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Objectives In this systematic review, we synthesize the current evidence on health-related quality of life (HRQoL) for the two of the most relevant outcomes of Zika virus infection in humans, microcephaly and Guillain-Barre Syndrome (GBS). Methods We searched the following databases: MEDLINE, Embase, CINAHL, LILACS, WHO's ICTRP clinical trials registries database and PROSPERO. Search terms included quality of life, microcephaly, and Guillain-Barre Syndrome. We included primary studies where HRQoL was quantitatively assessed for microcephaly and GBS using validated instruments. We used the Joanna Briggs Institute Critical Appraisal Tools to assess the risk of bias of individual studies. Results From a total of 1,657 abstracts screened and 66 full texts reviewed, 21 studies met the eligibility criteria; one study for microcephaly and 20 for GBS. Adjusted disutilities for microcephaly compared to a normative childhood utility ranged from −0.745 to −0.820. For GBS, time traded-off the expected lifetime ranged from 16 days to 3 years. HRQoL follows the clinical course of GBS, with lower scores in the first months, recovery within the first year post onset, and stabilization after one year. Conclusions Included studies reported a wide range of HRQoL for GBS, due in part to a high level of heterogeneity in methods, inclusion criteria, follow-up and reporting of results. Opportunities exist for primary studies assessing the longitudinal HRQoL over the entire course of the diseases to inform clinical practice, economic evaluations and health policy.

Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis.Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies.We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation.Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P.05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities.Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities.

Background Zika virus (ZIKV) has generated global interest in the last five years mostly due to its resurgence in the Americas between 2015 and 2016. It was previously thought to be a self-limiting infection causing febrile illness in less than one quarter of those infected. However, a rise in birth defects amongst children born to infected pregnant women, as well as increases in neurological manifestations in adults has been demonstrated. We systemically reviewed the literature to understand clinical manifestations and health outcomes in adults globally. Methods This review was registered prospectively with PROPSERO (CRD 42018096558). We systematically searched for studies in six databases from inception to the end of September 2020. There were no language restrictions. Critical appraisal was completed using the Joanna Briggs Institute Critical Appraisal Tools. Findings We identified 73 studies globally that reported clinical outcomes in ZIKV-infected adults, of which 55 studies were from the Americas. For further analysis, we considered studies that met 70% of critical appraisal criteria and described subjects with confirmed ZIKV. The most common symptoms included: exanthema (5,456/6,129; 89%), arthralgia (3,809/6,093; 63%), fever (3,787/6,124; 62%), conjunctivitis (2,738/3,283; 45%), myalgia (2,498/5,192; 48%), headache (2,165/4,722; 46%), and diarrhea (337/2,622; 13%). 36/14,335 (0.3%) of infected cases developed neurologic sequelae, of which 75% were Guillain-Barré Syndrome (GBS). Several subjects reported recovery from peak of neurological complications, though some endured chronic disability. Mortality was rare (0.1%) and hospitalization (11%) was often associated with co-morbidities or GBS. Conclusions The ZIKV literature in adults was predominantly from the Americas. The most common systemic symptoms were exanthema, fever, arthralgia, and conjunctivitis; GBS was the most prevalent neurological complication. Future ZIKV studies are warranted with standardization of testing and case definitions, consistent co-infection testing, reporting of laboratory abnormalities, separation of adult and pediatric outcomes, and assessing for causation between ZIKV and neurological sequelae., Author summary Interest in Zika virus (ZIKV) has increased in the last decade due to its emergence and rapid spread in the Americas. In this review, we examine ZIKV clinical manifestations and sequelae in adults. Among studies reporting subjects with confirmed ZIKV and critical appraisal scores of at least 70%, symptoms reported include exanthema, fever, arthralgia, conjunctivitis, myalgia, headache, and diarrhea. Neurological sequelae in this group occurred in 0.3% of subjects, of which 75% were Guillain-Barré Syndrome (GBS). Recovery from GBS was variable: some patients returned to health and others endured chronic disability. Mortality was rare (0.1%). Hospitalization (11%) was often associated co-morbidities or GBS; this percentage perhaps reflects studies in which all reported subjects were hospitalized. Synthesizing reported data is challenging given the wide range of case definitions and ZIKV testing practices.

