Adherence, Persistence, Readmissions, and Costs in Medicaid Members with Schizophrenia or Schizoaffective Disorder Initiating Paliperidone Palmitate Versus Switching Oral Antipsychotics: A Real-World Retrospective Investigation.

INTRODUCTION: Long-acting injectable antipsychotic agents have been suggested to improve adherence and patient outcomes in schizophrenia or schizoaffective disorder. The purpose of this study was to assess medication use patterns (i.e., medication adherence, persistence), hospital and emergency department readmissions, and total direct medical costs of Oklahoma Medicaid members with schizophrenia or schizoaffective disorder switching from an oral antipsychotic (OAP) to once-monthly paliperidone palmitate (PP1M) or to another OAP (OAP-switch). METHODS: A historical cohort analysis was conducted from 1 January 2016 to 31 December 2020 among adults aged ≥ 18 and ≤ 64 years with schizophrenia or schizoaffective disorder who were previously treated with an OAP. The first claim for PP1M or a new OAP defined the study index date. Members who transitioned from PP1M to 3-month formulation (PP3M) were included (i.e., PP1M/PP3M). Proportion of days covered (PDC), 45-day treatment gaps, 30-day readmissions to hospitals or emergency department, and total direct medical costs were assessed using multivariable, machine-learning least absolute shrinkage, and selection operator (Lasso) regressions controlling for numerous demographic, clinical, mental health, and provider characteristics. RESULTS: Among 295 Medicaid members meeting full inclusion criteria, 183 involved PP1M/PP3Ms (44 PP1M cases transitioned to PP3M) and 112 involved an OAP-switch. The multivariable-adjusted odds of readmission were significantly associated with a 45-day treatment gap (p < 0.05) and non-adherence (i.e., PDC < 80%) (p < 0.05). Relative to PP1M/PP3Ms, the multivariable analyses also indicated that OAP-switch was associated with an 18.5% lower PDC, 92.3% higher number of 45-day treatment gaps, and an approximately 90% higher odds of all-cause 30-day readmission (p < 0.05). The adjusted pre- to post-index change in cost was approximately 49% lower for OAP-switches versus PP1M/PP3Ms (p < 0.001), although unadjusted post-index costs did not differ between groups (p = 0.440). CONCLUSION: This real-world investigation of adult Medicaid members with schizophrenia or schizoaffective disorder observed improved adherence and persistence with fewer readmissions with PP1M/PP3Ms versus OAP-switches.

New-Onset Cancer Cases in FDA's Sentinel System: A Large Distributed System of US Electronic Healthcare Data.

BACKGROUND: Evaluations of cancer etiology and safety and effectiveness of cancer treatments are predicated on large numbers of patients with sufficient baseline and follow-up data. To assess feasibility of FDA's Sentinel System's electronic healthcare data for surveillance of malignancy onset and examination of product safety, this study examined patterns of enrollment surrounding new-onset cancers. METHODS: Using a retrospective cohort of patients based on administrative claims, we identified incident events of 19 cancers among 292.5 million health plan members from January 2000 to February 2020 using International Classification of Diseases (ICD) diagnosis codes. Annual incident cases were stratified by sex, age, medical and drug coverage, and insurer type. Descriptive statistics were calculated for observable time prior to and following diagnosis. RESULTS: We identified 10,697,573 incident cancer events among members with medical coverage. When drug coverage was additionally required, number of incident cancers was reduced by 41%. Medicare data contributed 61% of cases, with similar duration trends as other insurers. Mean duration of follow-up prior to diagnosis ranged from 4.0 to 4.6 years, whereas follow-up post diagnosis ranged from 1.1 to 3.3 years. Approximately a third (36.1%) had at least 2 years both prior to and following diagnosis. CONCLUSIONS: The FDA Sentinel System's electronic healthcare data may be useful for characterizing relatively short latency cancer risk, examining cancer drug utilization and safety after diagnosis, and conducting surveillance for acute adverse events among patients with cancers. IMPACT: A national distributed system with electronic health data, the Sentinel system provides opportunity for rapid pharmacoepidemiologic assessments relevant in oncology.

