array(41) {
  ["project_title"]=>
  string(128) "Mediation Analysis to explain comparative efficacy of antipsychotic medications for treatment of schizophrenia in short-term RCT"
  ["project_narrative_summary"]=>
  string(701) "Differences among antipsychotic medications for treatment of schizophrenia spanning from targeted
mechanism of action, side effects and efficacy have been observed in randomized trial settings and in clinical
practice. We will apply causal mediation analysis to study the interplay of symptoms and side effect in explaining how OPTICS trials treatments affect the final outcome of interest. We will compare drug and placebo (1) on primary outcomes: social functioning and negative symptoms ; (2) on secondary outcomes: (i) positive symptoms and (ii) side effects; (3) quantify mediating and interactive role of the secondary outcomes. The work has the potential to guide clinical practice." ["project_learn_source"]=> string(5) "other" ["project_learn_source_exp"]=> string(0) "" ["project_key_personnel"]=> array(1) { [0]=> array(6) { ["p_pers_f_name"]=> string(5) "Yiwen" ["p_pers_l_name"]=> string(3) "Zhu" ["p_pers_degree"]=> string(2) "BA" ["p_pers_pr_affil"]=> string(39) "Harvard TH Chan School of Public Health" ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(0) "" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(65) "External grants or funds are being used to support this research." ["label"]=> string(65) "External grants or funds are being used to support this research." } ["project_funding_source"]=> string(35) "Harvard Catalyst OPTICS Pilot Grant" ["project_assoc_trials"]=> array(1) { [0]=> object(WP_Post)#3680 (24) { ["ID"]=> int(1967) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2015-04-01 16:11:00" ["post_date_gmt"]=> string(19) "2015-04-01 16:11:00" ["post_content"]=> string(0) "" ["post_title"]=> string(19) "OPTICS Trial Bundle" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(5) "draft" ["comment_status"]=> string(6) "closed" ["ping_status"]=> string(6) "closed" ["post_password"]=> string(0) "" ["post_name"]=> string(19) "optics-trial-bundle" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-02-21 13:41:20" ["post_modified_gmt"]=> string(19) "2023-02-21 13:41:20" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(70) "https://dev-yoda.pantheonsite.io/?post_type=clinical_trial&p=1967" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } } ["project_date_type"]=> string(91) "Individual Participant-Level Data, which includes Full CSR and all supporting documentation" ["property_scientific_abstract"]=> string(1550) "Background: Differences among antipsychotic medications for treatment of schizophrenia spanning from targeted mechanism of action, side effects and efficacy have been observed in randomized trial settings and in clinical practice. Explaining why differences in efficacy are observed is important to inform development of new drugs and to guide appropriate treatment strategies.
Goal & Main Outcomes: To quantify the joint effect, potentially synergistic or antagonistic, of intermediate factors that can explain differential efficacy among treatments for schizophrenia. We will (1) compare drug effects on primary outcomes, social functioning and negative symptoms; (2) compare drug effects on secondary outcomes: (i) positive symptoms and (ii) side effects; (3) quantify how much of the relative efficacy on social functioning and negative symptoms is due to the mediating and interactive role of the secondary outcomes.
Study Design & Participants: We plan to investigate mechanisms that could explain treatment efficacy as a secondary analysis of four Paliperidone trials analyzed selected based on their comparability in study duration (6 weeks) and drug dosage (Paliperidone ER 6-12 mg, fixed doses).
Statistical Analysis: Mediation analysis is the study of the role of intermediate endpoints in explaining how a treatment affects the final outcome of interest. We will extend and apply mediation analysis approaches to meta-analysis of longitudinal trial data in the presence of multiple, potentially interacting, mediators." ["project_brief_bg"]=> string(3204) "Antipsychotic drugs are the cornerstone of treatment for schizophrenia. The first generation of antipsychotic medications were approved in the 1950?s, while the second generation started with the approval of clozapine in the early 1990?s. In the past 25 years a wealth of clinical trials and observational studies have evaluated relative efficacy, safety, and effectiveness of first and second generation medications. Such studies have shown that first and second generation antipsychotics differ significantly in (i) targeted mechanism of action (ii) side effects (iii) adherence to medication (iv) Positive Symptoms Scale (PANSS) scores improvement[1,2]. A consensus has not been reached on the relative efficacy and effectiveness of first and second generation antipsychotic drugs. This has induced an increasing trend in the administration of costly, and yet to be shown effective polytherapy and higher doses of antipsychotics[3]. Among psychotic patients, schizophrenia patients display the highest deficit in social functioning[4,5]. Social functioning has been recognized as an important contributor to overall quality of life and a determinant of treatment success. The ability of typical and atypical agents to improve social functioning has