IntroductionCanadians are living longer, many with multiple chronic conditions. This population of older, frail Canadians continues to grow in size as do concurrent demands for community-based, outpatient and ambulatory models of care. Ideally, a multifaceted, proactive, planned and integrated care model includes ehealth. Although several factors are known to facilitate the implementation of ehealth in chronic disease management (CDM), for example, adequate support, usability, alignment of programme objectives, there is a growing body of inconclusive evidence on what is critical for implementation. We aim to achieve a fulsome understanding of factors critical to implementation by conducting a realist review—an approach suitable for understanding complex interventions. Our proposed review will identify factors critical to the implementation of ehealth in CDM (heart failure, chronic obstructive pulmonary disease, chronic kidney disease and/or diabetes (type 1 or 2)) without limitations to care setting, language, publication year or geography. Findings will be presented in configurations of contexts, mechanisms and outcomes (CMOs).Methods and analysisA search strategy will be iteratively developed based on the concepts of ‘implementation’ and ‘adoption’ of ‘ehealth’ interventions used within ‘CDM’ to identify the peer-reviewed and grey literature published before 31 March 2021 from five databases (Medline, Embase, Cochrane, CINAHL and PsychInfo) on ehealth interventions actively involving a healthcare provider for CDM among adults. Data extraction and synthesis will be guided by Realist and Meta-review Evidence Synthesis: Evolving Standards (RAMESES) guidelines informing core concepts of CMOs, and a study output will include a middle-range-theory describing the implementation of ehealth in CDM.Ethics and disseminationFindings will be published in an open-access peer-reviewed journal and presented at relevant conferences. A multistakeholder (patients, caregivers, healthcare providers and practitioners, decision-makers and policy-makers) perspective will be used in our dissemination approach. No formal ethics approval is required for this review.PROSPERO registration numberCRD42020208275.

BackgroundLong-term sequelae associated with pneumococcal sepsis (PS) in pediatric patients in existing literature is currently unclear.AimTo review the evidence on sequelae and prognostic factors associated with PS among pediatric patients.MethodWe conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. We screened six databases from their inception to January 15, 2021. Study population were neonates, infants, children and adolescents less than 18 years old with suspected or confirmed PS disease. Outcomes included sequelae types, prognostic factors, pooled death estimate and length of hospital stay (LOS) for survivors and deceased patients. Quality of studies was assessed using Joanna Briggs Institute appraisal checklists.ResultsWe screened 981 abstracts, and 24 full-text articles for final review. Septic shock was the most prevalent physical sequelae reported (13%, n=1492 patients). No functional, cognitive or neurological sequelae were reported in included studies. Meta-analysis of pooled mortality estimate was 14.6% (95%CI: 9.9 −19.4%). Prognostic factors associated with increased risk of PS sequelae and death included pediatric risk of mortality score ≥ 10 and co-infection with meningitis. LOS for survivors and non-survivors ranged between 5-30 days and 1-30 days. Nine included studies met at least 50% of the quality assessment criteria.ConclusionPhysical sequelae and death are the PS sequelae types currently identified in existing literature. Lack of information about other possible sequelae types suggests the long-term consequences of PS disease maybe underreported, especially in resource-limited settings. Future studies should consider exploring reasons for the existing of this knowledge gap.

Objective The objective of this paper is to conduct a systematic review that summarizes the cost-effectiveness of cleft lip and/or palate (CL/P) care in low- and middle-income countries (LMICs) based on existing literature. Design We searched eleven electronic databases for articles from January 1, 2000 to December 29, 2020. This study is registered in PROSPERO (CRD42020148402). Two reviewers independently conducted primary and secondary screening, and data extraction. Setting All CL/P cost-effectiveness analyses in LMIC settings. Patients, Participants In total, 2883 citations were screened. Eleven articles encompassing 1,001,675 patients from 86 LMICs were included. Main Outcome Measures We used cost-effectiveness thresholds of 1% to 51% of a country's gross domestic product per capita (GDP/capita), a conservative threshold recommended for LMICs. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) checklist. Results Primary CL/P repair was cost-effective at the threshold of 51% of a country's GDP/capita across all studies. However, only 1 study met at least 70% of the JBI criteria. There is a need for context-specific cost and health outcome data for primary CL/P repair, complications, and existing multidisciplinary management in LMICs. Conclusions Existing economic evaluations suggest primary CL/P repair is cost-effective, however context-specific local data will make future cost-effectiveness analyses more relevant to local decision-makers and lead to better-informed resource allocation decisions in LMICs.