Pressure-Strain Loops, a Novel Non-invasive Approach for Assessment of Children with Cardiomyopathy.

Non-invasive myocardial work (MW) by left ventricular (LV) pressure-strain loops (PSL) is a novel method for assessing myocardial function while adjusting for afterload, yet pediatric data remain lacking. The aims of this study were to investigate the different patterns of LV PSL and non-invasive MW in pediatric patients with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and their association with exercise tolerance. We included 110 pediatric subjects (mean age, 13 ± 4 years, 35 DCM, 40 HCM, and 35 healthy controls). Standard and speckle-tracking echocardiography were performed. LV PSLs were generated, and global work index (GWI), MW efficiency (GWE), constructive work (GCW), and wasted work (GWW) were compared between groups. Regression analysis was used to assess the influence of ventricular function, dimensions, wall thickness, and wall stress on MW and to predict the association between MW and VO2 max as a surrogate of exercise capacity. Patients with DCM had significantly lower GWI compared to controls (GWI 479.6 ± 263.0 vs 1610.1 ± 211.0, P < 0.005). GWE was significantly reduced in DCM (79.3 ± 7.9 vs 95.2 ± 1.3, P < 0.005) due to significantly reduced GCW and increased GWW. HCM patients had significant reduction in GWI and GWE from normal (1237.7 ± 449.1 vs 1610.1 ± 211.0, P = 0.001 and 89.6 ± 4.9 vs 95.2 ± 1.3, P < 0.005, respectively), although less severe than with DCM. In a multivariate regression analysis, GWE had the highest association with VO2 max in both cohorts (DCM: ß = 0.68, P = 0.001, HCM: ß = 0.71, P = 0.007). Non-invasively assessed myocardial work and LV PSLs provide novel insights into the mechanisms of dysfunction in pediatric patients with cardiomyopathy with good prediction of clinical status and thus hold promise to further explore myocardial mechanistic with clinical relevance in different disease entities.

Assessment of Emergency Medicine Resident Performance in a Pediatric In Situ Simulation Using Multi-Source Feedback.

Introduction Multi-source feedback (MSF) is an evaluation method mandated by the Accreditation Council for Graduate Medical Education (ACGME). The Queen's Simulation Assessment Tool (QSAT) has been validated as being able to distinguish between resident performances in a simulation setting. The QSAT has also been demonstrated to have excellent MSF agreement when used in an adult simulation performed in a simulation lab. Using the QSAT, this study sought to determine the degree of agreement of MSF in a single pediatric (Peds) simulation case conducted in situ in a Peds emergency department (ED). Methods This Institutional Review Board-approved study was conducted in a four-year emergency medicine residency. A Peds resuscitation case was developed with specific behavioral anchors on the QSAT, which uses a 1-5 scale in each of five categories: Primary Assessment, Diagnostic Actions, Therapeutic Actions, Communication, and Overall Assessment. Data was gathered from six participants for each simulation. The lead resident self-evaluated and received MSF from a junior peer resident, a fixed Peds ED nurse, a random ED nurse, and two faculty (one fixed, the other from a dyad). The agreement was calculated with intraclass correlation coefficients (ICC). Results The simulation was performed on 35 separate days over two academic years. A total of 106 MSF participants were enrolled. Enrollees included three faculty members, 35 team leaders, 34 peers, 33 ED registered nurses (RN), and one Peds RN; 50% of the enrollees were female (n=53). Mean QSAT scores ranged from 20.7 to 23.4. A fair agreement was demonstrated via ICC; there was no statistically significant difference between sources of MSF. Removing self-evaluation led to the highest ICC. ICC for any single or grouped non-faculty source of MSF was poor. Conclusion Using the QSAT, the findings from this single-site cohort suggest that faculty must be included in MSF. Self-evaluation appears to be of limited value in MSF with the QSAT. The degree of MSF agreement as gathered by the QSAT was lower in this cohort than previously reported for adult simulation cases performed in the simulation lab. This may be due to either the pediatric nature of the case, the location of the simulation, or both.

A COVID-19-ready public health surveillance system: The Food and Drug Administration's Sentinel System.

