitoring of the data to assess efficacy, and we set Bayesian monitoring rules calibrated for type 1 error rate and power. RESULTS:The primary outcome is an 11-point ordinal scale. We present the operating characteristics of the proposed cumulative proportional odds model for estimating treatment effectiveness. The model can estimate the treatment's effect under enormous uncertainties in study design. We investigate to what degree the proportional odds assumption has to be violated to render the model inaccurate. We demonstrate the flexibility of a Bayesian monitoring approach by performing frequent interim analyses without increasing the probability of erroneous conclusions. CONCLUSION:This paper describes a translatable framework using simulation to support the design of prospective IPD meta-analyses.
Hippocampal Subfield Volumes Predict Disengagement from Maintenance Treatment in First Episode Schizophrenia
Qi, Wei; Marx, Julia; Zingman, Michael; Li, Yi; Petkova, Eva; Blessing, Esther; Ardekani, Babak; Sakalli Kani, Ayse; Cather, Corinne; Freudenreich, Oliver; Holt, Daphne; Zhao, Jingping; Wang, Jijun; Goff, Donald C
OBJECTIVES/OBJECTIVE:Disengagement from treatment is common in first episode schizophrenia (FES) and is associated with poor outcomes. Our aim was to determine whether hippocampal subfield volumes predict disengagement during maintenance treatment of FES. METHODS:FES patients were recruited from sites in Boston, New York, Shanghai, and Changsha. After stabilization on antipsychotic medication, participants were randomized to add-on citalopram or placebo and followed for 12 months. Demographic, clinical and cognitive factors at baseline were compared between completers and disengagers in addition to volumes of hippocampal subfields. RESULTS:Baseline data were available for 95 randomized participants. Disengagers (n = 38, 40%) differed from completers (n = 57, 60%) by race (more likely Black; less likely Asian) and in more alcohol use, parkinsonism, negative symptoms and more impairment in visual learning and working memory. Bilateral dentate gyrus (DG), CA1, CA2/3 and whole hippocampal volumes were significantly smaller in disengagers compared to completers. When all the eight volumes were entered into the model simultaneously, only left DG volume significantly predicted disengagement status and remained significant after adjusting for age, sex, race, intracranial volume, antipsychotic dose, duration of untreated psychosis, citalopram status, alcohol status, and smoking status (P < .01). Left DG volume predicted disengagement with 57% sensitivity and 83% specificity. CONCLUSIONS:Smaller left DG was significantly associated with disengagement status over 12 months of maintenance treatment in patients with FES participating in a randomized clinical trial. If replicated, these findings may provide a biomarker to identify patients at risk for disengagement and a potential target for interventions.
A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation
Lonze, Bonnie E; Spiegler, Peter; Wesson, Russell N; Alachkar, Nada; Petkova, Eva; Weldon, Elaina P; Dieter, Rebecca A; Li, Yi; Quinn, Max; Mattoo, Aprajita; Soomro, Irfana; Cohen, Steven M; Leung, Sherry; Deterville, Cecilia L; Landrum, B Mark; Ali, Muhammad Imran; Cohen, David J; Singer, Andrew L; Sen, Ayan; Chong, Edward; Hochman, Judith S; Troxel, Andrea B; Montgomery, Robert A
OBJECTIVES/OBJECTIVE:We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN/METHODS:Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING/METHODS:Five U.S. medical centers. PATIENTS/METHODS:Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS/METHODS:Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5â€‰mg) or high-dose (25â€‰mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS/RESULTS:The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival ,frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS:Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.
The integrity of the research record: a mess so big and so deep and so tall
Lee, William; Casey, Patricia; Poole, Norman; Kaufman, Kenneth R; Lawrie, Stephen M; Malhi, Gin; Petkova, Eva; Siddiqi, Najma; Bhui, Kamaldeep
SUMMARY/CONCLUSIONS:Poor research integrity is increasingly recognised as a serious problem in science. We outline some evidence for this claim and introduce the Royal College of Psychiatrists (RCPsych) journals' Research Integrity Group, which has been created to address this problem.