ObjectivesMathematical models are increasingly important in planning for the upcoming chronic hepatitis C (CHC) elimination efforts. Such models require reliable natural history inputs to make accurate predictions on health and economic outcomes. Yet, hepatitis C virus disease progression is known to vary widely in the literature and published inputs are currently outdated. The objectives of this study were to obtain updated estimates of fibrosis progression rates (FPR) in treatment-naïve patients with CHC and to explore sources of heterogeneity.DesignA systematic review was conducted using Ovid-MEDLINE, Ovid-EMBASE and PubMed databases (January 1990 to January 2018) to identify observational studies of hepatic fibrosis in treatment-naïve patients with CHC.OutcomesStage-constant FPRs were estimated for each study given the reported fibrosis scores and duration of infection. Stage-specific FPRs (ie, F0→F1; F1→F2; F2→F3; F3→F4) were estimated using Markov maximum likelihood estimation. Estimates were pooled using random-effects meta-analysis and heterogeneity was evaluated by stratification and random-effects meta-regression.ResultsThe review identified 111 studies involving 131 groups of patients (n=42 693). The pooled stage-constant FPR was 0.094 (95% CI 0.088 to 0.100); stage-specific FPRs were F0→F1: 0.107 (95% CI 0.097 to 0.118); F1→F2: 0.082 (95% CI 0.074 to 0.091); F2→F3: 0.117 (95% CI 0.107 to 0.129); F3→F4: 0.116 (95% CI 0.104 to 0.131). Stratified analysis revealed substantial variation in progression by study population. Meta-regression indicated associations between progression and infection age, duration, source, viral genotype and study population. Findings indicate that FPRs display substantial heterogeneity across study populations and pooled values from more homogenous subpopulations should be considered when estimating prognosis.ConclusionsThis large meta-analysis presents updated prognostic estimates for CHC derived from newer studies using better diagnostic methods and improves estimates for important patient populations in terms of clinical policy (eg, injection drug users, non-clinical populations, liver clinic patients) and should be a valuable resource for patients, clinicians and clinical policymakers.

Background Equity in health has become an important policy agenda around the world, prompting health economists to advance methods to enable the inclusion of equity in economic evaluations. Among the methods that have been proposed to explicitly include equity are the weighting analysis, equity impact analysis, and equity trade-off analysis. This is a new development and a comprehensive overview of trends and concepts of health equity in economic evaluations is lacking. Thus, our objective is to map the current state of the literature with respect to how health equity is considered in economic evaluations of health interventions reported in the academic and gray literature. Methods We will conduct a scoping review to identify and map evidence on how health equity is considered in economic evaluations of health interventions. We will search relevant electronic, gray literature and key journals. We developed a search strategy using text words and Medical Subject Headings terms related to health equity and economic evaluations of health interventions. Articles retrieved will be uploaded to reference manager software for screening and data extraction. Two reviewers will independently screen the articles based on their titles and abstracts for inclusion, and then will independently screen a full text to ascertain final inclusion. A simple numerical count will be used to quantify the data and a content analysis will be conducted to present the narrative; that is, a thematic summary of the data collected. Discussion The results of this scoping review will provide a comprehensive overview of the current evidence on how health equity is considered in economic evaluations of health interventions and its research gaps. It will also provide key information to decision-makers and policy-makers to understand ways to include health equity into the prioritization of health interventions when aiming for a more equitable distribution of health resources. Systematic review registration This protocol was registered with Open Science Framework (OSF) Registry on August 14, 2019 (https://osf.io/9my2z/registrations).

