Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Cannabis-based products for pediatric epilepsy: A systematic review.

OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation.

Scoping reviews, a type of knowledge synthesis, follow a systematic approach to map evidence on a topic and identify main concepts, theories, sources, and knowledge gaps. Although more scoping reviews are being done, their methodological and reporting quality need improvement. This document presents the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist and explanation. The checklist was developed by a 24-member expert panel and 2 research leads following published guidance from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network. The final checklist contains 20 essential reporting items and 2 optional items. The authors provide a rationale and an example of good reporting for each item. The intent of the PRISMA-ScR is to help readers (including researchers, publishers, commissioners, policymakers, health care providers, guideline developers, and patients or consumers) develop a greater understanding of relevant terminology, core concepts, and key items to report for scoping reviews.

Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies: The PRISMA-DTA Statement.

Importance: Systematic reviews of diagnostic test accuracy synthesize data from primary diagnostic studies that have evaluated the accuracy of 1 or more index tests against a reference standard, provide estimates of test performance, allow comparisons of the accuracy of different tests, and facilitate the identification of sources of variability in test accuracy. Objective: To develop the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagnostic test accuracy guideline as a stand-alone extension of the PRISMA statement. Modifications to the PRISMA statement reflect the specific requirements for reporting of systematic reviews and meta-analyses of diagnostic test accuracy studies and the abstracts for these reviews. Design: Established standards from the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network were followed for the development of the guideline. The original PRISMA statement was used as a framework on which to modify and add items. A group of 24 multidisciplinary experts used a systematic review of articles on existing reporting guidelines and methods, a 3-round Delphi process, a consensus meeting, pilot testing, and iterative refinement to develop the PRISMA diagnostic test accuracy guideline. The final version of the PRISMA diagnostic test accuracy guideline checklist was approved by the group. Findings: The systematic review (produced 64 items) and the Delphi process (provided feedback on 7 proposed items; 1 item was later split into 2 items) identified 71 potentially relevant items for consideration. The Delphi process reduced these to 60 items that were discussed at the consensus meeting. Following the meeting, pilot testing and iterative feedback were used to generate the 27-item PRISMA diagnostic test accuracy checklist. To reflect specific or optimal contemporary systematic review methods for diagnostic test accuracy, 8 of the 27 original PRISMA items were left unchanged, 17 were modified, 2 were added, and 2 were omitted. Conclusions and Relevance: The 27-item PRISMA diagnostic test accuracy checklist provides specific guidance for reporting of systematic reviews. The PRISMA diagnostic test accuracy guideline can facilitate the transparent reporting of reviews, and may assist in the evaluation of validity and applicability, enhance replicability of reviews, and make the results from systematic reviews of diagnostic test accuracy studies more useful.

Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis.

BACKGROUND: Serious infections are a major concern for patients considering treatments for rheumatoid arthritis. Evidence is inconsistent as to whether biological drugs are associated with an increased risk of serious infection compared with traditional disease-modifying antirheumatic drugs (DMARDs). We did a systematic review and meta-analysis of serious infections in patients treated with biological drugs compared with those treated with traditional DMARDs. METHODS: We did a systematic literature search with Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from their inception to Feb 11, 2014. Search terms included "biologics", "rheumatoid arthritis" and their synonyms. Trials were eligible for inclusion if they included any of the approved biological drugs and reported serious infections. We assessed the risk of bias with the Cochrane Risk of Bias Tool. We did a Bayesian network meta-analysis of published trials using a binomial likelihood model to assess the risk of serious infections in patients with rheumatoid arthritis who were treated with biological drugs, compared with those treated with traditional DMARDs. The odds ratio (OR) of serious infection was the primary measure of treatment effect and calculated 95% credible intervals using Markov Chain Monte Carlo methods. FINDINGS: The systematic review identified 106 trials that reported serious infections and included patients with rheumatoid arthritis who received biological drugs. Compared with traditional DMARDs, standard-dose biological drugs (OR 1.31, 95% credible interval [CrI] 1.09-1.58) and high-dose biological drugs (1.90, 1.50-2.39) were associated with an increased risk of serious infections, although low-dose biological drugs (0.93, 0.65-1.33) were not. The risk was lower in patients who were methotrexate naive compared with traditional DMARD-experienced or anti-tumour necrosis factor biological drug-experienced patients. The absolute increase in the number of serious infections per 1000 patients treated each year ranged from six for standard-dose biological drugs to 55 for combination biological therapy, compared with traditional DMARDs. INTERPRETATION: Standard-dose and high-dose biological drugs (with or without traditional DMARDs) are associated with an increase in serious infections in rheumatoid arthritis compared with traditional DMARDs, although low-dose biological drugs are not. Clinicians should discuss the balance between benefit and harm with the individual patient before starting biological treatment for rheumatoid arthritis. FUNDING: Rheumatology Division at the University of Alabama at Birmingham.

