Evaluating site-of-care-related racial disparities in kidney graft failure using a novel federated learning framework.

OBJECTIVES: Racial disparities in kidney transplant access and posttransplant outcomes exist between non-Hispanic Black (NHB) and non-Hispanic White (NHW) patients in the United States, with the site of care being a key contributor. Using multi-site data to examine the effect of site of care on racial disparities, the key challenge is the dilemma in sharing patient-level data due to regulations for protecting patients' privacy. MATERIALS AND METHODS: We developed a federated learning framework, named dGEM-disparity (decentralized algorithm for Generalized linear mixed Effect Model for disparity quantification). Consisting of 2 modules, dGEM-disparity first provides accurately estimated common effects and calibrated hospital-specific effects by requiring only aggregated data from each center and then adopts a counterfactual modeling approach to assess whether the graft failure rates differ if NHB patients had been admitted at transplant centers in the same distribution as NHW patients were admitted. RESULTS: Utilizing United States Renal Data System data from 39 043 adult patients across 73 transplant centers over 10 years, we found that if NHB patients had followed the distribution of NHW patients in admissions, there would be 38 fewer deaths or graft failures per 10 000 NHB patients (95% CI, 35-40) within 1 year of receiving a kidney transplant on average. DISCUSSION: The proposed framework facilitates efficient collaborations in clinical research networks. Additionally, the framework, by using counterfactual modeling to calculate the event rate, allows us to investigate contributions to racial disparities that may occur at the level of site of care. CONCLUSIONS: Our framework is broadly applicable to other decentralized datasets and disparities research related to differential access to care. Ultimately, our proposed framework will advance equity in human health by identifying and addressing hospital-level racial disparities.

Efficient Synthesis of DNA Duplexes Containing Reduced Acetaldehyde Interstrand Cross-Links.

DNA interstrand cross-links (ICLs) prevent DNA replication and transcription and can lead to potentially lethal events, such as cancer or bone marrow failure. ICLs are typically repaired by proteins within the Fanconi Anemia (FA) pathway, although the details of the pathway are not fully established. Methods to generate DNA containing ICLs are key to furthering the understanding of DNA cross-link repair. A major route to ICL formation in vivo involves reaction of DNA with acetaldehyde, derived from ethanol metabolism. This reaction forms a three-carbon bridged ICL involving the amino groups of adjacent guanines in opposite strands of a duplex resulting in amino and imino functionalities. A stable reduced form of the ICL has applications in understanding the recognition and repair of these types of adducts. Previous routes to creating DNA duplexes containing these adducts have involved lengthy post-DNA synthesis chemistry followed by reduction of the imine. Here, an efficient and high-yielding approach to the reduced ICL using a novel N2-((R)-4-trifluoroacetamidobutan-2-yl)-2'-deoxyguanosine phosphoramidite is described. Following standard automated DNA synthesis and deprotection, the ICL is formed overnight in over 90% yield upon incubation at room temperature with a complementary oligodeoxyribonucleotide containing 2-fluoro-2'-deoxyinosine. The cross-linked duplex displayed a melting transition 25 °C higher than control sequences. Importantly, we show using the Xenopus egg extract system that an ICL synthesized by this method is repaired by the FA pathway. The simplicity and efficiency of this methodology for preparing reduced acetaldehyde ICLs will facilitate access to these DNA architectures for future studies on cross-link repair.

Factors associated with increased suicidality risk following referral for isotretinoin commencement.

OBJECTIVE: To establish whether there is a significant change in suicidality risk following psychiatric assessment for commencement of isotretinoin and identify factors that underpin any potential risk change. METHOD: Retrospective cohort study. Suicidality risk was defined as a combination of the following: (i) actual/intended self-harm and/or attempted/completed suicide, and (ii) increased service utilisation associated with suicidal ideation/behaviour. All patients referred to Psychiatry for assessment prior to commencement of isotretinoin between 2014 and 2019 were examined. Inclusion criteria: >16 years of age, assessed for commencement of isotretinoin, complete clinical records. Data were collected by reviewing the Electronic Patient Records. Fifty-seven patients were eligible. We employed descriptive statistics, parametric/non-parametric/normality tests and logistic regression analysis, using socio-demographic and clinical characteristics as independent parameters, and suicidality risk as the dependent parameter. RESULTS: Actual/intended self-harm/attempted suicide decreased significantly following assessment without significant change in service utilisation. Female gender, absence of protective factors and assessment by Consultation-Liaison Psychiatry were linked to increased suicidality risk, after controlling for age, ethnicity, recommendation for isotretinoin, and substance misuse. CONCLUSIONS: Psychiatric assessment is helpful before commencing isotretinoin. Female gender, and absence of ongoing psychopharmacological and/or psychological intervention and/or regular psychiatric follow-up predict increased suicidality risk among patients assessed for prescription of isotretinoin.