The US Food and Drug Administration's Sentinel System was established in 2009 to use routinely collected electronic health data for improving the national capability to assess post-market medical product safety. Over more than a decade, Sentinel has become an integral part of FDA's surveillance capabilities and has been used to conduct analyses that have contributed to regulatory decisions. FDA's role in the COVID-19 pandemic response has necessitated an expansion and enhancement of Sentinel. Here we describe how the Sentinel System has supported FDA's response to the COVID-19 pandemic. We highlight new capabilities developed, key data generated to date, and lessons learned, particularly with respect to working with inpatient electronic health record data. Early in the pandemic, Sentinel developed a multi-pronged approach to support FDA's anticipated data and analytic needs. It incorporated new data sources, created a rapidly refreshed database, developed protocols to assess the natural history of COVID-19, validated a diagnosis-code based algorithm for identifying patients with COVID-19 in administrative claims data, and coordinated with other national and international initiatives. Sentinel is poised to answer important questions about the natural history of COVID-19 and is positioned to use this information to study the use, safety, and potentially the effectiveness of medical products used for COVID-19 prevention and treatment.

Assessment of Training Outcomes of Nurse Readers for Diabetic Retinopathy Telescreening: Validation Study.

BACKGROUND: With the high prevalence of diabetic retinopathy and its significant visual consequences if untreated, timely identification and management of diabetic retinopathy is essential. Teleophthalmology programs have assisted in screening a large number of individuals at risk for vision loss from diabetic retinopathy. Training nonophthalmological readers to assess remote fundus images for diabetic retinopathy may further improve the efficiency of such programs. OBJECTIVE: This study aimed to evaluate the performance, safety implications, and progress of 2 ophthalmology nurses trained to read and assess diabetic retinopathy fundus images within a hospital diabetic retinopathy telescreening program. METHODS: In this retrospective interobserver study, 2 ophthalmology nurses followed a specific training program within a hospital diabetic retinopathy telescreening program and were trained to assess diabetic retinopathy images at 2 levels of intervention: detection of diabetic retinopathy (level 1) and identification of referable disease (level 2). The reliability of the assessment by level 1-trained readers in 266 patients and of the identification of patients at risk of vision loss from diabetic retinopathy by level 2-trained readers in 559 more patients were measured. The learning curve, sensitivity, and specificity of the readings were evaluated using a group consensus gold standard. RESULTS: An almost perfect agreement was measured in identifying the presence of diabetic retinopathy in both level 1 readers (κ=0.86 and 0.80) and in identifying referable diabetic retinopathy by level 2 readers (κ=0.80 and 0.83). At least substantial agreement was measured in the level 2 readers for macular edema (κ=0.79 and 0.88) for all eyes. Good screening threshold sensitivities and specificities were obtained for all level readers, with sensitivities of 90.6% and 96.9% and specificities of 95.1% and 85.1% for level 1 readers (readers A and B) and with sensitivities of 86.8% and 91.2% and specificities of 91.7% and 97.0% for level 2 readers (readers A and B). This performance was achieved immediately after training and remained stable throughout the study. CONCLUSIONS: Notwithstanding the small number of trained readers, this study validates the screening performance of level 1 and level 2 diabetic retinopathy readers within this training program, emphasizing practical experience, and allows the establishment of an ongoing assessment clinic. This highlights the importance of supervised, hands-on experience and may help set parameters to further calibrate the training of diabetic retinopathy readers for safe screening programs.

Quantifying how small variations in design elements affect risk in an incident cohort study in claims.

BACKGROUND: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. METHODS: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look-back or follow-up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow-up time, and risk estimates. RESULTS: Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow-up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control-group subjects in 1:1 matching. CONCLUSIONS: Exposure-related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies.

Identification of potential drug name confusion errors in the Sentinel System.