DEFINING RAPID REVIEWS: A MODIFIED DELPHI CONSENSUS APPROACH.

OBJECTIVES: Rapid reviews are characterized as an accelerated evidence synthesis approach with no universally accepted methodology or definition. This modified Delphi consensus study aimed to develop a comprehensive set of defining characteristics for rapid reviews that may be used as a functional definition. METHODS: Expert panelists with knowledge in rapid reviews and evidence synthesis were identified. In the first round, panelists were asked to answer a seventeen-item survey addressing a variety of rapid review topics. Results led to the development of statements describing the characteristics of rapid reviews that were circulated to experts for agreement in a second survey round and further revised in a third round. Consensus was reached if ≥70 percent of experts agreed and there was stability in free-text comments. RESULTS: A panel of sixty-six experts participated. Consensus was reached on ten of eleven statements describing the characteristics of rapid reviews. According to the panel, rapid reviews aim to meet the requirements and timelines of a decision maker and should be conducted in less time than a systematic review. They use a variety of approaches to accelerate the evidence synthesis process, tailor the methods conventionally used to carry out systematic reviews, and use the most rigorous methods that the delivery time frame will allow. CONCLUSIONS: This study achieved consensus on ten statements describing the defining characteristics of rapid reviews based on the opinion of a panel of knowledgeable experts. Areas of disagreement were also highlighted. Findings emphasize the role of the decision maker and stress the importance of transparent reporting.

Triptans in the Acute Treatment of Migraine: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Although triptans are widely used in the acute management of migraine, there is uncertainty around the comparative efficacy of triptans among each other and vs non-triptan migraine treatments. We conducted systematic reviews and network meta-analyses to compare the relative efficacy of triptans (alone or in combination with other drugs) for acute treatment of migraines compared with other triptan agents, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA), acetaminophen, ergots, opioids, or anti-emetics. METHODS: The Cochrane Library, MEDLINE, and EMBASE were searched for randomized controlled trials that compared triptans (alone or in combination with other drugs) with placebo-controlled or active migraine treatments. Study selection, data extraction, and quality assessment were completed independently by multiple reviewers. Outcome data were combined and analyzed using a Bayesian network meta-analysis. For each outcome, odds ratios, relative risks, and absolute probability of response were calculated. RESULTS: A total of 133 randomized controlled trials met the inclusion criteria. Standard dose triptans relieved headaches within 2 hours in 42 to 76% of patients, and 2-hour sustained freedom from pain was achieved for 18 to 50% of patients. Standard dose triptans provided sustained headache relief at 24 hours in 29 to 50% of patients, and sustained freedom from pain in 18 to 33% of patients. Use of rescue medications ranged from 20 to 34%. For 2-hour headache relief, standard dose triptan achieved better outcomes (42 to 76% response) than ergots (38%); equal or better outcomes than NSAIDs, ASA, and acetaminophen (46 to 52%); and equal or slightly worse outcomes than combination therapy (62 to 80%). Among individual triptans, sumatriptan subcutaneous injection, rizatriptan ODT, zolmitriptan ODT, and eletriptan tablets were associated with the most favorable outcomes. INTERPRETATION/CONCLUSIONS: Triptans are effective for migraine relief. Standard dose triptans are associated with better outcomes than ergots, and most triptans are associated with equal or better outcomes compared with NSAIDs, ASA, and acetaminophen. Use of triptans in combination with ASA or acetaminophen, or using alternative modes of administration such as injectables, may be associated with slightly better outcomes than standard dose triptan tablets.