Economic evaluation of quality improvement interventions to prevent catheter-associated urinary tract infections in the hospital setting: a systematic review.

BACKGROUND: Hospitals have implemented diverse quality improvement (QI) interventions to reduce rates of catheter-associated urinary tract infections (CAUTIs). The economic value of these QI interventions is uncertain. OBJECTIVE: To systematically review economic evaluations of QI interventions designed to prevent CAUTI in acute care hospitals. METHODS: A search of Ovid MEDLINE, Econlit, Centre for Reviews & Dissemination, New York Academy of Medicine's Grey Literature Report, WorldCat, IDWeek conference abstracts and prior systematic reviews was conducted from January 2000 to October 2020.We included English-language studies of any design that evaluated organisational or structural changes to prevent CAUTI in acute care hospitals, and reported programme and infection-related costs.Dual reviewers assessed study design, effectiveness, costs and study quality. For each eligible study, we performed a cost-consequences analysis from the hospital perspective, estimating the incidence rate ratio (IRR) and incremental net cost/savings per hospital over 3 years. Unadjusted weighted regression analyses tested predictors of these measures, weighted by catheter days per study. RESULTS: Fifteen unique economic evaluations were eligible, encompassing 74 hospitals. Across 12 studies amenable to standardisation, QI interventions were associated with a 43% decline in infections (mean IRR 0.57, 95% CI 0.44 to 0.70) and wide ranges of net costs (mean US$52 000, 95% CI -$288 000 to $392 000), relative to usual care. CONCLUSIONS: QI interventions were associated with large declines in infection rates and net costs to hospitals that varied greatly but that, on average, were not significantly different from zero over 3 years. Future research should examine specific practices associated with cost-savings and clinical effectiveness, and examine whether or not more comprehensive interventions offer hospitals and patients the best value.

Evaluation of COVID-19 coagulopathy; laboratory characterization using thrombin generation and nonconventional haemostasis assays.

INTRODUCTION: Patients with COVID-19 are known to have a coagulopathy with a thrombosis risk. It is unknown whether this is due to a generalized humoral prothrombotic state or endothelial factors such as inflammation and dysfunction. The aim was to further characterize thrombin generation using a novel analyser (ST Genesia, Diagnostica Stago, Asnières, France) and a panel of haematological analytes in patients with COVID-19. METHODS: Platelet poor plasma of 34 patients with noncritical COVID-19 was compared with 75 patients with critical COVID-19 (as defined by WHO criteria) in a retrospective study by calibrated automated thrombography and ELISA. Patients were matched for baseline characteristics of age and gender. RESULTS: Critical patients had significantly increased fibrinogen, CRP, interleukin-6 and D-dimer compared to noncritical patients. Thrombin generation, in critical patients, was right shifted without significant differences in peak, velocity index or endogenous thrombin potential. Tissue plasminogen activator (tPA), tissue factor pathway inhibitor (TFPI) and vascular endothelial growth factor (VEGF) were significantly increased in the critical versus noncritical patients. Critically ill patients were on haemodiafiltration (31%; heparin used in the circuit) or often received escalated prophylactic low-molecular weight heparin. CONCLUSION: These results confirm increased fibrinogen and D-dimer in critical COVID-19-infected patients. Importantly, disease severity did not increase thrombin generation (including thrombin-antithrombin complexes and prothrombin fragment 1 + 2) when comparing both cohorts; counter-intuitively critical patients were hypocoaguable. tPA, TFPI and VEGF were increased in critical patients, which are hypothesized to reflect endothelial dysfunction and/or contribution of heparin (which may cause endothelial TFPI/tPA release).