PURPOSE: In July 2015, the US Food and Drug Administration (FDA) published a drug safety communication regarding errors in prescribing and dispensing of the antidepressant Brintellix (vortioxetine) and the antiplatelet Brilinta (ticagrelor) that arose due to proprietary drug name confusion. Brintellix is indicated for major depressive disorder; Brilinta is indicated to reduce cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or history of myocardial infarction. Brintellix was renamed to Trintellix in May 2016. Using Brilinta and Brintellix as a proof-of-concept feasibility use case, we assessed whether drug name confusion errors between the pair could be identified in electronic health care data via the combination of a claims-based algorithm and limited manual claims data review. METHODS: Using data from the Sentinel System, we defined potential errors as Brintellix users without an on- or off-label indication for Brintellix, without a dispensing for a drug with the same indications as Brintellix, and with an on- or off-label indication for Brilinta between -365 and +30 days after index Brintellix dispensing; the reverse was done for Brilinta. We manually reviewed claims profiles of potential cases. RESULTS: We identified 27 (0.1%) potential errors among 21 208 Brintellix users; 16 appeared to be likely errors based on claims profile review. Fifty-one (0.3%) of the 16 779 Brilinta users were identified as potential errors, and four appeared to be likely errors. CONCLUSIONS: A claims-based algorithm combined with manual review of claims profiles could identify potential drug name confusion errors, and narrow down likely errors that warrant further investigation.

Evaluating the use of bootstrapping in cohort studies conducted with 1:1 propensity score matching-A plasmode simulation study.

PURPOSE: Bootstrapping can account for uncertainty in propensity score (PS) estimation and matching processes in 1:1 PS-matched cohort studies. While theory suggests that the classical bootstrap can fail to produce proper coverage, practical impact of this theoretical limitation in settings typical to pharmacoepidemiology is not well studied. METHODS: In a plasmode-based simulation study, we compared performance of the standard parametric approach, which ignores uncertainty in PS estimation and matching, with two bootstrapping methods. The first method only accounted for uncertainty introduced during the matching process (the observation resampling approach). The second method accounted for uncertainty introduced during both PS estimation and matching processes (the PS reestimation approach). Variance was estimated based on percentile and empirical standard errors, and treatment effect estimation was based on median and mean of the estimated treatment effects across 1000 bootstrap resamples. Two treatment prevalence scenarios (5% and 29%) across two treatment effect scenarios (hazard ratio of 1.0 and 2.0) were evaluated in 500 simulated cohorts of 10 000 patients each. RESULTS: We observed that 95% confidence intervals from the bootstrapping approaches but not the standard approach, resulted in inaccurate coverage rates (98%-100% for the observation resampling approach, 99%-100% for the PS reestimation approach, and 95%-96% for standard approach). Treatment effect estimation based on bootstrapping approaches resulted in lower bias than the standard approach (less than 1.4% vs 4.1%) at 5% treatment prevalence; however, the performance was equivalent at 29% treatment prevalence. CONCLUSION: Use of bootstrapping led to variance overestimation and inconsistent coverage, while coverage remained more consistent with parametric estimation.

Assessment of Emergency Medicine Resident Performance in an Adult Simulation Using a Multisource Feedback Approach.

INTRODUCTION: The Accreditation Council for Graduate Medical Education (ACGME) specifically notes multisource feedback (MSF) as a recommended means of resident assessment in the emergency medicine (EM) Milestones. High-fidelity simulation is an environment wherein residents can receive MSF from various types of healthcare professionals. Previously, the Queen's Simulation Assessment Tool (QSAT) has been validated for faculty to assess residents in five categories: assessment; diagnostic actions; therapeutic actions; interpersonal communication, and overall assessment. We sought to determine whether the QSAT could be used to provide MSF using a standardized simulation case. METHODS: Prospectively after institutional review board approval, residents from a dual ACGME/osteopathic-approved postgraduate years (PGY) 1-4 EM residency were consented for participation. We developed a standardized resuscitation after overdose case with specific 1-5 Likert anchors used by the QSAT. A PGY 2-4 resident participated in the role of team leader, who completed a QSAT as self-assessment. The team consisted of a PGY-1 peer, an emergency medical services (EMS) provider, and a nurse. Two core faculty were present to administer the simulation case and assess. Demographics were gathered from all participants completing QSATs. We analyzed QSATs by each category and on cumulative score. Hypothesis testing was performed using intraclass correlation coefficients (ICC), with 95% confidence intervals. Interpretation of ICC results was based on previously published definitions. RESULTS: We enrolled 34 team leader residents along with 34 nurses. A single PGY-1, a single EMS provider and two faculty were also enrolled. Faculty provided higher cumulative QSAT scores than the other sources of MSF. QSAT scores did not increase with team leader PGY level. ICC for inter-rater reliability for all sources of MSF was 0.754 (0.572-0.867). Removing the self-evaluation scores increased inter-rater reliability to 0.838 (0.733-0.910). There was lesser agreement between faculty and nurse evaluations than from the EMS or peer evaluation. CONCLUSION: In this single-site cohort using an internally developed simulation case, the QSAT provided MSF with excellent reliability. Self-assessment decreases the reliability of the MSF, and our data suggest self-assessment should not be a component of MSF. Use of the QSAT for MSF may be considered as a source of data for clinical competency committees.

Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System.

The self-controlled tree-temporal scan statistic-a new signal-detection method-can evaluate whether any of a wide variety of health outcomes are temporally associated with receipt of a specific vaccine, while adjusting for multiple testing. Neither health outcomes nor postvaccination potential periods of increased risk need be prespecified. Using US medical claims data in the Food and Drug Administration's Sentinel system, we employed the method to evaluate adverse events occurring after receipt of quadrivalent human papillomavirus vaccine (4vHPV). Incident outcomes recorded in emergency department or inpatient settings within 56 days after first doses of 4vHPV received by 9- through 26.9-year-olds in 2006-2014 were identified using International Classification of Diseases, Ninth Revision, diagnosis codes and analyzed by pairing the new method with a standard hierarchical classification of diagnoses. On scanning diagnoses of 1.9 million 4vHPV recipients, 2 statistically significant categories of adverse events were found: cellulitis on days 2-3 after vaccination and "other complications of surgical and medical procedures" on days 1-3 after vaccination. Cellulitis is a known adverse event. Clinically informed investigation of electronic claims records of the patients with "other complications" did not suggest any previously unknown vaccine safety problem. Considering that thousands of potential short-term adverse events and hundreds of potential risk intervals were evaluated, these findings add significantly to the growing safety record of 4vHPV.

Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0.

PURPOSE: Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. METHODS: We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. CONCLUSION: Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases.

Reporting to Improve Reproducibility and Facilitate Validity Assessment for Healthcare Database Studies V1.0.

PURPOSE: Defining a study population and creating an analytic dataset from longitudinal healthcare databases involves many decisions. Our objective was to catalogue scientific decisions underpinning study execution that should be reported to facilitate replication and enable assessment of validity of studies conducted in large healthcare databases. METHODS: We reviewed key investigator decisions required to operate a sample of macros and software tools designed to create and analyze analytic cohorts from longitudinal streams of healthcare data. A panel of academic, regulatory, and industry experts in healthcare database analytics discussed and added to this list. CONCLUSION: Evidence generated from large healthcare encounter and reimbursement databases is increasingly being sought by decision-makers. Varied terminology is used around the world for the same concepts. Agreeing on terminology and which parameters from a large catalogue are the most essential to report for replicable research would improve transparency and facilitate assessment of validity. At a minimum, reporting for a database study should provide clarity regarding operational definitions for key temporal anchors and their relation to each other when creating the analytic dataset, accompanied by an attrition table and a design diagram. A substantial improvement in reproducibility, rigor and confidence in real world evidence generated from healthcare databases could be achieved with greater transparency about operational study parameters used to create analytic datasets from longitudinal healthcare databases.

Near real-time surveillance for Guillain-Barré syndrome after influenza vaccination among the Medicare population, 2010/11 to 2013/14.