The effectiveness of PTSD treatment for adolescents in the juvenile justice system: A systematic review
Baetz, Carly Lyn; Branson, Christopher Edward; Weinberger, Emily; Rose, Raquel E; Petkova, Eva; Horwitz, Sarah McCue; Hoagwood, Kimberly Eaton
OBJECTIVE:The objective of this study was to systematically review existing empirical evidence on the effectiveness of trauma-specific treatment for justice-involved adolescents and evaluate the impact of the interventions on the reduction of posttraumatic stress disorder (PTSD) symptoms, co-occurring mental health symptoms, and juvenile justice-related outcomes. METHOD/METHODS:A systematic literature search was conducted using a four-step process. Studies were included if they used a manualized, trauma-specific treatment with at least one control or comparison group and a sample comprised exclusively of justice-involved adolescents. RESULTS:In total, 1,699 unique records were identified, and 56 full-text articles were reviewed, of which 7 met the criteria for inclusion. Trauma-specific interventions led to a decrease in PTSD symptoms compared with a control group in four of seven studies, and two studies also demonstrated a reduction in trauma-related depressive symptoms. Finally, juvenile justice-related outcomes were measured in only four studies, with one study finding moderately reduced rates of delinquent behavior and recidivism following trauma-specific treatment. CONCLUSIONS:The results from this systematic review suggest that trauma-specific treatment interventions have promising effects for justice-involved adolescents. However, the results reveal a dearth of quality intervention research for treating youths with histories of trauma in the justice system. Significant gaps in the literature are highlighted, and suggestions for future directions are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
A sparse additive model for treatment effect-modifier selection
Park, Hyung; Petkova, Eva; Tarpey, Thaddeus; Ogden, R Todd
Sparse additive modeling is a class of effective methods for performing high-dimensional nonparametric regression. This article develops a sparse additive model focused on estimation of treatment effect modification with simultaneous treatment effect-modifier selection. We propose a version of the sparse additive model uniquely constrained to estimate the interaction effects between treatment and pretreatment covariates, while leaving the main effects of the pretreatment covariates unspecified. The proposed regression model can effectively identify treatment effect-modifiers that exhibit possibly nonlinear interactions with the treatment variable that are relevant for making optimal treatment decisions. A set of simulation experiments and an application to a dataset from a randomized clinical trial are presented to demonstrate the method.
Efficacy and Safety of COVID-19 Convalescent Plasma in Hospitalized Patients: A Randomized Clinical Trial
Ortigoza, Mila B; Yoon, Hyunah; Goldfeld, Keith S; Troxel, Andrea B; Daily, Johanna P; Wu, Yinxiang; Li, Yi; Wu, Danni; Cobb, Gia F; Baptiste, Gillian; O'Keeffe, Mary; Corpuz, Marilou O; Ostrosky-Zeichner, Luis; Amin, Amee; Zacharioudakis, Ioannis M; Jayaweera, Dushyantha T; Wu, Yanyun; Philley, Julie V; Devine, Megan S; Desruisseaux, Mahalia S; Santin, Alessandro D; Anjan, Shweta; Mathew, Reeba; Patel, Bela; Nigo, Masayuki; Upadhyay, Rabi; Kupferman, Tania; Dentino, Andrew N; Nanchal, Rahul; Merlo, Christian A; Hager, David N; Chandran, Kartik; Lai, Jonathan R; Rivera, Johanna; Bikash, Chowdhury R; Lasso, Gorka; Hilbert, Timothy P; Paroder, Monika; Asencio, Andrea A; Liu, Mengling; Petkova, Eva; Bragat, Alexander; Shaker, Reza; McPherson, David D; Sacco, Ralph L; Keller, Marla J; Grudzen, Corita R; Hochman, Judith S; Pirofski, Liise-Anne; Parameswaran, Lalitha; Corcoran, Anthony T; Rohatgi, Abhinav; Wronska, Marta W; Wu, Xinyuan; Srinivasan, Ranjini; Deng, Fang-Ming; Filardo, Thomas D; Pendse, Jay; Blaser, Simone B; Whyte, Olga; Gallagher, Jacqueline M; Thomas, Ololade E; Ramos, Danibel; Sturm-Reganato, Caroline L; Fong, Charlotte C; Daus, Ivy M; Payoen, Arianne Gisselle; Chiofolo, Joseph T; Friedman, Mark T; Wu, Ding Wen; Jacobson, Jessica L; Schneider, Jeffrey G; Sarwar, Uzma N; Wang, Henry E; Huebinger, Ryan M; Dronavalli, Goutham; Bai, Yu; Grimes, Carolyn Z; Eldin, Karen W; Umana, Virginia E; Martin, Jessica G; Heath, Timothy R; Bello, Fatimah O; Ransford, Daru Lane; Laurent-Rolle, Maudry; Shenoi, Sheela V; Akide-Ndunge, Oscar Bate; Thapa, Bipin; Peterson, Jennifer L; Knauf, Kelly; Patel, Shivani U; Cheney, Laura L; Tormey, Christopher A; Hendrickson, Jeanne E
Importance/UNASSIGNED:There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. Objective/UNASSIGNED:To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. Design, Setting, and Participants/UNASSIGNED:CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. Interventions/UNASSIGNED:A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). Main Outcomes and Measures/UNASSIGNED:The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. Results/UNASSIGNED:Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1]â€‰=â€‰72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1]â€‰=â€‰76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1]â€‰=â€‰93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1]â€‰=â€‰97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (Pâ€‰=â€‰.57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (Pâ€‰=â€‰.06). Conclusions and Relevance/UNASSIGNED:In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. Trial Registration/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04364737.