How can we improve the recognition, reporting and resolution of medical device-related incidents in hospitals? A qualitative study of physicians and registered nurses.

BACKGROUND: To explore factors that influence and to identify initiatives to improve the recognition, reporting and resolution of device-related incidents. METHODS: Semi-structured telephone interviews with 16 health professionals in two tertiary care hospitals were conducted. Purposive sampling was used to identify appropriate study participants. Transcribed interviews were read independently by one individual to identify, define and organize themes and verified by another reviewer. RESULTS: Themes related to incident recognition were the hospital staff's knowledge and professional experience, medical device performance and clinical manifestations of patients, while incident reporting was influenced by error severity, personal attitudes of clinicians, feedback received on the error reported. Physicians often discontinued using medical devices if they malfunctioned. Education and training and the implementation of registries were discussed as important initiatives to improve medical device surveillance in clinical practice. CONCLUSIONS: Results from the telephone interviews suggest that multiple factors that influence participation in medical device surveillance activities are consistent with results for medical errors as reported in previous studies. The study results helped to propose a conceptual framework for a medical device surveillance system in a hospital context that would enhance patient safety and health care delivery.

Patterns of utilization of complementary and alternative medicine in 2 pediatric gastroenterology clinics.

OBJECTIVES: The aim of the present study was to assess the prevalence and patterns of complementary and alternative medicine (CAM) use among pediatric patients with gastrointestinal (GI) disorders at academic clinics in Canada. METHODS: The survey was carried out at 2 hospital-based gastroenterology clinics: the Stollery Children's Hospital in Edmonton and the Children's Hospital of Eastern Ontario (CHEO) in Ottawa. RESULTS: CAM use at the Stollery was 83% compared with 36% at CHEO (P < 0.001). The most common reason for not using CAM was lack of knowledge about it. Most respondents felt comfortable discussing CAM in their clinic and wanted more information on CAM. The most common CAM products being taken were multivitamins (91%), calcium (35%), vitamin C (32%), probiotics (14%), and fish oil/omega-3 fatty acids (13%). The most common CAM practices being used were massage (43%), chiropractic (27%), faith healing (25%), and relaxation (18%). Most respondents believed that CAM was helpful, and most of the 23 reported adverse effects were minor. Seven were reported as moderate, and 3 were reported as severe. Many (42%) patients used CAM at the same time as prescription medicines, and of these patients, concurrent use was discussed with their physician (76%) or pharmacist (52%). CONCLUSIONS: CAM use is high among pediatric patients with GI disorders and is much greater among those in Edmonton than in Ottawa. Most respondents reported their CAM use as helpful, with little or no associated harm. Many patients fail to disclose their concurrent use of CAM and conventional medicines to their doctors, increasing the likelihood of interactions.

Rapid review: an emerging approach to evidence synthesis in health technology assessment.

BACKGROUND: Increasingly, healthcare decision makers demand quality evidence in a short timeframe to support urgent and emergent decisions related to procurement, clinical practice, and policy. Health technology assessment (HTA) producers are responding by developing innovative approaches to evidence synthesis that can be executed more quickly than traditional systematic review. These approaches, and the broader implications they bring to bear on health decision making and policy development, however, are generally neither well-understood nor well-described. This study intends to contribute to an emerging literature around methodological approaches to rapid review in HTA by outlining those developed and implemented by the Canadian Agency for Drugs and Technologies in Health (CADTH). METHODS: Since 2005, CADTH has developed and implemented a rapid review approach that synthesizes evidence to support informed healthcare decisions and policy. Rapid Response reports are tailored to the identified needs of Canadian health decision makers, representing a range of options with regard to depth, breadth, and time-to-delivery. RESULTS: Preliminary observations indicate that CADTH's approach to rapid evidence review is generally well-received by Canadian health decision makers; real-world case studies provide pragmatic examples of how health decision makers have used Rapid Response reports to support evidence-informed health decisions across Canada. CONCLUSIONS: Rapid review is becoming an increasingly important approach to evidence synthesis, both within and external to the field of HTA. Transparent reporting of the methods used to develop rapid review products will be critical to the assessment of their relevance, utility and effects in a range of contexts.