Learning from local to global: An efficient distributed algorithm for modeling time-to-event data.

OBJECTIVE: We developed and evaluated a privacy-preserving One-shot Distributed Algorithm to fit a multicenter Cox proportional hazards model (ODAC) without sharing patient-level information across sites. MATERIALS AND METHODS: Using patient-level data from a single site combined with only aggregated information from other sites, we constructed a surrogate likelihood function, approximating the Cox partial likelihood function obtained using patient-level data from all sites. By maximizing the surrogate likelihood function, each site obtained a local estimate of the model parameter, and the ODAC estimator was constructed as a weighted average of all the local estimates. We evaluated the performance of ODAC with (1) a simulation study and (2) a real-world use case study using 4 datasets from the Observational Health Data Sciences and Informatics network. RESULTS: On the one hand, our simulation study showed that ODAC provided estimates nearly the same as the estimator obtained by analyzing, in a single dataset, the combined patient-level data from all sites (ie, the pooled estimator). The relative bias was <0.1% across all scenarios. The accuracy of ODAC remained high across different sample sizes and event rates. On the other hand, the meta-analysis estimator, which was obtained by the inverse variance weighted average of the site-specific estimates, had substantial bias when the event rate is <5%, with the relative bias reaching 20% when the event rate is 1%. In the Observational Health Data Sciences and Informatics network application, the ODAC estimates have a relative bias <5% for 15 out of 16 log hazard ratios, whereas the meta-analysis estimates had substantially higher bias than ODAC. CONCLUSIONS: ODAC is a privacy-preserving and noniterative method for implementing time-to-event analyses across multiple sites. It provides estimates on par with the pooled estimator and substantially outperforms the meta-analysis estimator when the event is uncommon, making it extremely suitable for studying rare events and diseases in a distributed manner.

Testing small study effects in multivariate meta-analysis.

Small study effects occur when smaller studies show different, often larger, treatment effects than large ones, which may threaten the validity of systematic reviews and meta-analyses. The most well-known reasons for small study effects include publication bias, outcome reporting bias, and clinical heterogeneity. Methods to account for small study effects in univariate meta-analysis have been extensively studied. However, detecting small study effects in a multivariate meta-analysis setting remains an untouched research area. One of the complications is that different types of selection processes can be involved in the reporting of multivariate outcomes. For example, some studies may be completely unpublished while others may selectively report multiple outcomes. In this paper, we propose a score test as an overall test of small study effects in multivariate meta-analysis. Two detailed case studies are given to demonstrate the advantage of the proposed test over various naive applications of univariate tests in practice. Through simulation studies, the proposed test is found to retain nominal Type I error rates with considerable power in moderate sample size settings. Finally, we also evaluate the concordance between the proposed tests with the naive application of univariate tests by evaluating 44 systematic reviews with multiple outcomes from the Cochrane Database.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement: Explanation and Elaboration.

The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed to promote the conduct of, and provide guidance for, predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risk with versus without the intervention, taking into account all relevant patient attributes simultaneously, to support more personalized clinical decision making than can be made on the basis of only an overall average treatment effect. The authors distinguished 2 categories of predictive HTE approaches (a "risk-modeling" and an "effect-modeling" approach) and developed 4 sets of guidance statements: criteria to determine when risk-modeling approaches are likely to identify clinically meaningful HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. They discuss limitations of these methods and enumerate research priorities for advancing methods designed to generate more personalized evidence. This explanation and elaboration document describes the intent and rationale of each recommendation and discusses related analytic considerations, caveats, and reservations.

The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.