not been fully explored[6]. Consensus has been reached on the impact of negative symptoms on social functioning[7]. Although first and second generation drugs target positive symptoms, several studies have shown the impact of second-generation drugs on negative symptoms through indirect mechanisms. It is of interest to investigate further the efficacy of first and second generation antipsychotics on negative symptoms and social functioning and to assess the mechanisms that explain their relative efficacy. Clarity on the relative efficacy and effectiveness of typical and atypical antipsychotic drugs can be made only by accounting for the complex effects of antipsychotics. It is critical to investigate the interplay of symptoms and side effects that impact the overall well-being of the patient over the course of treatment. Secondary analyses of efficacy trials that explain treatment mechanism of action have recently become popular in the field of psychiatry. Mediation analysis is an important approach for quantifying how much of the treatment effect on a primary outcome is through intermediate factors (also referred to as mediators) and how much is through pathways independent of the mediators. Recently, Dr. Valeri developed methods and software for mediation analysis[8]. We will apply this methodology to understand whether (i) positive symptoms and (ii) side effects could act as mediators of the effect of antipsychotic medications for schizophrenia on negative symptoms, precursors of social functioning. We will allow the mediators to act synergistically or antagonistically. We will quantify how much of the effect of the antipsychotics on negative symptoms and social function is due to the effect through the mediators (indirect), the effect independent of the mediators (direct), and the effect due to drug-mediators and mediators-mediators interaction integrating data from four Paliperidone trials to improve power." ["project_specific_aims"]=> string(1073) "Study objective: Develop and apply causal mediation analysis approaches to explaining comparative efficacy in a trial of high, medium and low-dose oral paliperidone extended release (ER) vs. placebo/olanzapine on social functioning after 6 weeks follow-up.
AIM 1 Compare drug effects on the primary outcomes, negative symptoms and social functioning.
Hypothesis 1 Paliperidone will result in decreased negative symptoms and increased social functioning relative to placebo.
AIM 2 Compare drug effects on secondary outcomes, (i) PANSS Factor Scores for positive symptoms (ii) side effects.
Hypothesis 2 Paliperidone will result in improved PANSS positive symptoms and will increase the risk of side effects relative placebo.
AIM 3 Explaining comparative efficacy of treatment on the primary outcomes, negative symptoms and social functioning, via the mediating and interactive role of secondary outcomes.
Hypothesis 3 Secondary outcomes will be both mediators and modifiers of treatment effect on negative symptoms and social functioning." ["project_study_design"]=> string(0) "" ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(10) { [0]=> array(2) { ["value"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" ["label"]=> string(114) "New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations" } [1]=> array(2) { ["value"]=> string(49) "New research question to examine treatment safety" ["label"]=> string(49) "New research question to examine treatment safety" } [2]=> array(2) { ["value"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" ["label"]=> string(76) "Confirm or validate previously conducted research on treatment effectiveness" } [3]=> array(2) { ["value"]=> string(69) "Confirm or validate previously conducted research on treatment safety" ["label"]=> string(69) "Confirm or validate previously conducted research on treatment safety" } [4]=> array(2) { ["value"]=> string(59) "Preliminary research to be used as part of a grant proposal" ["label"]=> string(59) "Preliminary research to be used as part of a grant proposal" } [5]=> array(2) { ["value"]=> string(32) "Summary-level data meta-analysis" ["label"]=> string(32) "Summary-level data meta-analysis" } [6]=> array(2) { ["value"]=> string(66) "Summary-level data meta-analysis using only data from YODA Project" ["label"]=> string(66) "Summary-level data meta-analysis using only data from YODA Project" } [7]=> array(2) { ["value"]=> string(36) "Participant-level data meta-analysis" ["label"]=> string(36) "Participant-level data meta-analysis" } [8]=> array(2) { ["value"]=> string(66) "Summary-level data meta-analysis using only data from YODA Project" ["label"]=> string(66) "Summary-level data meta-analysis using only data from YODA Project" } [9]=> array(2) { ["value"]=> string(34) "Research on clinical trial methods" ["label"]=> string(34) "Research on clinical trial methods" } } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(1053) "We will use data from 4 6-week randomized, double-blind, placebo- and active controlled, parallel group studies (NCT00083668,NCT00397033,NCT00650793,NCT00077714,) of high dose (15 mg/d or 12 mg/d), medium dose (9 mg/d) and low dose (3 mg/d) paliperidone extendedrelease (ER) versus placebo, in patients with schizoaffective disorder. In our study we will consider the Social Performance Scale (SPS) and PANSS Factor Scores for negative symptoms measured at the last study visit as the primary endpoint.