Clinical and safety outcomes associated with treatment of acute venous thromboembolism: a systematic review and meta-analysis.

IMPORTANCE: Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe. OBJECTIVE: To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism. DATA SOURCES: A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014. STUDY SELECTION: Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis. MAIN OUTCOMES AND MEASURES: The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively. RESULTS: Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination. CONCLUSIONS AND RELEVANCE: Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.

Complementary and alternative medicine: A survey of its use in children with chronic respiratory illness.

BACKGROUND: The use of complementary and alternative medicine (CAM) has increased in recent years, with especially high prevalence in individuals with chronic illnesses. In the United States, the prevalence of CAM use in pediatric asthma patients is as high as 89%. OBJECTIVE: To investigate the epidemiology of pediatric CAM use in respiratory subspecialty clinics. METHODS: A survey was conducted at two hospital-based respiratory clinics in Edmonton (Alberta) and Ottawa (Ontario). Caregivers (most often parents) of children <18 years of age were asked questions regarding child and caregiver use of CAM, including products and practices used, beliefs about CAM, trust in information sources about CAM and characteristics of the respondents themselves. RESULTS: A total of 202 survey questionnaires were completed (151 from Edmonton and 51 from Ottawa). Pediatric CAM use in Edmonton was 68% compared with 45% in Ottawa, and was associated with caregiver CAM use, poorer health and health insurance coverage for CAM. The majority (67%) of children using CAM had taken prescription drugs concurrently and 58% of caregivers had discussed this with their doctor. DISCUSSION: Lifetime use of CAM at these pediatric clinics was higher than reported for children who do not have chronic diseases. CAM practices that are popular may be worthy of further research to evaluate their effectiveness and safety profile with regard to drug interactions. Health care providers should be encouraged to discuss CAM use at every visit, and explore their patient's health-related beliefs, behaviours and treatment preferences.

HISTORIQUE: L'utilisation de la médecine complémentaire et parallèle (MCP) a augmenté ces dernières années. Sa prévalence est particulièrement élevée chez les personnes atteintes d'une maladie chronique. Aux États-Unis, sa prévalence chez les patients asthmatiques d'âge pédiatrique atteint les 89 %. OBJECTIF: Examiner l'épidémiologie de l'utilisation de la MCP en pédiatrie dans des cliniques spécialisées en santé respiratoire. MÉTHODOLOGIE: Les chercheurs ont effectué un sondage dans deux cliniques de santé respiratoire en milieu hospitalier, à Edmonton (Alberta) et à Ottawa (Ontario). Les personnes qui s'occupaient d'enfants de 18 ans ou moins (en général, les parents) se sont fait poser des questions sur l'utilisation de la MCP par l'enfant et par elles, y compris les produits et pratiques utilisés, les croyances au sujet de la MCP, la confiance envers les sources d'information sur la MCP et leurs caractéristiques personnelles. RÉSULTATS: Au total, 202 sondages ont été remplis (151 à Edmonton et 51 à Ottawa). L'utilisation de la MCP en pédiatrie à Edmonton s'élevait à 68 %, et à 45 % à Ottawa. Elle s'associait à l'utilisation de MCP par la personne qui s'occupait de l'enfant, à une moins bonne santé et à une couverture d'assurance pour la MCP. La majorité des enfants (67 %) qui utilisaient la MCP prenaient simultanément des médicaments sur ordonnance, et 58 % des personnes qui s'occupaient d'eux en avaient parlé avec leur médecin. EXPOSÉ: À ces cliniques de pédiatrie, l'utilisation générale de MCP était plus élevée que celle déclarée chez les enfants qui n'ont pas de maladie chronique. Les pratiques de MCP qui sont populaires devraient peut-être faire l'objet de recherches supplémentaires pour en évaluer l'efficacité et le profil d'innocuité en matière d'interactions médicamenteuses. Il faut encourager les dispensateurs de soins à parler de MCP à chaque rendez-vous et à explorer les croyances de leurs patients liées à la santé, leurs comportements et leurs préférences thérapeutiques.

Risk of bias in cross-sectional studies: Protocol for a scoping review of concepts and tools.