Heterogeneity of treatment effect (HTE) refers to the nonrandom variation in the magnitude or direction of a treatment effect across levels of a covariate, as measured on a selected scale, against a clinical outcome. In randomized controlled trials (RCTs), HTE is typically examined through a subgroup analysis that contrasts effects in groups of patients defined "1 variable at a time" (for example, male vs. female or old vs. young). The authors of this statement present guidance on an alternative approach to HTE analysis, "predictive HTE analysis." The goal of predictive HTE analysis is to provide patient-centered estimates of outcome risks with versus without the intervention, taking into account all relevant patient attributes simultaneously. The PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement was developed using a multidisciplinary technical expert panel, targeted literature reviews, simulations to characterize potential problems with predictive approaches, and a deliberative process engaging the expert panel. The authors distinguish 2 categories of predictive HTE approaches: a "risk-modeling" approach, wherein a multivariable model predicts the risk for an outcome and is applied to disaggregate patients within RCTs to define risk-based variation in benefit, and an "effect-modeling" approach, wherein a model is developed on RCT data by incorporating a term for treatment assignment and interactions between treatment and baseline covariates. Both approaches can be used to predict differential absolute treatment effects, the most relevant scale for clinical decision making. The authors developed 4 sets of guidance: criteria to determine when risk-modeling approaches are likely to identify clinically important HTE, methodological aspects of risk-modeling methods, considerations for translation to clinical practice, and considerations and caveats in the use of effect-modeling approaches. The PATH Statement, together with its explanation and elaboration document, may guide future analyses and reporting of RCTs.

Engaging Patients and Other Non-Researchers in Health Research: Defining Research Engagement.

With the increase in patient and consumer activism through the late twentieth century and into this century, patient roles in research evolved into a new model of research engagement, with patients serving as active advisors and co-leading or leading clinical research. By requiring active engagement of patients and other stakeholders, several government research funders have advanced this model, particularly in Canada, the United States (US), United Kingdom (UK), and Australia. A consortium of individuals from these countries formed a Multi-Stakeholder Engagement (MuSE) consortium to examine critical issues in engaged research, establish consensus on definitions, and provide guidance for the field, beginning with an overview of how to involve stakeholders in health research (Concannon et al. J Gen Intern Med. 2019;34(3):458-463) and continuing here with an examination of definitions of research engagement. The political and advocacy roots of engaged research are reflected in definitions. Engagement is conceptualized with reference to research project goals, from informing specific clinical decisions to informing health-system level decisions. Political and cultural differences across countries are evident. Some of these government funders focus on empirical rather than ethical rationales. In countries with centralized health technology assessment, the link between societal values and engaged research is explicit. Ethical rationales for engagement are explicit in most of the published literature on research engagement. Harmonization of definitions is recommended so that research engagement elements, methods, and outcomes and impacts can be clearly examined and understood, and so that the field of research engagement can proceed from a clear conceptual foundation. Specific recommendations for terminology definitions are provided. Placing engaged research on a continuum from specific clinical decisions to more global public and social justice concerns clarifies the type of engaged research, supports appropriate comparisons, and improves the rigor of engaged research methods. The results help identify knowledge gaps in this growing field.

A diagnostic solution for haemostasis laboratories for patients taking direct oral anticoagulants using DOAC-Remove.

This study describes the use of a simple charcoal product (DOAC-RemoveTM ) to allow haemostasis assays on patients taking direct oral anticoagulants (DOAC). In the proposed algorithm, patients taking DOAC are screened using the dilute thrombin time (dTT) and anti-Xa assay. If either are positive then DOAC-Remove is utilised. In a validation, DOAC-Remove did not interfere with coagulation testing in normal plasma or in patients on DOAC with a known lupus anticoagulant (LA). Of 1566 routine patient samples tested, 125 (8%) had evidence of anti-Xa activity (>0·1 iu/ml) or prolonged dTT suggestive of either a direct/indirect Xa inhibitor or direct thrombin inhibitor. All of these 125 patients had a prolonged dilute Russell viper venom time (dRVVT) screening test and 106 had a LA detected by dRVVT after phospholipid correction. After DOAC-Remove, 91 patients (73%) had a negative dRVVT screen. After further investigation only 9 (7%) had a positive LA. DOAC-Remove prevented 5% of patients having a LA inappropriately detected. DOAC did not significantly affect the LA activated partial thromboplastin time (aPTT) ratio, protein S antigen or protein C activity. DOAC cause low intrinsic factor assays, high prothrombin time/aPTT and high activated protein C sensitivity ratio, which DOAC-Remove reversed (P < 0·05). Despite recommendations, haemostasis testing for patients on DOAC continues; this algorithm aids diagnostic accuracy. Further validation and research are warranted.