Secondary endpoints are: (i) PANSS Factor Scores for positive symptoms (ii) side effects, measured at the visit prior to the last study visit. We will estimate the mean difference in primary and secondary outcomes, comparing (a) patients randomly assigned to
paliperidone to those assigned to placebo, and (b) patients randomly assigned to paliperidone to those assigned to olanzapine. We will then proceed to evaluate the role of these secondary outcomes as mediators allowing for mediator-mediator and treatment-mediator interactions." ["project_main_outcome_measure"]=> string(443) "We will consider the Social Performance Scale (SPS) and PANSS Factor Scores for negative symptoms (PANSS-) measured at the last study visit as the primary endpoints.
Secondary endpoints are: (i) PANSS Factor Scores for positive symptoms (ii) PANSS Factor Scores for negative symptoms (iii) side effects, measured at the visit prior to the last study visit.
All outcome variables will be considered as continuous or count variables." ["project_main_predictor_indep"]=> string(994) "In our analyses, assignment to paliperidone, placebo, or olanzapine is by definition assessed at baseline. The primary outcome, Social Performance Scale (SPS), will be derived from assessments at baseline and week 6, or last study visit. We will consider assessments of secondary outcomes at baseline and week 4, or visit prior to last study visit. These will consist of PANSS Factor Scores for positive symptoms and number of adverse event reports. Further, we will consider assessments of the Clinical Global Impressions-Severity of Illness Scale for Schizoaffective Disorder (CGI-S-SCA), the Clinical Global Impressions-Change Scale for Schizoaffective Disorder (CGI-S-SCA), Youth Mania Rating Scale (YRMS), 21-item Hamilton Depression Rating Scale, at baseline. These were chosen as a priori known predictors of the primary and secondary outcomes. In our models we will also consider baseline covariates for
age, sex, race, weight (kg), prolactin (ng/mL), and fasting glucose (mg/dL)." ["project_other_variables_interest"]=> string(0) "" ["project_stat_analysis_plan"]=> string(1686) "Analysis 1: Compare drug effects on the primary outcomes, social functioning (SPS) and Panss negative symptoms (PANSS-). We will compare the outcomes at last visit for each paliperidone dose to placebo . We will use a linear regression model for SPS or PANSS - given treatment status, baseline SPS, PANSS Factor Scores for positive symptoms and negative symptoms, and baseline covariates.
Analysis 2: Compare drug effects on secondary outcomes. The second analysis will compare each paliperidone dose to placebo or olanzapine in terms of: (i) PANSS Factor Scores for positive symptoms (ii) number of side effects at previous to last visit. We will use a multivariate linear regression model for the, potentially correlated, secondary outcomes given treatment status, baseline SPS, PANSS Factor Scores for positive symptoms, PANSS Factor Scores for negative symptoms, and baseline covariates.
Analysis 3: Explaining comparative efficacy of treatment on the primary outcome, social functioning, via the mediating and interactive role of secondary outcomes. The third analysis will involve two steps. In the first step we will compare SPS at last visit between each paliperidone dose and placebo or olanzapine, while adjusting for the secondary outcomes at previous to last visit. We will use a linear regression model for the primary outcome given the secondary outcomes, treatment status, baseline SPS, and baseline covariates. The model will allow for treatment-mediator and mediator-mediator interaction. In the second step, we will estimate direct and indirect effects of treatment, potentially mediated by the secondary outcomes employing approaches developed by the PI." ["project_timeline"]=> string(647) "Start date: February 15th 2016.
End date: May 15th 2017.
Analysis completion date: September 15th 2016
Manuscript drafted date: December 15th 2016
Manuscript submitted and results reported back to YODA: February 15th 2017
UPDATE: Manuscript accepted for publication (former single trial analysis proposed)
NEW ANALYSES:
Start date: April 1st 2018.
End date: May 30th 2019.
Analysis completion date: August 1st 2018
Manuscript drafted date: October 1st 2018
Manuscript submitted and results reported back to YODA: December 1st 2018
Expect to work on revision until May 2019." ["project_dissemination_plan"]=> string(787) "PAPER 1 (BEFORE EDIT)
Audience: Psychiatric community
Journal: npj Schizophrenia
Title: The role of PANSS symptoms and adverse events in explaining the effects of Paliperidone on social functioning: a causal mediation analysis approach
ACCEPTED
PAPER 2 (BEFORE EDIT)
Audience: Psychiatric and Statistics community
Journal: American Journal of Epidemiology
Title: Decomposition of the total effect in the presence of multiple mediators and interactions
ACCEPTED
PAPER 3 (NEW)
Audience: Psychiatric and Statistics community
Journal: Statistics in Medicine
Title: INTEGRATING PALIPERIDONE EFFICACY TRIALS FOR MORE POWERFUL CAUSAL MEDIATION ANALYSES: A COMPARISON OF HIERARCHICAL LINEAR MODELING AND META-ANALYSIS" ["project_bibliography"]=> string(2073) "

