Paediatric reference intervals and curves for haemoglobin and ferritin: protocol for a systematic review and meta-analysis.

INTRODUCTION: Reference intervals and reference curves provide clinicians with a point of reference when evaluating patients' laboratory test results. In practical applications, the 2.5th and 97.5th percentiles of healthy reference population are typically used as lower and upper reference limits. Guidelines outlining analytical and methodological steps involved in reference intervals and curves estimation are available and there have been large-scale world-wide initiatives to provide reference intervals and curves for children. However, there is a lack of synthesised evidence regarding the results of such initiatives in general, but specifically in iron-related biomarkers, ferritin (in serum and plasma) and haemoglobin. Objectives of this review are to identify studies that have produced reference intervals and curves for ferritin and haemoglobin in paediatric populations and to synthesise all available evidence. We also aim to quantify heterogeneity across reference intervals and curves and identify and elucidate sources of heterogeneity, including heterogeneity in the methods employed in their development. METHODS AND ANALYSIS: Using a comprehensive search strategy, we will identify eligible studies. Following electronic databases will be searched from inception: EMBASE, MEDLINE, SCOPUS and The Cochrane Library. We will also perform grey literature search to capture unpublished reference intervals and curves from healthy cohorts. Two researchers will independently screen retrieved citations against eligibility criteria in two stages, focusing first on titles and abstracts and then on full-text articles. Studies that provide reference intervals and curves for ferritin and haemoglobin for paediatric population will be eligible. Data extraction will include study characteristics, characteristics of reference population, methodological and analytical considerations and estimated reference intervals and curves. We will consider narrative synthesis and quantitative synthesis when appropriate. ETHICS AND DISSEMINATION: Ethical approval is not required as data from already published studies will be used. Results will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023399802.

Establishing normal ranges for fetal and neonatal small and large intestinal lengths: results from a prospective postmortem study.

Objective: To establish reference intervals (RIs) for fetal and neonatal small and large intestinal lengths. Methods: Linear measurements on small and large intestines were made upon postmortem examination of 131 preterm and term infants with gestational ages between 13 and 41 weeks. All cases were referred from the Eastern Ontario and Western Québec regions to a tertiary care hospital. Age and sex partitions were considered and RI limits were estimated. Results: Data consisted of 72 male (54.96%) and 59 female (45.04%) fetuses and neonates with mean gestational age of 25.6 weeks. Results showed that small and large intestinal lengths increased linearly with gestational age. RIs for small intestinal length (cm) of fetuses and neonates aged 13-20 weeks were (21.1, 122.4); of those aged 21-28 weeks were (57.7, 203.8); of those aged 29-36 weeks were (83.6, 337.1); and of those aged 37-41 weeks were (132.8, 406.4). RIs for large intestinal length (cm) of fetuses and neonates from the same four age groups were (5.1, 21.4), (12.7, 39.7), (32.4, 62.4), and (29.1, 82.2). Conclusions: Establishing accurate RIs for premature and term infants has clinical relevance for pathologists performing postmortem analysis and for surgeons planning postoperative management of patients. The results of this study reaffirm that fetal small and large intestinal lengths increase linearly with gestational age irrespective of sex. Future studies should aim to further investigate the role of possible confounders on growth of fetal intestinal length, including maternal factors such as age and substance use during pregnancy.

Evaluating the French version of an online training course for a pediatric pain assessment scale / Évaluation de la version française d'une formation en ligne sur l'appropriation d'une échelle d'évaluation de la douleur pédiatrique

Context: There is no French-language training to educate nurses on the use of the Face, Legs, Activity, Cry, Consolability (FLACC) pain scale, whose scores guide the treatment of pediatric pain. Aims: The aim of this study was to evaluate a French online training program for the FLACC scale offered to Francophone undergraduate nursing students. Methods: Online training was offered to nursing students enrolled in a pediatric nursing course. Participants completed online questionnaires pre- and post-training to assess their perception of their knowledge and confidence, the accuracy of their pain assessment scores, as well as the usefulness and user-friendliness of the training. Results: The FLACC online training improved students' perceived knowledge (p = 0.0004) and confidence (p = 0.0053) in the FLACC pediatric pain scale. Students' accuracy of severe pain assessment scores significantly improved (p = 0.0159) and slightly improved for moderate pain (p = 0.6363). However, accuracy for mild pain assessment was slightly decreased post-training (p = 0.7686). Discussion: An improvement of the quality of videos linked to mild pain, and the quantity of videos for all levels of pain, is required for this study to be replicated among a larger sample. Conclusion: The online training fills the gap in nurses' lack of knowledge about the use of the FLACC pain scale and improves access to quality training in French.

Contexte: Il n'existe aucune formation pour éduquer les infirmières quant à l'utilisation de l'échelle d'évaluation de la douleur pédiatrique Faces-Legs-Activity-Cry-Consolability (FLACC), dont les scores obtenus guident le traitement adéquat de la douleur. Objectif: Cette étude visait à évaluer une formation en ligne portant sur l'échelle FLACC. Méthode: La formation a été offerte aux étudiantes inscrites à un cours de soins infirmiers pédiatriques offert lors de la 3e année du baccalauréat en sciences infirmières. Les participantes ont rempli des questionnaires en ligne avant et après la formation afin d'évaluer leur perception quant à leurs connaissances et leur confiance, l'exactitude de leurs scores d'évaluation de la douleur, ainsi que l'utilité et la fonctionnalité de la formation. Résultats: La formation augmente les connaissances (p = 0,0004) et la confiance (p = 0,0053), selon les participantes. Elle améliore l'exactitude des scores de l'évaluation de la douleur sévère des étudiantes (p = 0,0159) et celle des scores de douleur modérée (p = 0,6363), mais diminue l'exactitude de leurs scores de douleur faible (p = 0,7686). Discussion: La qualité des vidéos reliées à la douleur faible et la quantité des vidéos pour tous les niveaux de douleur devront être améliorées. Conclusion: La formation rehausse l'éducation quant à l'utilisation appropriée de l'échelle FLACC et accroît le nombre de formations de qualité en français.