Comparative Clinical Effectiveness of Nonsurgical Treatment Methods in Patients With Lumbar Spinal Stenosis: A Randomized Clinical Trial.

Importance: Lumbar spinal stenosis (LSS) is the most common reason for spine surgery in older US adults. There is an evidence gap about nonsurgical LSS treatment options. Objective: To explore the comparative clinical effectiveness of 3 nonsurgical interventions for patients with LSS. Design, Setting, and Participants: Three-arm randomized clinical trial of 3 years' duration (November 2013 to June 2016). Analysis began in August 2016. All interventions were delivered during 6 weeks with follow-up at 2 months and 6 months at an outpatient research clinic. Patients older than 60 years with LSS were recruited from the general public. Eligibility required anatomical evidence of central canal and/or lateral recess stenosis (magnetic resonance imaging/computed tomography) and clinical symptoms associated with LSS (neurogenic claudication; less symptoms with flexion). Analysis was intention to treat. Interventions: Medical care, group exercise, and manual therapy/individualized exercise. Medical care consisted of medications and/or epidural injections provided by a physiatrist. Group exercise classes were supervised by fitness instructors in senior community centers. Manual therapy/individualized exercise consisted of spinal mobilization, stretches, and strength training provided by chiropractors and physical therapists. Main Outcomes and Measures: Primary outcomes were between-group differences at 2 months in self-reported symptoms and physical function measured by the Swiss Spinal Stenosis questionnaire (score range, 12-55) and a measure of walking capacity using the self-paced walking test (meters walked for 0 to 30 minutes). Results: A total of 259 participants (mean [SD] age, 72.4 [7.8] years; 137 women [52.9%]) were allocated to medical care (88 [34.0%]), group exercise (84 [32.4%]), or manual therapy/individualized exercise (87 [33.6%]). Adjusted between-group analyses at 2 months showed manual therapy/individualized exercise had greater improvement of symptoms and physical function compared with medical care (-2.0; 95% CI, -3.6 to -0.4) or group exercise (-2.4; 95% CI, -4.1 to -0.8). Manual therapy/individualized exercise had a greater proportion of responders (≥30% improvement) in symptoms and physical function (20%) and walking capacity (65.3%) at 2 months compared with medical care (7.6% and 48.7%, respectively) or group exercise (3.0% and 46.2%, respectively). At 6 months, there were no between-group differences in mean outcome scores or responder rates. Conclusions and Relevance: A combination of manual therapy/individualized exercise provides greater short-term improvement in symptoms and physical function and walking capacity than medical care or group exercises, although all 3 interventions were associated with improvements in long-term walking capacity. Trial Registration: ClinicalTrials.gov Identifier: NCT01943435.

27 years of prenatal diagnosis for Huntington disease in the United Kingdom.

PURPOSE: There is little long-term, population-based data on uptake of prenatal diagnosis for Huntington disease (HD), a late-onset autosomal dominant neurodegenerative disorder, and the effect of the availability of preimplantation genetic diagnosis (PGD) on families' decisions about conventional prenatal diagnosis is not known. We report trends in prenatal diagnosis and preimplantation diagnosis for HD in the United Kingdom since services commenced. METHODS: Long-term UK-wide prospective case record-based service evaluation in 23 UK Regional Genetic Centres 1988-2015, and four UK PGD centers 2002-2015. RESULTS: From 1988 to 2015, 479 prenatal diagnoses were performed in the UK for HD. An exclusion approach was used in 150 (31%). The annual rate of HD prenatal diagnosis has remained around 18 (3.5/million) over 27 years, despite a steady increase in the use of PGD for HD since 2002. CONCLUSION: Although increasing number of couples are choosing either direct or exclusion PGD to prevent HD in their offspring, both direct and exclusion prenatal diagnosis remain important options in a health system where both PGD and prenatal diagnosis are state funded. At-risk couples should be informed of all options available to them, preferably prepregnancy.

Economic Evaluation of Quality Improvement Interventions Designed to Improve Glycemic Control in Diabetes: A Systematic Review and Weighted Regression Analysis.

