Sample size estimation and power calculations for vaccine efficacy trials for exceedingly rare diseases

The implementation of vaccines is one of the most profound advancements in the world of public health. While the scientific process underlying vaccine development is important, determining a vaccine’s efficacy and safety profile would not be possible without vaccine efficacy trials. In terms of trial design, sample size estimation is one of the essential considerations to be made, ensuring that the trial achieves the targeted power, minimizing chances of a false-negative finding. An often considered hypothesis for such trials is testing if a new vaccine is more efficacious than a placebo or the current standard-of-care. We investigated two relevant methods, the Z-Test Normal Approximation and the Exact Conditional Test under Poisson Assumption as presented by Chan and Bohidar. While the Normal Approximation is a generally acceptable method, the Exact Conditional approach may be better suited for trials with low disease incidence. In this Thesis, we develop SAS code for estimating sample size via both methods, in addition to calculating exact power. Sample size and power calculations are performed under a range of different scenarios, stratified by high, intermediate, and low incidence of disease in the control group. Furthermore, under each scenario, simulations are utilized to evaluate the performance of the Exact Conditional approach. Both methods are generally reasonable approaches to sample size estimation and power calculations for vaccine efficacy trials. In trials of higher disease incidence, the Normal Approximation is simpler to implement, and should adequately power the trial. For scenarios of low incidence (< 0.01), the Exact Conditional approach may be more favorable, as it may provide greater power to the trial. To minimize the chance of an underpowered trial, we propose implementing a strategic inflation of sample size. Lastly, we highlight the importance of congruency between methods used for sample size estimation, trial design, and data analysis. Public Health Significance: Vaccine efficacy trials are required for vaccine licensure and distribution to the public. A robustly estimated sample size is crucial, as it ensures a trial is adequately powered, thereby improving the odds of obtaining conclusive results. The methods investigated here represent viable approaches to sample size estimation for such trials

Methods to account for measured and unmeasured confounders in influenza relative vaccine effectiveness studies:A brief review of the literature

Observational seasonal influenza relative vaccine effectiveness (rVE) studies employ a variety of statistical methods to account for confounding and biases. To better understand the range of methods employed and implications for policy, we conducted a brief literature review. Across 37 included rVE studies, 10 different types of statistical methods were identified, and only eight studies reported methods to detect residual confounding, highlighting the heterogeneous state of the literature. To improve the comparability and credibility of future rVE research, researchers should clearly explain methods and design choices and implement methods to detect and quantify residual confounding

Patient and practice level factors associated with seasonal influenza vaccine uptake among at-risk adults in England, 2011 to 2016:An age-stratified retrospective cohort study

We sought to gain insights into the determinants of seasonal influenza vaccine (SIV) uptake by conducting an age-stratified analysis (18-64 and 65+) of factors associated with SIV uptake among at-risk adults registered to English practices. Records for at-risk English adults between 2011 and 2016 were identified using the Clinical Practice Research Datalink database. SIV uptake was assessed annually. The associations of patient, practice, and seasonal characteristics with SIV uptake were assessed via cross-sectional and longitudinal analyses, using mixed-effects and general estimating equation logistic regression models. Overall SIV uptake was 35.3% and 74.0% for adults 18-64 and 65+, respectively. Relative to white patients, black patients were least likely to be vaccinated (OR18-64: 0.82 (95% CI: 0.80, 0.85); OR65+: 0.59 (95% CI: 0.56, 0.62)), while Asian patients among 18-64 year olds were most likely to be vaccinated (OR18-64: 1.10 (95% CI: 1.07, 1.13)). Females were more likely than males to be vaccinated among 18-64 year olds (OR18-64: 1.19 (95% CI: 1.18, 1.20)). Greater socioeconomic deprivation was associated with decreased odds of uptake among older patients (OR65+: 0.74 (95% CI: 0.71, 0.77)). For each additional at-risk condition, odds of uptake increased (OR18-64: 2.33 (95% CI: 2.31, 2.36); OR65+: 1.39 (95% CI: 1.38, 1.39)). Odds of uptake were highest among younger patients with diabetes (OR18-64: 4.25 (95% CI: 4.18, 4.32)) and older patients with chronic respiratory disease (OR65+: 1.60 (95% CI: 1.58, 1.63)), whereas they were lowest among morbidly obese patients of all ages (OR18-64: 0.68 (95% CI: 0.67, 0.70); OR65+: 0.97 (95% CI: 0.94, 0.99)). Prior influenza season severity and vaccine effectiveness were marginally predictive of uptake. Our age-stratified analysis uncovered SIV uptake disparities by ethnicity, sex, age, socioeconomic deprivation, and co-morbidities, warranting further attention by GPs and policymakers alike