Development and Validation of a Treatment Benefit Index to Identify Hospitalized Patients With COVID-19 Who May Benefit From Convalescent Plasma
Park, Hyung; Tarpey, Thaddeus; Liu, Mengling; Goldfeld, Keith; Wu, Yinxiang; Wu, Danni; Li, Yi; Zhang, Jinchun; Ganguly, Dipyaman; Ray, Yogiraj; Paul, Shekhar Ranjan; Bhattacharya, Prasun; Belov, Artur; Huang, Yin; Villa, Carlos; Forshee, Richard; Verdun, Nicole C; Yoon, Hyun Ah; Agarwal, Anup; Simonovich, Ventura Alejandro; Scibona, Paula; Burgos Pratx, Leandro; Belloso, Waldo; Avendaño-SolÃ¡, Cristina; Bar, Katharine J; Duarte, Rafael F; Hsue, Priscilla Y; Luetkemeyer, Anne F; Meyfroidt, Geert; Nicola, André M; Mukherjee, Aparna; Ortigoza, Mila B; Pirofski, Liise-Anne; Rijnders, Bart J A; Troxel, Andrea; Antman, Elliott M; Petkova, Eva
Importance:Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective:To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients' baseline characteristics. Design, Setting, and Participants:This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure:Receipt of CCP. Main Outcomes and Measures:World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results:A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance:The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.
Association of Convalescent Plasma Treatment With Clinical Status in Patients Hospitalized With COVID-19: A Meta-analysis
Troxel, Andrea B; Petkova, Eva; Goldfeld, Keith; Liu, Mengling; Tarpey, Thaddeus; Wu, Yinxiang; Wu, Danni; Agarwal, Anup; Avendaño-SolÃ¡, Cristina; Bainbridge, Emma; Bar, Katherine J; Devos, Timothy; Duarte, Rafael F; Gharbharan, Arvind; Hsue, Priscilla Y; Kumar, Gunjan; Luetkemeyer, Annie F; Meyfroidt, Geert; Nicola, André M; Mukherjee, Aparna; Ortigoza, Mila B; Pirofski, Liise-Anne; Rijnders, Bart J A; Rokx, Casper; Sancho-Lopez, Arantxa; Shaw, Pamela; Tebas, Pablo; Yoon, Hyun-Ah; Grudzen, Corita; Hochman, Judith; Antman, Elliott M
Importance:COVID-19 convalescent plasma (CCP) is a potentially beneficial treatment for COVID-19 that requires rigorous testing. Objective:To compile individual patient data from randomized clinical trials of CCP and to monitor the data until completion or until accumulated evidence enables reliable conclusions regarding the clinical outcomes associated with CCP. Data Sources:From May to August 2020, a systematic search was performed for trials of CCP in the literature, clinical trial registry sites, and medRxiv. Domain experts at local, national, and international organizations were consulted regularly. Study Selection:Eligible trials enrolled hospitalized patients with confirmed COVID-19, not receiving mechanical ventilation, and randomized them to CCP or control. The administered CCP was required to have measurable antibodies assessed locally. Data Extraction and Synthesis:A minimal data set was submitted regularly via a secure portal, analyzed using a prespecified bayesian statistical plan, and reviewed frequently by a collective data and safety monitoring board. Main Outcomes and Measures:Prespecified coprimary end points-the World Health Organization (WHO) 11-point ordinal scale analyzed using a proportional odds model and a binary indicator of WHO score of 7 or higher capturing the most severe outcomes including mechanical ventilation through death and analyzed using a logistic model-were assessed clinically at 14 days after randomization. Results:Eight international trials collectively enrolled 2369 participants (1138 randomized to control and 1231 randomized to CCP). A total of 2341 participants (median [IQR] age, 60 [50-72] years; 845 women [35.7%]) had primary outcome data as of April 2021. The median (IQR) of the ordinal WHO scale was 3 (3-6); the cumulative OR was 0.94 (95% credible interval [CrI], 0.74-1.19; posterior probability of OR <1 of 71%). A total of 352 patients (15%) had WHO score greater than or equal to 7; the OR was 0.94 (95% CrI, 0.69-1.30; posterior probability of OR <1 of 65%). Adjusted for baseline covariates, the ORs for mortality were 0.88 at day 14 (95% CrI, 0.61-1.26; posterior probability of OR <1 of 77%) and 0.85 at day 28 (95% CrI, 0.62-1.18; posterior probability of OR <1 of 84%). Heterogeneity of treatment effect sizes was observed across an array of baseline characteristics. Conclusions and Relevance:This meta-analysis found no association of CCP with better clinical outcomes for the typical patient. These findings suggest that real-time individual patient data pooling and meta-analysis during a pandemic are feasible, offering a model for future research and providing a rich data resource.