OBJECTIVE: Quality improvement (QI) interventions can improve glycemic control, but little is known about their value. We systematically reviewed economic evaluations of QI interventions for glycemic control among adults with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: We used English-language studies from high-income countries that evaluated organizational changes and reported program and utilization-related costs, chosen from PubMed, EconLit, Centre for Reviews and Dissemination, New York Academy of Medicine's Grey Literature Report, and WorldCat (January 2004 to August 2016). We extracted data regarding intervention, study design, change in HbA1c, time horizon, perspective, incremental net cost (studies lasting ≤3 years), incremental cost-effectiveness ratio (ICER) (studies lasting ≥20 years), and study quality. Weighted least-squares regression analysis was used to estimate mean changes in HbA1c and incremental net cost. RESULTS: Of 3,646 records, 46 unique studies were eligible. Across 19 randomized controlled trials (RCTs), HbA1c declined by 0.26% (95% CI 0.17-0.35) or 3 mmol/mol (2 to 4) relative to usual care. In 8 RCTs lasting ≤3 years, incremental net costs were $116 (95% CI -$612 to $843) per patient annually. Long-term ICERs were $100,000-$115,000/quality-adjusted life year (QALY) in 3 RCTs, $50,000-$99,999/QALY in 1 RCT, $0-$49,999/QALY in 4 RCTs, and dominant in 1 RCT. Results were more favorable in non-RCTs. Our limitations include the fact that the studies had diverse designs and involved moderate risk of bias. CONCLUSIONS: Diverse multifaceted QI interventions that lower HbA1c appear to be a fair-to-good value relative to usual care, depending on society's willingness to pay for improvements in health.

A Payer-Guided Approach To Widespread Diffusion Of Behavioral Health Homes In Real-World Settings.

People with serious mental illness experience decreased life expectancy related to co-occurring medical conditions. A nonprofit behavioral health managed care organization implemented an innovative behavioral health home, in partnership with community mental health providers, to build a culture of wellness among all staff members, with a focus on prevention and holistic (that is, behavioral, social, and physical) health. The behavioral health home added one of two distinct care approaches, one patient driven and the other provider driven. The innovative approaches were implemented at eleven community mental health providers: Six delivered patient-driven care, and five delivered provider-driven care. We studied outcomes in the period October 2013-January 2016. Multiple diffusion strategies were utilized to encourage uptake. Our results revealed that both approaches significantly increased patient activation in care (more quickly in provider-supported care), engagement in primary and specialty care, and perceived mental health status. The success of this behavioral health home in improving important outcomes and the use of novel diffusion strategies led to its dissemination to forty-three additional providers across Pennsylvania.

The Cost of Interventions to Increase Influenza Vaccination: A Systematic Review.

CONTEXT: Influenza vaccination rates remain below Healthy People 2020 goals. This project sought to systematically review economic evaluations of healthcare-based quality improvement interventions for improving influenza vaccination uptake among general populations and healthcare workers. EVIDENCE ACQUISITION: The databases MEDLINE, Econlit, Centre for Reviews & Dissemination, Greylit, and Worldcat were searched in July 2016 for papers published from January 2004 to July 2016. Eligible studies evaluated efforts by bodies within the healthcare system to encourage influenza vaccination by means of an organizational or structural change. For each study, program costs per enrollee and per additional enrollee vaccinated were derived (excluding vaccine costs, standardized to 2017 U.S. dollars). Complete economic evaluations were examined when available. EVIDENCE SYNTHESIS: Of 2,350 records, 18 articles were eligible and described 29 unique interventions. Most interventions improved vaccine uptake. Among 23 interventions in general populations, the median program cost was $3.27 (interquartile range, $0.82-$11.53) per enrollee and $50.78 (interquartile range, $27.85-$124.84) per additional enrollee vaccinated. Among ten complete economic evaluations in general populations, three studies reported net cost savings, four reported costs <$50,000 per quality-adjusted life year, and three reported costs <$60,000 per life saved. Among six interventions in healthcare workers, the median program cost was $8.09 (interquartile range, $5.03-$10.31) per worker enrolled and $125.24 (interquartile range, $96.06-$171.38) per additional worker vaccinated (there were no complete economic analyses). CONCLUSIONS: Quality improvement interventions for influenza vaccination involve per-enrollee costs that are similar to the cost of the vaccine itself ($11.78-$36.08/dose). Based on limited available evidence in general populations, quality improvement interventions may be cost saving to cost effective for the health system.