Geographic Variation in Influenza Vaccination Disparities Between Hispanic and Non-Hispanic White US Nursing Home Residents

BACKGROUND: Disparities in influenza vaccination exist between Hispanic and non-Hispanic White US nursing home (NH) residents, but the geographic areas with the largest disparities remain unknown. We examined how these racial/ethnic disparities differ across states and hospital referral regions (HRRs). METHODS: This retrospective cohort study included >14 million short-stay and long-stay US NH resident-seasons over 7 influenza seasons from October 1, 2011, to March 31, 2018, where residents could contribute to 1 or more seasons. Residents were aged ≥65 years and enrolled in Medicare fee-for-service. We used the Medicare Beneficiary Summary File to ascertain race/ethnicity and Minimum Data Set assessments for influenza vaccination. We calculated age- and sex-standardized percentage point (pp) differences in the proportions vaccinated between non-Hispanic White and Hispanic (any race) resident-seasons. Positive pp differences were considered disparities, where the proportion of non-Hispanic White residents vaccinated was greater than the proportion of Hispanic residents vaccinated. States and HRRs with ≥100 resident-seasons per age–sex stratum per racial/ethnic group were included in analyses. RESULTS: Among 7 442 241 short-stay resident-seasons (94.1% non-Hispanic White, 5.9% Hispanic), the median standardized disparities in influenza vaccination were 4.3 pp (minimum, maximum: 0.3, 19.2; n = 22 states) and 2.8 pp (minimum, maximum: −3.6, 10.3; n = 49 HRRs). Among 6 758 616 long-stay resident-seasons (93.7% non-Hispanic White, 6.5% Hispanic), the median standardized differences were −0.1 pp (minimum, maximum: −4.1, 11.4; n = 18 states) and −1.8 pp (minimum, maximum: −6.5, 7.6; n = 34 HRRs). CONCLUSIONS: Wide geographic variation in influenza vaccination disparities existed across US states and HRRs. Localized interventions targeted toward areas with high disparities may be a more effective strategy to promote health equity than one-size-fits-all national interventions

Relationships between Community Virus Activity and Cardiorespiratory Rehospitalizations From Post-Acute Care

OBJECTIVES: Quantify the relationship between increasing influenza and respiratory syncytial virus (RSV) community viral activity and cardiorespiratory rehospitalizations among older adults discharged to skilled nursing facilities (SNFs). DESIGN: Retrospective cohort. SETTING AND PARTICIPANTS: Adults aged ≥65 years who were hospitalized and then discharged to a US SNF between 2012 and 2015. METHODS: We linked Medicare Provider Analysis and Review claims to Minimum Data Set version 3.0 assessments, PRISM Climate Group data, and the Centers for Disease Control and Prevention viral testing data. All data were aggregated to US Department of Health and Human Services regions. Negative binomial regression models quantified the relationship between increasing viral activity for RSV and 3 influenza strains (H1N1pdm09, H3N2, and B) and cardiorespiratory rehospitalizations from SNFs. Incidence rate ratios described the relationship between a 5% increase in circulating virus and the rates of rehospitalization for cardiorespiratory outcomes. Analyses were repeated using the same model, but influenza and RSV were considered "in season" or "out of season" based on a 10% positive testing threshold. RESULTS: Cardiorespiratory rehospitalization rates increased by approximately 1% for every 5% increase in circulating influenza A(H3N2), influenza B, and RSV, but decreased by 1% for every 5% increase in circulating influenza A(H1N1pdm09). When respiratory viruses were in season (vs out of season), cardiorespiratory rehospitalization rates increased by approximately 6% for influenza A(H3N2), 3% for influenza B, and 5% for RSV, but decreased by 6% for influenza A(H1N1pdm09). CONCLUSIONS AND IMPLICATIONS: The respiratory season is a particularly important period to implement interventions that reduce cardiorespiratory hospitalizations among SNF residents. Decreasing viral transmission in SNFs through practices such as influenza vaccination for residents and staff, use of personal protective equipment, improved environmental cleaning measures, screening and testing of residents and staff, surveillance of viral activity, and quarantining infected individuals may be potential strategies to limit viral infections and associated cardiorespiratory rehospitalizations