Background Chronic hepatitis B (CHB) infection poses a significant burden to public health worldwide. Most cases are clinically silent until late in the disease course. The main goal of current therapy is to improve survival and quality of life by preventing disease progression to cirrhosis and liver failure, and consequently hepatocellular carcinoma development. The objective of this review is to provide a contemporary and comprehensive evaluation of the effectiveness of treatment options. Methods We performed a systematic review of peer-reviewed literature for randomized controlled trials involving treatment-naïve CHB adult population who received antiviral therapy. The endpoints were virologic response (VR), normalization of alanine aminotransferase (ALT norm), HBeAg loss, HBeAg seroconversion, and HBsAg loss for the HBeAg-positive population; and VR and ALT norm for the HBeAg-negative population. Network meta-analysis (NMA) was performed to synthesize evidence on the efficacy of treatment. Results Forty-two publications were selected. Twenty-three evaluated HBeAg-positive population, 13 evaluated HBeAg-negative population, and six evaluated both. We applied NMA to the efficacy outcomes of the two populations separately. Treatment strategies were ranked by the probability of achieving outcomes, and pairwise comparisons calculated from NMA were reported in odds ratios (OR). For HBeAg-positive population, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) were the best for VR; OR vs adefovir = 14.29, 95% CI 7.69–25 and 12.5, 95% CI 4.35–33.33 respectively. TAF was the best for achieving ALT norm (OR vs placebo = 12.5, 95% CI 4.55–33.33), HBeAg loss, and seroconversion (OR vs entecavir/TDF combination = 3.03, 95% CI 1.04–8.84 and 3.33, 95% CI 1.16–10 respectively). In the HBeAg-negative population, TDF and TAF were the best for VR (OR vs adefovir = 9.79, 95% CI 2.38–42.7 and 11.71, 95% CI 1.03–150.48 respectively). Telbivudine and TAF were the best for ALT norm. Certain nucleos(t)ide combinations also had high probability of achieving positive outcomes. Conclusions Our results are consonant with current clinical guidelines and other evidence reviews. For both HBeAg-positive and HBeAg-negative populations, TDF and TAF are the most effective agents for virologic suppression, and TAF is effective across all outcomes. Electronic supplementary material The online version of this article (10.1186/s13643-019-1126-1) contains supplementary material, which is available to authorized users.

Background Heart failure (HF) is a complex chronic condition, leading to frequent hospitalization, decreased quality of life, and increased mortality. Current guidelines recommend that multidisciplinary care be provided in specialized HF clinics. A number of studies have demonstrated the effectiveness of these clinics; however, there is a wide range in the services provided across different clinics. This network meta-analysis will aim to identify the aspects of HF clinic care that are associated with the best outcomes: a reduction in mortality, hospitalization, and visits to emergency department (ED) and improvements to quality of life. Methods Relevant electronic databases will be systematically searched to identify eligible studies. Controlled trials and observational cohort studies of adult (≥ 18 years of age) patients will be eligible for inclusion if they evaluate at least one component of guideline-based HF clinic care and report all-cause or HF-related mortality, hospitalizations, or ED visits or health-related quality of life assessed after a minimum follow-up of 30 days. Both controlled trials and observational studies will be included to allow us to compare the efficacy of the interventions in an ideal context versus their effectiveness in the real world. Two reviewers will independently perform both title and abstract full-text screenings and data abstraction. Study quality will be assessed through a modified Cochrane risk of bias tool for randomized controlled trials (RCTs) or the ROBINS-I tool for observational studies. The strength of evidence will be assessed using a modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Network meta-analysis methods will be applied to synthesize the evidence across included studies. To contrast findings between study designs, data from RCTs will be analyzed separately from non-randomized controlled trials and cohort studies. We will estimate both the probability that a particular component of care is the most effective and treatment effects for specified combinations of care. Discussion To our knowledge, this will be the first study to evaluate the comparative effectiveness of the different components of care offered in HF clinics. The findings from this systematic review will provide valuable insight about which components of HF clinic care are associated with improved outcomes, potentially informing clinical guidelines as well as the design of future care interventions in dedicated HF clinics. Systematic review registration PROSPERO CRD42017058003 Electronic supplementary material The online version of this article (10.1186/s13643-019-0953-4) contains supplementary material, which is available to authorized users.