Cross-sectional studies are commonly used to study human health and disease, but are especially susceptible to bias. This scoping review aims to identify and describe available tools to assess the risk of bias (RoB) in cross-sectional studies and to compile the key bias concepts relevant to cross-sectional studies into an item bank. Using the JBI scoping review methodology, the strategy to locate relevant RoB concepts and tools is a combination of database searches, prospective review of PROSPERO registry records; and consultation with knowledge users and content experts. English language records will be included if they describe tools, checklists, or instruments which describe or permit assessment of RoB for cross-sectional studies. Systematic reviews will be included if they consider eligible RoB tools or use RoB tools for RoB of cross-sectional studies. All records will be independently screened, selected, and extracted by one researcher and checked by a second. An analytic framework will be used to structure the extraction of data. Results for the scoping review are pending. Results from this scoping review will be used to inform future selection of RoB tools and to consider whether development of a new RoB tool for cross-sectional studies is needed.

Outlier analysis for accelerating clinical discovery: An augmented intelligence framework and a systematic review.

Clinical discoveries largely depend on dedicated clinicians and scientists to identify and pursue unique and unusual clinical encounters with patients and communicate these through case reports and case series. This process has remained essentially unchanged throughout the history of modern medicine. However, these traditional methods are inefficient, especially considering the modern-day availability of health-related data and the sophistication of computer processing. Outlier analysis has been used in various fields to uncover unique observations, including fraud detection in finance and quality control in manufacturing. We propose that clinical discovery can be formulated as an outlier problem within an augmented intelligence framework to be implemented on any health-related data. Such an augmented intelligence approach would accelerate the identification and pursuit of clinical discoveries, advancing our medical knowledge and uncovering new therapies and management approaches. We define clinical discoveries as contextual outliers measured through an information-based approach and with a novelty-based root cause. Our augmented intelligence framework has five steps: define a patient population with a desired clinical outcome, build a predictive model, identify outliers through appropriate measures, investigate outliers through domain content experts, and generate scientific hypotheses. Recognizing that the field of obstetrics can particularly benefit from this approach, as it is traditionally neglected in commercial research, we conducted a systematic review to explore how outlier analysis is implemented in obstetric research. We identified two obstetrics-related studies that assessed outliers at an aggregate level for purposes outside of clinical discovery. Our findings indicate that using outlier analysis in clinical research in obstetrics and clinical research, in general, requires further development.

A scoping review shows that no single existing risk of bias assessment tool considers all sources of bias for cross-sectional studies.

OBJECTIVES: Different tools to assess the potential risk of bias (RoB) for cross-sectional studies have been developed, but it is unclear whether all pertinent bias concepts are addressed. We aimed to identify RoB concepts applicable to cross-sectional research validity and to explore coverage for each in existing appraisal tools. STUDY DESIGN AND SETTING: This scoping review followed the Joanna Briggs Institute methodology. We included records of any study design describing or reporting methods, concepts or tools used to consider RoB in health research reported to be descriptive/prevalence survey or analytic/association (cross-sectional) study designs. Synthesis included quantitative and qualitative analysis. RESULTS: Of the 4556 records screened, 90 were selected for inclusion; 67 (74%) described the development of, or validation process for, appraisal tools, 15 (17%) described methodological content or theory relevant to RoB for cross-sectional studies and 8 (9%) records of methodological systematic reviews. Review of methodological reports identified important RoB concepts for both descriptive/prevalence and analytic/association studies. Tools identified (n = 64 unique tools) were either intended to appraise quality or assess RoB in multiple study designs including cross-sectional studies (n = 21; 33%) or cross-sectional designs alone (n = 43; 67%). Several existing tools were modified (n = 17; 27%) for application to cross-sectional studies. The RoB items most frequently addressed in the RoB tools were validity and reliability of the exposure (53%) or outcome (65%) measurement and representativeness of the study population (59%). Most tools did not consider nonresponse or missingness appropriately or at all. CONCLUSION: Assessing cross-sectional studies involve unique RoB considerations. We identified RoB tools designed for broad applicability across various study designs as well as those specifically tailored for cross-sectional studies. However, none of the identified tools comprehensively address all potential biases pertinent to cross-sectional studies. Our findings indicate a need for continued improvement of RoB tools and suggest that the development of context-specific or more precise tools for this study design may be necessary.