Geographic variation in influenza vaccination among U.S. nursing home residents:A national study

OBJECTIVES: Estimates of influenza vaccine use are not available at the county level for U.S. nursing home (NH) residents but are critically necessary to guide the implementation of quality improvement programs aimed at increasing vaccination. Furthermore, estimates that account for differences in resident characteristics between counties are unavailable. We estimated risk‐standardized vaccination rates (RSVRs) among short‐ and long‐stay NH residents by U.S. county and identified drivers of geographic variation. METHODS: We conducted a retrospective cohort study utilizing 100% of 2013–2015 fee‐for‐service Medicare claims, Minimum Data Set assessments, Certification and Survey Provider Enhanced Reports, and Long‐Term Care: Facts on Care in the U.S. We separately evaluated short‐stay (<100 days) and long‐stay (≥100 days) residents aged 65 and older across the 2013–2014 and 2014–2015 influenza seasons. We estimated RSVRs via hierarchical logistic regression adjusting for 32 resident‐level covariates. We then used multivariable linear regression models to assess associations between county‐level NHs predictors and RSVRs. RESULTS: The study cohort consisted of 2,817,217 residents in 14,658 NHs across 2798 counties. Short‐stay residents had lower RSVRs than long‐stay residents (2013–2014: median [interquartile range], 69.6% [62.8–74.5] vs 84.0% [80.8–86.4]), and there was wide variation within each population (range, 11.4–89.8 vs 49.1–92.6). Several modifiable facility‐level characteristics were associated with increased RSVRs, including higher registered nurse to total nurse ratio and higher total staffing for licensed practical nurses, speech‐language pathologists, and social workers. Characteristics associated with lower RSVRs included higher percentage of residents restrained, with a pressure ulcer, and NH‐level hospitalizations per resident‐year. CONCLUSIONS: Substantial county‐level variation in influenza vaccine use exists among short‐ and long‐stay NH residents. Quality improvement interventions to improve vaccination rates can leverage these results to target NHs located in counties with lower risk‐standardized vaccine use

Decomposing Racial and Ethnic Disparities in Nursing Home Influenza Vaccination

OBJECTIVES: Quantify how observable characteristics contribute to influenza vaccination disparities among White, Black, and Hispanic nursing home (NH) residents. DESIGN: Retrospective cohort. SETTING AND PARTICIPANTS: Short- and long-stay U.S. NH residents aged ≥65 years. METHODS: We linked Minimum Data Set (MDS) and Medicare data to LTCFocUS and other facility data. We included residents with 6-month continuous enrollment in Medicare and an MDS assessment between October 1, 2013, and March 31, 2014. Residents were classified as short-stay (<100 days in NH) or long-stay (≥100 days in NH). We fit multivariable logistic regression models to assess the relationships between 27 resident and NH-level characteristics and receipt of influenza vaccination. Using nonlinear Oaxaca-Blinder decomposition, we decomposed the disparity in influenza vaccination between White versus Black and White versus Hispanic NH residents. Analyses were repeated separately for short- and long-stay residents. RESULTS: Our study included 630,373 short-stay and 1,029,593 long-stay residents. Proportions vaccinated against influenza included 67.2% of White, 55.1% of Black, and 54.5% of Hispanic individuals among short-stay residents and 84.2%, 76.7%, and 80.8%, respectively among long-stay residents. Across 4 comparisons, the crude disparity in influenza vaccination ranged from 3.4 to 12.7 percentage points. By equalizing 27 prespecified characteristics, these disparities could be reduced 37.7% to 59.2%. Living in a predominantly White facility and proxies for NH quality were important contributors across all analyses. Characteristics unmeasured in our data (eg, NH staff attitudes and beliefs) may have also contributed significantly to the disparity. CONCLUSIONS AND IMPLICATIONS: The racial/ethnic disparity in influenza vaccination was most dramatic among short-stay residents. Intervening on factors associated with NH quality would likely reduce these disparities; however, future qualitative research is essential to explore potential contributors that were unmeasured in our data and to understand the degree to which these factors contribute to the overall disparity in influenza vaccination