AHRQ series on complex intervention systematic reviews-paper 5: advanced analytic methods.

BACKGROUND AND OBJECTIVE: Advanced analytic methods for synthesizing evidence about complex interventions continue to be developed. In this paper, we emphasize that the specific research question posed in the review should be used as a guide for choosing the appropriate analytic method. METHODS: We present advanced analytic approaches that address four common questions that guide reviews of complex interventions: (1) How effective is the intervention? (2) For whom does the intervention work and in what contexts? (3) What happens when the intervention is implemented? and (4) What decisions are possible given the results of the synthesis? CONCLUSION: The analytic approaches presented in this paper are particularly useful when each primary study differs in components, mechanisms of action, context, implementation, timing, and many other domains.

AHRQ series on complex intervention systematic reviews-paper 4: selecting analytic approaches.

BACKGROUND: Systematic reviews of complex interventions can vary widely in purpose, data availability and heterogeneity, and stakeholder expectations. RATIONALE: This article addresses the uncertainty that systematic reviewers face in selecting methods for reviews of complex interventions. Specifically, it lays out parameters for systematic reviewers to consider when selecting analytic approaches that best answer the questions at hand and suggests analytic techniques that may be appropriate in different circumstances. DISCUSSION: Systematic reviews of complex interventions comprising multiple questions may use multiple analytic approaches. Parameters to consider when choosing analytic methods for complex interventions include nature and timing of the decision (clinical practice guideline, policy, or other); purpose of the review; extent of existing evidence; logistic factors such as the timeline, process, and resources for deciding the scope of the review; and value of information to be obtained from choosing specific systematic review methods. Reviewers may elect to revise their analytic approach based on new or changing considerations during the course of the review but should guard against bias through transparency of reporting.

Economic Evaluation of Quality Improvement Interventions Designed to Prevent Hospital Readmission: A Systematic Review and Meta-analysis.

Importance: Quality improvement (QI) interventions can reduce hospital readmission, but little is known about their economic value. Objective: To systematically review economic evaluations of QI interventions designed to reduce readmissions. Data Sources: Databases searched included PubMed, Econlit, the Centre for Reviews & Dissemination Economic Evaluations, New York Academy of Medicine's Grey Literature Report, and Worldcat (January 2004 to July 2016). Study Selection: Dual reviewers selected English-language studies from high-income countries that evaluated organizational or structural changes to reduce hospital readmission, and that reported program and readmission-related costs. Data Extraction and Synthesis: Dual reviewers extracted intervention characteristics, study design, clinical effectiveness, study quality, economic perspective, and costs. We calculated the risk difference and net costs to the health system in 2015 US dollars. Weighted least-squares regression analyses tested predictors of the risk difference and net costs. Main Outcomes and Measures: Main outcomes measures included the risk difference in readmission rates and incremental net cost. This systematic review and data analysis is reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Results: Of 5205 articles, 50 unique studies were eligible, including 25 studies in populations limited to heart failure (HF) that included 5768 patients, 21 in general populations that included 10 445 patients, and 4 in unique populations. Fifteen studies lasted up to 30 days while most others lasted 6 to 24 months. Based on regression analyses, readmissions declined by an average of 12.1% among patients with HF (95% CI, 8.3%-15.9%; P < .001; based on 22 studies with complete data) and by 6.3% among general populations (95% CI, 4.0%-8.7%; P < .001; 18 studies). The mean net savings to the health system per patient was $972 among patients with HF (95% CI, -$642 to $2586; P = .23; 24 studies), and the mean net loss was $169 among general populations (95% CI, -$2610 to $2949; P = .90; 21 studies), reflecting nonsignificant differences. Among general populations, interventions that engaged patients and caregivers were associated with greater net savings ($1714 vs -$6568; P = .006). Conclusions and Relevance: Multicomponent QI interventions can be effective at reducing readmissions relative to the status quo, but net costs vary. Interventions that engage general populations of patients and their caregivers may offer greater value to the health system, but the implications for patients and caregivers are unknown.