Case studies that illustrate disinvestment and resource allocation decision-making processes in health care: a systematic review.

OBJECTIVE: Technological change accounts for approximately 25 percent of health expenditure growth. To date, limited research has been published on case studies of disinvestment and resource allocation decision making in clinical practice. Our research objective is to systematically review and catalogue the application of frameworks and tools for disinvestment and resource allocation decision making in health care. METHODS: An electronic literature search was executed for studies on disinvestment, obsolete and ineffective technologies, and priority healthcare setting, published from January 1990 until January 2012. Databases searched were MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, Embase, The Cochrane Library, PubMed, and HEED. RESULTS: Fourteen case studies on the application of frameworks and tools for disinvestment and resource allocation decisions were included. Most studies described the application of program budgeting and marginal analysis (PBMA), and two reports used health technology assessment (HTA) methods for coverage decisions in a national fee-for-service structure. Numerous healthcare technologies and services were covered across the studies. We describe the multiple criteria considered for decision making, and the strengths and limitations of these frameworks and tools are highlighted. CONCLUSIONS: Disinvestment and resource allocation decisions require evidence to ensure their transparency and objectivity. PBMA was used to assess resource allocation of health services and technologies in a fixed budget jurisdiction, while HTA reviews focused on specific technologies, principally in fee-for-service structures. Future research can review the data requirements and explore opportunities to increase the quantity of available evidence for disinvestment and resource allocation decisions.

Do Case Reports and Case Series Generate Clinical Discoveries About Preeclampsia? A Systematic Review.

Background: Preeclampsia is a leading cause of maternal and perinatal mortality and morbidity. The management of preeclampsia has not changed much in more than two decades, and its aetiology is still not fully understood. Case reports and case series have traditionally been used to communicate new knowledge about existing conditions. Whether this is true for preeclampsia is not known. Objective: To determine whether recent case reports or case series have generated new knowledge and clinical discoveries about preeclampsia. Methods: A detailed search strategy was developed in consultation with a medical librarian. Two bibliographic databases were searched through Ovid: Embase and MEDLINE. We selected case reports or case series published between 2015 and 2020, comprising pregnant persons diagnosed with hypertensive disorders of pregnancy, including preeclampsia. Two reviewers independently screened all publications. One reviewer extracted data from included studies, while another conducted a quality check of extracted data. We developed a codebook to guide our data extraction and outcomes assessment. The quality of each report was determined based on Joanna Briggs Institute (JBI) critical appraisal checklist for case reports and case series. Results: We included 104 case reports and three case series, together comprising 118 pregnancies. A severe presentation or complication of preeclampsia was reported in 81% of pregnancies, and 84% had a positive maternal outcome, free of death or persistent complications. Only 8% of the case reports were deemed to be of high quality, and 53.8% of moderate quality; none of the case series were of high quality. A total of 26 of the 107 publications (24.3%) included a novel clinical discovery as a central theme. Conclusion: Over two-thirds of recent case reports and case series about preeclampsia do not appear to present new knowledge or discoveries about preeclampsia, and most are of low quality.

Augmented Intelligence for Clinical Discovery in Hypertensive Disorders of Pregnancy Using Outlier Analysis.