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Seasonal Influenza Vaccine: Factors of Uptake and Interventions to Increase Coverage

Seasonal influenza vaccines (SIVs) are the most effective means of reducing influenza associated morbidity and mortality, conferring both substantial public health and economic benefits to society. Yet, SIV coverage remains suboptimal and stagnant across many jurisdictions. Effective policy and strategies to improve SIV coverage are built upon a sound understanding of the underlying determinants of SIV uptake. Further, there is an apparent need to develop and assess of innovative, low-cost, scalable interventions so as to increase coverage.Accordingly, there are two primary objectives we aim to accomplish in this Thesis: 1) investigate the factors of SIV uptake among an age-stratified at-risk adult population, and 2) develop and assess innovative, scalable interventions to increase SIV uptake. 1. Investigate Factors of SIV Uptake among an Age-Stratified At-Risk Adult Population Using a large primary care database from England, we investigate patient-, practice-, and season-level factors associated with SIV uptake among an age-stratified population of at-risk adults. With this study, we aim to not only identify uptake determinants, but also identify factors that are differentially associated by age, as these findings may help inform policy and the design of targeted interventions. 2. Develop and Assess Innovative, Scalable Interventions to Increase SIV Uptake First, leveraging big data and predictive modeling, we develop and validate a clinical prediction tool for seasonal influenza vaccination. Based solely upon patient characteristics identified in a primary care database, we train and validate models to predict patient-level SIV uptake among a population of at-risk adults. With HCPs under increasingly restrictive time constraints, timely identification of patients likely to miss influenza vaccination may help HCPs tailor services and to improve efficiency.Second, in collaboration with a national network of retail pharmacies (Walmart, US), we design, implement, and evaluate a multimodal approach to improving SIV uptake during the 2019/20 influenza season. Specifically, we assess the impact of a randomized Peer Comparison (PC) intervention and a previously developed relational communications training on pharmacy-level SIV uptake across more than 4,500 retail pharmacy sites in the US.Ph.D

DTaP combination vaccine use and adherence: A retrospective cohort study

Despite universal recommendation of the 4-dose diphtheria, tetanus, and pertussis (DTaP) vaccine series, coverage and timeliness in the US remain suboptimal. DTaP-containing combination vaccines (i.e. quadrivalent and pentavalent) are presumed to improve vaccine coverage rates and timeliness, but research supporting this claim is limited. We sought to investigate the associations between DTaP-containing vaccine use and adherence to the recommended DTaP immunization schedule among children in the US. Using a large claims database, we identified privately insured children born between 2009 and 2016 that received >= 1 DTaP-containing vaccine and had >= 24 months of enrollment from birth, excluding those with DTaP vaccinations not aligned with approved dose indications. Children were classified by DTaP-containing vaccine receipt: combination vaccines only, stand-alone vaccines only, or a mixture of both. Outcome measures included: 1) completion of the 4-dose series and 2) timely receipt of doses. Outcomes were adjusted for gender, birth year, race, and socioeconomic status. The study cohort contained 412,441 children. Of these, 40.5% (167,084) received combination vaccines only, 14.9% (61,342) received stand-alone vaccines only, and 44.6% (184,015) received a mixture of both. Combination vaccine recipients were nearly 3 times as likely to complete the 4-dose series (OR 2.93 (95% CI: 2.88, 2.99)) and for all doses received, more than 4 times as likely to receive doses on time (OR 4.12 (4.04, 4.21), relative to stand-alone vaccine recipients. Significance disparities in adherence were also observed, where minorities were up to 30% less likely (OR 0.70 (0.68, 0.71)) to complete the 4-dose series and up to 27% less likely (OR 0.73 (0.72, 0.75)) to receive doses on time, relative to white children. Our findings demonstrated that adherence to the recommended DTaP immunization schedule was significantly greater among combination vaccine recipients, relative to stand-alone recipients. Further research is needed to investigate underlying causes of disparities in adherence. (C) 2021 The Author(s). Published by Elsevier Ltd