BACKGROUND: Guillain-Barré syndrome (GBS) is a serious acute demyelinating disease that causes weakness and paralysis. The Food and Drug Administration (FDA) began collaborating with the Centers for Medicare and Medicaid Services (CMS) to develop near real-time vaccine safety surveillance capabilities in 2006 and has been monitoring for the risk of GBS after influenza vaccination for every influenza season since 2008. METHODS: We present results from the 2010/11 to 2013/14 influenza seasons using the Updating Sequential Probability Ratio Test (USPRT), with an overall 1-sided α of 0.05 apportioned equally using a constant alpha-spending plan among 20 consecutive weekly tests, 5 ad hoc tests, and a 26th final end of season test. Observed signals were investigated using the self-controlled risk interval (SCRI) design. RESULTS: Over 15 million people were vaccinated in each influenza season. In the 2010/11 influenza season, we observed an elevated GBS risk during the season, with an end of season SCRI analysis finding a nonsignificant increased risk (RR=1.25, 95% CI: 0.96-1.63). A sensitivity analysis applying the positive predictive value of the ICD-9 code for GBS from the 2009/10 season estimated a RR=1.98 (95% CI: 1.42-2.76). Although the 2010/11 influenza vaccine suggested an increased GBS risk, surveillance of the identical vaccine in the 2011/12 influenza season did not find an increased GBS risk after vaccination. No signal was observed in the subsequent three influenza seasons. CONCLUSIONS: Conducting near real-time surveillance using USPRT has proven to be an excellent method for near real-time GBS surveillance after influenza vaccination, as demonstrated by our surveillance efforts during the 2010/11-2013/14 influenza seasons. In the 2010/2011 influenza season, in addition to the 2009 H1N1 influenza pandemic, using near real-time surveillance we were able to observe a signal early in the influenza season and the method has now become routine.

Fluorescence Adherence Inhibition Assay: A Novel Functional Assessment of Blocking Virus Attachment by Vaccine-Induced Antibodies.

Neutralizing antibodies induced by vaccination or natural infection play a critically important role in protection against the viral diseases. In general, neutralization of the viral infection occurs via two major pathways: pre- and post-attachment modes, the first being the most important for such infections as influenza and polio, the latter being significant for filoviruses. Neutralizing capacity of antibodies is typically evaluated by virus neutralization assays that assess reduction of viral infectivity to the target cells in the presence of functional antibodies. Plaque reduction neutralization test, microneutralization and immunofluorescent assays are often used as gold standard virus neutralization assays. However, these methods are associated with several important prerequisites such as use of live virus requiring safety precautions, tedious evaluation procedure and long assessment time. Hence, there is a need for a robust, inexpensive high throughput functional assay that can be performed rapidly using inactivated virus, without extensive safety precautions. Herein, we report a novel high throughput Fluorescence Adherence Inhibition assay (fADI) using inactivated virus labeled with fluorescent secondary antibodies virus and Vero cells or erythrocytes as targets. It requires only few hours to assess pre-attachment neutralizing capacity of donor sera. fADI assay was tested successfully on donors immunized with polio, yellow fever and influenza vaccines. To further simplify and improve the throughput of the assay, we have developed a mathematical approach for calculating the 50% titers from a single sample dilution, without the need to analyze multi-point titration curves. Assessment of pre- and post-vaccination human sera from subjects immunized with IPOL®, YF-VAX® and 2013-2014 Fluzone® vaccines demonstrated high efficiency of the assay. The results correlated very well with microneutralization assay performed independently by the FDA Center of Biologics Evaluation and Research, with plaque reduction neutralization test performed by Focus Diagnostics, and with hemaglutination inhibition assay performed in-house at Sanofi Pasteur. Taken together, fADI assay appears to be a useful high throughput functional immunoassay for assessment of antibody-related neutralization of the viral infections for which pre-attachment neutralization pathway is predominant, such as polio, influenza, yellow fever and dengue.

Evaluation of the short-term executive plus intervention for executive dysfunction after traumatic brain injury: a randomized controlled trial with minimization.