[1] Lieberman, J. A., Stroup, T. S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., … & Hsiao,
J. K. (2005). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal
of Medicine, 353(12), 1209-1223.
[2] Centorrino, F., Masters, G. A., Talamo, A., Baldessarini, R. J., & ngu?r, D. (2012). Metabolic syndrome in
psychiatrically hospitalized patients treated with antipsychotics and other psychotropics. Human
Psychopharmacology: Clinical and Experimental, 27(5), 521-526.
[3] Centorrino, F., Goren, J. L., Hennen, J., Salvatore, P., Kelleher, J. P., & Baldessarini, R. J. (2014). Multiple
versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus
benefits. American Journal of Psychiatry.
[4] Nasrallah, H., Morosini, P., & Gagnon, D. D. (2008). Reliability, validity and ability to detect change of the
Personal and Social Performance scale in patients with stable schizophrenia. Psychiatry research, 161(2),
213-224.
[5] Martin, E. A., ngu?r, D., Cohen, B. M., & Lewandowski, K. E. (2015). Social functioning and age across
affective and nonaffective psychoses. The Journal of nervous and mental disease, 203(1), 37-42.
[6] Burns, T., & Patrick, D. (2007). Social functioning as an outcome measure in schizophrenia studies. Acta
Psychiatrica Scandinavica, 116(6), 403-418.
[7] Green, M. F., Olivier, B., Crawley, J. N., Penn, D. L., & Silverstein, S. (2005). Social cognition in
schizophrenia: recommendations from the measurement and treatment research to improve cognition in
schizophrenia new approaches conference. Schizophrenia Bulletin, 31(4), 882-887.
[8] Valeri, L., & VanderWeele, T. J. (2013). Mediation analysis allowing for exposure?mediator interactions and causal interpretation: Theoretical assumptions and implementation with SAS and SPSS macros. Psychological methods, 18(2), 137.