Amy Tawfik,1,2 Joanna M Bielecki,2 Murray Krahn,1,2 Paul Dorian,3,4 Jeffrey S Hoch,1,3,5 Heather Boon,1 Don Husereau,6 Petros Pechlivanoglou2 1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, 2Toronto Health Economics and Technology Assessment (THETA) Collaborative, University of Toronto, 3Centre for Excellence in Economic Analysis Research (CLEAR), Li Ka Shing Knowledge Institute, St Michael’s Hospital, 4Department of Medicine and Cardiology, University of Toronto, 5Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto, ON, 6Institute of Health Economics, Edmonton, AB, Canada Background: In the last 4 years, four novel oral anticoagulants have been developed as alternatives to warfarin and antiplatelet agents for stroke prevention in atrial fibrillation (AF) patients. The objective of this review was to estimate the comparative effectiveness of all antithrombotic treatments for AF patients.Materials and methods: Data sources were Medline Ovid (1946 to October 2015), Embase Ovid (1980 to October 2015), and the Cochrane Central Register of Controlled Trials (­CENTRAL, Issue 9, 2015). Randomized controlled trials of AF patients were selected if they compared at least two of the following: placebo, aspirin, aspirin and clopidogrel combination therapy, adjusted-dose warfarin (target international normalized ratio 2.0–3.0), dabigatran, rivaroxaban, apixaban, and edoxaban. Bayesian network meta-analyses were conducted for outcomes of interest (all stroke, ischemic stroke, myocardial infarction, overall mortality, major bleeding, and intracranial hemorrhage).Results: Based on 16 randomized controlled trials of 96,826 patients, all oral anticoagulants were more effective than antiplatelet agents at reducing the risk of ischemic stroke and all strokes. Compared to warfarin, dabigatran 150 mg (rate ratio 0.65, 95% credible interval 0.52–0.82) and apixaban (rate ratio 0.82, 95% credible interval 0.69–0.97) reduced the risk of all strokes. Dabigatran 150 mg was also more effective than warfarin at reducing ischemic stroke risk (rate ratio 0.76, 95% credible interval 0.59–0.99). Aspirin, apixaban, dabigatran 110 mg, and edoxaban were associated with less major bleeding than warfarin.Conclusion: All oral anticoagulants reduce the risk of stroke in AF patients. Some novel oral anticoagulants are associated with a lower stroke and/or major bleeding risk than warfarin. In addition to the safety and effectiveness of drug therapy, as reported in this study, individual treatment recommendations should also consider the patient’s underlying stroke and bleeding risk profile. Keywords: meta-analysis, cerebrovascular disorders/drug therapy, stroke prevention, platelet-aggregation inhibitors, atrial fibrillation/prevention and control

A systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating the core components of cardiac rehabilitation (CR), nutritional counseling (NC), risk factor modification (RFM), psychosocial management (PM), patient education (PE), and exercise training (ET)) was undertaken. Published RCTs were identified from database inception dates to April 2017, and risk of bias assessed using Cochrane’s tool. Endpoints included mortality (all-cause and cardiovascular (CV)) and morbidity (fatal and non-fatal myocardial infarction (MI), coronary artery bypass surgery (CABG), percutaneous coronary intervention (PCI), and hospitalization (all-cause and CV)). Meta-regression models decomposed treatment effects into the main effects of core components, and two-way or all-way interactions between them. Ultimately, 148 RCTs (50,965 participants) were included. Main effects models were best fitting for mortality (e.g., for all-cause, specifically PM (hazard ratio HR = 0.68, 95% credible interval CrI = 0.54⁻0.85) and ET (HR = 0.75, 95% CrI = 0.60⁻0.92) components effective), MI (e.g., for all-cause, specifically PM (hazard ratio HR = 0.76, 95% credible interval CrI = 0.57⁻0.99), ET (HR = 0.75, 95% CrI = 0.56⁻0.99) and PE (HR = 0.68, 95% CrI = 0.47⁻0.99) components effective) and hospitalization (e.g., all-cause, PM (HR = 0.76, 95% CrI = 0.58⁻0.96) effective). For revascularization (including CABG and PCI individually), the full interaction model was best-fitting. Given that each component, individual or in combination, was associated with mortality and/or morbidity, recommendations for comprehensive CR are warranted.