OBJECTIVE: To determine whether the Short-Term Executive Plus (STEP) cognitive rehabilitation program improves executive dysfunction after traumatic brain injury (TBI). DESIGN: Randomized, waitlist controlled trial with minimization and blinded outcome assessment. SETTING: Community. PARTICIPANTS: Participants with TBI and executive dysfunction (N=98; TBI severity 50% moderate/severe; mean time since injury ± SD, 12±14y; mean age ± SD, 45±14y; 62% women; 76% white). INTERVENTION: STEP program: 12 weeks (9h/wk) of group training in problem solving and emotional regulation and individual sessions of attention and compensatory strategies training. MAIN OUTCOME MEASURES: Factor analysis was used to create a composite executive function measure using the Problem Solving Inventory, Frontal Systems Behavior Scale, Behavioral Assessment of the Dysexecutive Syndrome, and Self-Awareness of Deficits Interview. Emotional regulation was assessed with the Difficulties in Emotion Regulation Scale. The primary attention measure was the Attention Rating and Monitoring Scale. Secondary measures included neuropsychological measures of executive function, attention, and memory and measures of affective distress, self-efficacy, social participation, and quality of life. RESULTS: Intention-to-treat mixed-effects analyses revealed significant treatment effects for the composite executive function measure (P=.008) and the Frontal Systems Behavior Scale (P=.049) and Problem Solving Inventory (P=.016). We found no between-group differences on the neuropsychological measures or on measures of attention, emotional regulation, self-awareness, affective distress, self-efficacy, participation, or quality of life. CONCLUSIONS: The STEP program is efficacious in improving self-reported post-TBI executive function and problem solving. Further research is needed to identify the roles of the different components of the intervention and its effectiveness with different TBI populations.

Post-licensure rapid immunization safety monitoring program (PRISM) data characterization.

BACKGROUND: The Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program is the immunization safety monitoring component of FDA's Mini-Sentinel project, a program to actively monitor the safety of medical products using electronic health information. FDA sought to assess the surveillance capabilities of this large claims-based distributed database for vaccine safety surveillance by characterizing the underlying data. METHODS: We characterized data available on vaccine exposures in PRISM, estimated how much additional data was gained by matching with select state and local immunization registries, and compared vaccination coverage estimates based on PRISM data with other available data sources. We generated rates of computerized codes representing potential health outcomes relevant to vaccine safety monitoring. Standardized algorithms including ICD-9 codes, number of codes required, exclusion criteria and location of the encounter were used to obtain the background rates. RESULTS: The majority of the vaccines routinely administered to infants, children, adolescents and adults were well captured by claims data. Immunization registry data in up to seven states comprised between 5% and 9% of data for all vaccine categories with the exception of 10% for hepatitis B and 3% and 4% for rotavirus and zoster respectively. Vaccination coverage estimates based on PRISM's computerized data were similar to but lower than coverage estimates from the National Immunization Survey and Healthcare Effectiveness Data and Information Set. For the 25 health outcomes of interest studied, the rates of potential outcomes based on ICD-9 codes were generally higher than rates described in the literature, which are typically clinically confirmed cases. CONCLUSION: PRISM program's data on vaccine exposures and health outcomes appear complete enough to support robust safety monitoring.

Health outcomes of interest for evaluation in the Post-Licensure Rapid Immunization Safety Monitoring Program.

Active vaccine safety surveillance systems commonly use computerized diagnostic codes to identify potential health outcomes of interest. Evidence concerning the accuracy of these codes is variable, and few systematic reviews are available. This project's aim was to select a list of health outcomes of interest most suitable for evaluation in the Food and Drug Administration's Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program. We conducted an expert elicitation process to develop the list. A comprehensive list of potential health outcomes of interest was formed based on input from a wide variety of vaccine safety experts. We then selected five panelists with senior leadership roles in vaccine safety from both within and outside the FDA. We elicited the experts' recommendations via a structured, iterative process that included an Internet-assisted telephone conference call and formal voting procedures. The expert panelists identified several criteria as important in their choices, including clinical severity, public health importance, rare or uncommon incidence, relevance to two or more vaccines, and historical association with vaccines. The list of 24 outcomes chosen by the experts and refined by the FDA included ten neurologic outcomes, two circulatory system outcomes, and two musculoskeletal outcomes. The PRISM program plans to conduct a set of evidence reviews on the positive predictive value and other characteristics of existing computerized codes and algorithms to identify these health outcomes of interest.