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2016-0716

General Information

How did you learn about the YODA Project?: Other

Conflict of Interest

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Associated Trial(s):
  1. OPTICS Trial Bundle
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Data Request Status

Status: Published

Research Proposal

Project Title: Mediation Analysis to explain comparative efficacy of antipsychotic medications for treatment of schizophrenia in short-term RCT

Scientific Abstract: Background: Differences among antipsychotic medications for treatment of schizophrenia spanning from targeted mechanism of action, side effects and efficacy have been observed in randomized trial settings and in clinical practice. Explaining why differences in efficacy are observed is important to inform development of new drugs and to guide appropriate treatment strategies.
Goal & Main Outcomes: To quantify the joint effect, potentially synergistic or antagonistic, of intermediate factors that can explain differential efficacy among treatments for schizophrenia. We will (1) compare drug effects on primary outcomes, social functioning and negative symptoms; (2) compare drug effects on secondary outcomes: (i) positive symptoms and (ii) side effects; (3) quantify how much of the relative efficacy on social functioning and negative symptoms is due to the mediating and interactive role of the secondary outcomes.
Study Design & Participants: We plan to investigate mechanisms that could explain treatment efficacy as a secondary analysis of four Paliperidone trials analyzed selected based on their comparability in study duration (6 weeks) and drug dosage (Paliperidone ER 6-12 mg, fixed doses).
Statistical Analysis: Mediation analysis is the study of the role of intermediate endpoints in explaining how a treatment affects the final outcome of interest. We will extend and apply mediation analysis approaches to meta-analysis of longitudinal trial data in the presence of multiple, potentially interacting, mediators.

Brief Project Background and Statement of Project Significance: Antipsychotic drugs are the cornerstone of treatment for schizophrenia. The first generation of antipsychotic medications were approved in the 1950?s, while the second generation started with the approval of clozapine in the early 1990?s. In the past 25 years a wealth of clinical trials and observational studies have evaluated relative efficacy, safety, and effectiveness of first and second generation medications. Such studies have shown that first and second generation antipsychotics differ significantly in (i) targeted mechanism of action (ii) side effects (iii) adherence to medication (iv) Positive Symptoms Scale (PANSS) scores improvement[1,2]. A consensus has not been reached on the relative efficacy and effectiveness of first and second generation antipsychotic drugs. This has induced an increasing trend in the administration of costly, and yet to be shown effective polytherapy and higher doses of antipsychotics[3]. Among psychotic patients, schizophrenia patients display the highest deficit in social functioning[4,5]. Social functioning has been recognized as an important contributor to overall quality of life and a determinant of treatment success. The ability of typical and atypical agents to improve social functioning has
not been fully explored[6]. Consensus has been reached on the impact of negative symptoms on social functioning[7]. Although first and second generation drugs target positive symptoms, several studies have shown the impact of second-generation drugs on negative symptoms through indirect mechanisms. It is of interest to investigate further the efficacy of first and second generation antipsychotics on negative symptoms and social functioning and to assess the mechanisms that explain their relative efficacy. Clarity on the relative efficacy and effectiveness of typical and atypical antipsychotic drugs can be made only by accounting for the complex effects of antipsychotics. It is critical to investigate the interplay of symptoms and side effects that impact the overall well-being of the patient over the course of treatment. Secondary analyses of efficacy trials that explain treatment mechanism of action have recently become popular in the field of psychiatry. Mediation analysis is an important approach for quantifying how much of the treatment effect on a primary outcome is through intermediate factors (also referred to as mediators) and how much is through pathways independent of the mediators. Recently, Dr. Valeri developed methods and software for mediation analysis[8]. We will apply this methodology to understand whether (i) positive symptoms and (ii) side effects could act as mediators of the effect of antipsychotic medications for schizophrenia on negative symptoms, precursors of social functioning. We will allow the mediators to act synergistically or antagonistically. We will quantify how much of the effect of the antipsychotics on negative symptoms and social function is due to the effect through the mediators (indirect), the effect independent of the mediators (direct), and the effect due to drug-mediators and mediators-mediators interaction integrating data from four Paliperidone trials to improve power.