Objectives Clinical discoveries are heralded by observing unique and unusual clinical cases. The effort of identifying such cases rests on the shoulders of busy clinicians. We assess the feasibility and applicability of an augmented intelligence framework to accelerate the rate of clinical discovery in preeclampsia and hypertensive disorders of pregnancy-an area that has seen little change in its clinical management. Methods We conducted a retrospective exploratory outlier analysis of participants enrolled in the folic acid clinical trial (FACT, N=2,301) and the Ottawa and Kingston birth cohort (OaK, N=8,085). We applied two outlier analysis methods: extreme misclassification contextual outlier and isolation forest point outlier. The extreme misclassification contextual outlier is based on a random forest predictive model for the outcome of preeclampsia in FACT and hypertensive disorder of pregnancy in OaK. We defined outliers in the extreme misclassification approach as mislabelled observations with a confidence level of more than 90%. Within the isolation forest approach, we defined outliers as observations with an average path length z score less or equal to -3, or more or equal to 3. Content experts reviewed the identified outliers and determined if they represented a potential novelty that could conceivably lead to a clinical discovery. Results In the FACT study, we identified 19 outliers using the isolation forest algorithm and 13 outliers using the random forest extreme misclassification approach. We determined that three (15.8%) and 10 (76.9%) were potential novelties, respectively. Out of 8,085 participants in the OaK study, we identified 172 outliers using the isolation forest algorithm and 98 outliers using the random forest extreme misclassification approach; four (2.3%) and 32 (32.7%), respectively, were potential novelties. Overall, the outlier analysis part of the augmented intelligence framework identified a total of 302 outliers. These were subsequently reviewed by content experts, representing the human part of the augmented intelligence framework. The clinical review determined that 49 of the 302 outliers represented potential novelties.  Conclusions Augmented intelligence using extreme misclassification outlier analysis is a feasible and applicable approach for accelerating the rate of clinical discoveries. The use of an extreme misclassification contextual outlier analysis approach has resulted in a higher proportion of potential novelties than using the more traditional point outlier isolation forest approach. This finding was consistent in both the clinical trial and real-world cohort study data. Using augmented intelligence through outlier analysis has the potential to speed up the process of identifying potential clinical discoveries. This approach can be replicated across clinical disciplines and could exist within electronic medical records systems to automatically identify outliers within clinical notes to clinical experts.

The effect of English-language restriction on systematic review-based meta-analyses: a systematic review of empirical studies.

OBJECTIVES: The English language is generally perceived to be the universal language of science. However, the exclusive reliance on English-language studies may not represent all of the evidence. Excluding languages other than English (LOE) may introduce a language bias and lead to erroneous conclusions. STUDY DESIGN AND SETTING: We conducted a comprehensive literature search using bibliographic databases and grey literature sources. Studies were eligible for inclusion if they measured the effect of excluding randomized controlled trials (RCTs) reported in LOE from systematic review-based meta-analyses (SR/MA) for one or more outcomes. RESULTS: None of the included studies found major differences between summary treatment effects in English-language restricted meta-analyses and LOE-inclusive meta-analyses. Findings differed about the methodological and reporting quality of trials reported in LOE. The precision of pooled estimates improved with the inclusion of LOE trials. CONCLUSIONS: Overall, we found no evidence of a systematic bias from the use of language restrictions in systematic review-based meta-analyses in conventional medicine. Further research is needed to determine the impact of language restriction on systematic reviews in particular fields of medicine.

Core Outcome Sets for Medium-Chain Acyl-CoA Dehydrogenase Deficiency and Phenylketonuria.

BACKGROUND: Evidence to guide treatment of pediatric medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency and phenylketonuria (PKU) is fragmented because of large variability in outcome selection and measurement. Our goal was to develop core outcome sets (COSs) for these diseases to facilitate meaningful future evidence generation and enhance the capacity to compare and synthesize findings across studies. METHODS: Parents and/or caregivers, health professionals, and health policy advisors completed a Delphi survey and participated in a consensus workshop to select core outcomes from candidate lists of outcomes for MCAD deficiency and PKU. Delphi participants rated the importance of outcomes on a nine-point scale (1-3: not important, 4-6: important but not critical, 7-9: critical). Candidate outcomes were progressively narrowed down over 3 survey rounds. At the workshop, participants evaluated the remaining candidate outcomes using an adapted nominal technique, open discussion, and voting. After the workshop, we finalized the COSs and recommended measurement instruments for each outcome. RESULTS: There were 85, 61, and 53 participants across 3 Delphi rounds, respectively. The candidate core outcome lists were narrowed down to 20 outcomes per disease to be discussed at the consensus workshop. Voting by 18 workshop participants led to COSs composed of 8 and 9 outcomes for MCAD deficiency and PKU, respectively, with measurement recommendations. CONCLUSIONS: These are the first known pediatric COSs for MCAD deficiency and PKU. Adoption in future studies will help to ensure best use of limited research resources to ultimately improve care for children with these rare diseases.