Background Out-of-hospital cardiac arrest (OHCA) is a significant cause of death in developed countries. The majority of OHCA patients are elderly (≥65 years), and it was documented that they were less likely than younger patients to receive the evidence-based interventions, even though the improvement in survival in the elderly age group was higher than in younger population. Our goal is to investigate any disparity in the provision of post-arrest care for the elderly with OHCA and a sustained return of spontaneous circulation (ROSC). Methods/design Eight relevant, electronic databases will be systematically searched to identify eligible studies. The searches will be supplemented with gray literature searching of theses, dissertations, and hand searching of pertinent journals. Two independent reviewers will screen the titles and abstracts and select studies for full text analysis using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) method, and both will extract information from the selected studies employing a form based on the Data Extraction Template for Cochrane Reviews. A team of three reviewers will assess the quality of the studies with the modified Downs and Black scale. Statistical methods for evidence synthesis, such as meta-analysis and meta-regression, will be applied to compare and combine the evidence regarding the association between age and intervention provision/utilization, adjusting for a number of significant confounders, such as patient characteristics and co-morbidities and availability of intervention techniques, as well as study specific characteristics. The strength of evidence from the selected studies will be assessed using a modified Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Discussion The findings obtained from this systematic review should inform whether disparity exists in the provision of post-arrest care for the elderly (≥ 65 years old) with OHCA or not. Addressing this problem has a potential to substantially increase the number of > 65-year-old, long-term survivors. The results of our review might also point to the gaps in the published literature that specifically examines disparity in provision of care for this population. This systematic review was designed in accordance with the Preferred Reporting Guidelines for Systematic reviews and Meta-analyses (PRISMA statement), while the protocol follows the Preferred Reporting items for Systematic review and Meta-analysis protocols (PRISMA-P) statement. Systematic review registration PROSPERO CRD42015027822 Electronic supplementary material The online version of this article (doi:10.1186/s13643-016-0234-4) contains supplementary material, which is available to authorized users.

Background The concept of early health technology assessment, discussed well over a decade, has now been collaboratively implemented by industry, government, and academia to select and expedite the development of emerging technologies that may address the needs of patients and health systems. Early economic evaluation is essential to assess the value of emerging technologies, but empirical data to inform the current practice of early evaluation is limited. We propose a systematic review of early economic evaluation studies in order to better understand the current practice. Methods/design This protocol describes a systematic review of economic evaluation studies of regulated health technologies in which the evaluation is conducted prior to regulatory approval and when the technology effectiveness is not well established. Included studies must report an economic evaluation, defined as the comparative analysis of alternatives with respect to their associated costs and health consequences, and must evaluate some regulated health technology such as pharmaceuticals, biologics, high-risk medical devices, or biomarkers. We will conduct the literature search on multiple databases, including MEDLINE, EMBASE, the Centre for Reviews and Dissemination Databases, and EconLit. Additional citations will be identified via scanning reference lists and author searching. We suspect that many early economic evaluation studies are unpublished, especially those conducted for internal use only. Additionally, we use a chain-referral sampling approach to identify authors of unpublished studies who work in technology discovery and development, starting out with our contact lists and authors who published relevant studies. Citation screening and full-text review will be conducted by pairs of reviewers. Abstracted data will include those related to the decision context and decision problem of the early evaluation, evaluation methods (e.g., data sources, methods, and assumptions used to identify, measure, and value the likely effectiveness and the costs and consequences of the new technology, handling of uncertainty), and whether the study results adequately address the main study question or objective. Data will be summarized overall and stratified by publication status. Discussion This study is timely to inform early economic evaluation practice, given the international trend in early health technology assessment initiatives.