Specific Aims of the Project: Study objective: Develop and apply causal mediation analysis approaches to explaining comparative efficacy in a trial of high, medium and low-dose oral paliperidone extended release (ER) vs. placebo/olanzapine on social functioning after 6 weeks follow-up.
AIM 1 Compare drug effects on the primary outcomes, negative symptoms and social functioning.
Hypothesis 1 Paliperidone will result in decreased negative symptoms and increased social functioning relative to placebo.
AIM 2 Compare drug effects on secondary outcomes, (i) PANSS Factor Scores for positive symptoms (ii) side effects.
Hypothesis 2 Paliperidone will result in improved PANSS positive symptoms and will increase the risk of side effects relative placebo.
AIM 3 Explaining comparative efficacy of treatment on the primary outcomes, negative symptoms and social functioning, via the mediating and interactive role of secondary outcomes.
Hypothesis 3 Secondary outcomes will be both mediators and modifiers of treatment effect on negative symptoms and social functioning.

Study Design:

What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment effectiveness on secondary endpoints and/or within subgroup populations New research question to examine treatment safety Confirm or validate previously conducted research on treatment effectiveness Confirm or validate previously conducted research on treatment safety Preliminary research to be used as part of a grant proposal Summary-level data meta-analysis Summary-level data meta-analysis using only data from YODA Project Participant-level data meta-analysis Summary-level data meta-analysis using only data from YODA Project Research on clinical trial methods

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: We will use data from 4 6-week randomized, double-blind, placebo- and active controlled, parallel group studies (NCT00083668,NCT00397033,NCT00650793,NCT00077714,) of high dose (15 mg/d or 12 mg/d), medium dose (9 mg/d) and low dose (3 mg/d) paliperidone extendedrelease (ER) versus placebo, in patients with schizoaffective disorder. In our study we will consider the Social Performance Scale (SPS) and PANSS Factor Scores for negative symptoms measured at the last study visit as the primary endpoint.
Secondary endpoints are: (i) PANSS Factor Scores for positive symptoms (ii) side effects, measured at the visit prior to the last study visit. We will estimate the mean difference in primary and secondary outcomes, comparing (a) patients randomly assigned to
paliperidone to those assigned to placebo, and (b) patients randomly assigned to paliperidone to those assigned to olanzapine. We will then proceed to evaluate the role of these secondary outcomes as mediators allowing for mediator-mediator and treatment-mediator interactions.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: We will consider the Social Performance Scale (SPS) and PANSS Factor Scores for negative symptoms (PANSS-) measured at the last study visit as the primary endpoints.
Secondary endpoints are: (i) PANSS Factor Scores for positive symptoms (ii) PANSS Factor Scores for negative symptoms (iii) side effects, measured at the visit prior to the last study visit.
All outcome variables will be considered as continuous or count variables.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: In our analyses, assignment to paliperidone, placebo, or olanzapine is by definition assessed at baseline. The primary outcome, Social Performance Scale (SPS), will be derived from assessments at baseline and week 6, or last study visit. We will consider assessments of secondary outcomes at baseline and week 4, or visit prior to last study visit. These will consist of PANSS Factor Scores for positive symptoms and number of adverse event reports. Further, we will consider assessments of the Clinical Global Impressions-Severity of Illness Scale for Schizoaffective Disorder (CGI-S-SCA), the Clinical Global Impressions-Change Scale for Schizoaffective Disorder (CGI-S-SCA), Youth Mania Rating Scale (YRMS), 21-item Hamilton Depression Rating Scale, at baseline. These were chosen as a priori known predictors of the primary and secondary outcomes. In our models we will also consider baseline covariates for
age, sex, race, weight (kg), prolactin (ng/mL), and fasting glucose (mg/dL).

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:

Statistical Analysis Plan: Analysis 1: Compare drug effects on the primary outcomes, social functioning (SPS) and Panss negative symptoms (PANSS-). We will compare the outcomes at last visit for each paliperidone dose to placebo . We will use a linear regression model for SPS or PANSS - given treatment status, baseline SPS, PANSS Factor Scores for positive symptoms and negative symptoms, and baseline covariates.
Analysis 2: Compare drug effects on secondary outcomes. The second analysis will compare each paliperidone dose to placebo or olanzapine in terms of: (i) PANSS Factor Scores for positive symptoms (ii) number of side effects at previous to last visit. We will use a multivariate linear regression model for the, potentially correlated, secondary outcomes given treatment status, baseline SPS, PANSS Factor Scores for positive symptoms, PANSS Factor Scores for negative symptoms, and baseline covariates.
Analysis 3: Explaining comparative efficacy of treatment on the primary outcome, social functioning, via the mediating and interactive role of secondary outcomes. The third analysis will involve two steps. In the first step we will compare SPS at last visit between each paliperidone dose and placebo or olanzapine, while adjusting for the secondary outcomes at previous to last visit. We will use a linear regression model for the primary outcome given the secondary outcomes, treatment status, baseline SPS, and baseline covariates. The model will allow for treatment-mediator and mediator-mediator interaction. In the second step, we will estimate direct and indirect effects of treatment, potentially mediated by the secondary outcomes employing approaches developed by the PI.

Narrative Summary: Differences among antipsychotic medications for treatment of schizophrenia spanning from targeted
mechanism of action, side effects and efficacy have been observed in randomized trial settings and in clinical
practice. We will apply causal mediation analysis to study the interplay of symptoms and side effect in explaining how OPTICS trials treatments affect the final outcome of interest. We will compare drug and placebo (1) on primary outcomes: social functioning and negative symptoms ; (2) on secondary outcomes: (i) positive symptoms and (ii) side effects; (3) quantify mediating and interactive role of the secondary outcomes. The work has the potential to guide clinical practice.

Project Timeline: Start date: February 15th 2016.
End date: May 15th 2017.
Analysis completion date: September 15th 2016
Manuscript drafted date: December 15th 2016
Manuscript submitted and results reported back to YODA: February 15th 2017
UPDATE: Manuscript accepted for publication (former single trial analysis proposed)
NEW ANALYSES:
Start date: April 1st 2018.
End date: May 30th 2019.
Analysis completion date: August 1st 2018
Manuscript drafted date: October 1st 2018
Manuscript submitted and results reported back to YODA: December 1st 2018
Expect to work on revision until May 2019.

Dissemination Plan: PAPER 1 (BEFORE EDIT)
Audience: Psychiatric community
Journal: npj Schizophrenia
Title: The role of PANSS symptoms and adverse events in explaining the effects of Paliperidone on social functioning: a causal mediation analysis approach
ACCEPTED
PAPER 2 (BEFORE EDIT)
Audience: Psychiatric and Statistics community
Journal: American Journal of Epidemiology
Title: Decomposition of the total effect in the presence of multiple mediators and interactions
ACCEPTED
PAPER 3 (NEW)
Audience: Psychiatric and Statistics community
Journal: Statistics in Medicine
Title: INTEGRATING PALIPERIDONE EFFICACY TRIALS FOR MORE POWERFUL CAUSAL MEDIATION ANALYSES: A COMPARISON OF HIERARCHICAL LINEAR MODELING AND META-ANALYSIS

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