An improved method for analysis of interrupted time series (ITS) data: accounting for patient heterogeneity using weighted analysis.

Interrupted time series (ITS) design is commonly used to evaluate the impact of interventions in healthcare settings. Segmented regression (SR) is the most commonly used statistical method and has been shown to be useful in practical applications involving ITS designs. Nevertheless, SR is prone to aggregation bias, which leads to imprecision and loss of power to detect clinically meaningful differences. The objective of this article is to present a weighted SR method, where variability across patients within the healthcare facility and across time points is incorporated through weights. We present the methodological framework, provide optimal weights associated with data at each time point and discuss relevant statistical inference. We conduct extensive simulations to evaluate performance of our method and provide comparative analysis with the traditional SR using established performance criteria such as bias, mean square error and statistical power. Illustrations using real data is also provided. In most simulation scenarios considered, the weighted SR method produced estimators that are uniformly more precise and relatively less biased compared to the traditional SR. The weighted approach also associated with higher statistical power in the scenarios considered. The performance difference is much larger for data with high variability across patients within healthcare facilities. The weighted method proposed here allows us to account for the heterogeneity in the patient population, leading to increased accuracy and power across all scenarios. We recommend researchers to carefully design their studies and determine their sample size by incorporating heterogeneity in the patient population.

Anti-vascular endothelial growth factor therapy for age-related macular degeneration: a systematic review and network meta-analysis.

BACKGROUND: The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. METHODS: Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). RESULTS: After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05-0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05-0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06-0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06-0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0-4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0-4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0-4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0-4.67). CONCLUSION: The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42015022041.

Process evaluation of an implementation strategy to support uptake of a tuberculosis treatment adherence intervention to improve TB care and outcomes in Malawi.

OBJECTIVE: To assess implementation and to identify barriers and facilitators to implementation, sustainability and scalability of an implementation strategy to provide lay health workers (LHWs) with the knowledge, skills and tools needed to implement an intervention to support patient tuberculosis (TB) treatment adherence. DESIGN: Mixed-methods design including a cluster randomised controlled trial and process evaluation informed by the RE-AIM framework. SETTING: Forty-five health centres (HCs) in four districts in the south east zone of Malawi, who had an opportunity to receive cascade training. PARTICIPANTS: Forty-five peer-trainers (PTs), 23 patients and 20 LHWs. INTERVENTION: Implementation strategy employing peer-led educational outreach, a clinical support tool and peer support network to implement a TB treatment adherence intervention. OUTCOME MEASURES: Process data were collected from study initiation to the end-of-study PT meeting, and included: LHW and patient interviews, quarterly PT meeting notes, training logs and study team observations and meeting notes. Data sources were first analysed in isolation, followed by method, data source and analyst triangulation. Analyses were conducted independently by two study team members, and themes revised through discussion and involvement of additional study team members as needed. RESULTS: Forty-one HCs (91%) trained at least one LHW. Of 256 LHWs eligible to participate at study start 152 (59%) completed training, with the proportion trained per HC ranging from 0% to 100% at the end of initial cascade training. Lack of training incentives was the primary barrier to implementation, with intrinsic motivation to improve knowledge and skills, and to improve patient care and outcomes the primary facilitators of participation. CONCLUSION: We identified important challenges to and potential facilitators of implementation, scalability and sustainability, of the TB treatment adherence intervention. Findings provide guidance to scale-up, and use of the implementation strategies employed, to address LHW training and supervision in other areas. TRIAL REGISTRATION NUMBER: NCT02533089.

Reference intervals for hemoglobin and mean corpuscular volume in an ethnically diverse community sample of Canadian children 2 to 36 months.

OBJECTIVE: To establish reference intervals for hemoglobin and mean corpuscular volume (MCV) in an ethnically diverse community sample of Canadian children 36 months and younger. METHODS: We collected blood samples from young children at scheduled primary care health supervision visits at 2 weeks, 2, 4, 6, 9, 12, 15, 18, 24, and 36 months of age. Samples were analyzed on the Sysmex XN-9000 Hematology Analyzer. We followed the Clinical and Laboratory Standards Institute guidelines in our analysis. Data were partitioned by sex and also combined. We considered large age partitions (3 and 6 months) as well as monthly partitions. Reference intervals (lower and upper limits) and 90% confidence intervals were calculated. RESULTS: Data from 2106 children were included. The age range was 2 weeks to 36 months, 46% were female, 48% were European and 23% were of mixed ethnicity. For hemoglobin, from 2 to 36 months of age, we found a wide reference interval and the 90% confidence intervals indicated little difference across age groups or according to sex. For MCV, from 2 to 7 months of age there was considerable decrease in the reference interval, which was lowest during the second year of life, followed by a slight increase in the last months of the third year of life. CONCLUSION: These findings suggest adoption of a single hemoglobin reference interval for children 2-36 months of age. Further studies in children under 4 months of age are needed. TRIAL REGISTRATION: TARGet Kids! cohort is registered at ClinicalTrials.gov. www.clinicaltrials.gov . Identifier: NCT01869530 .

Effectiveness of an eHealth self-management tool for older adults with multimorbidity (KeepWell): protocol for a hybrid effectiveness-implementation randomised controlled trial.

INTRODUCTION: In response to the burden of chronic disease among older adults, different chronic disease self-management tools have been created to optimise disease management. However, these seldom consider all aspects of disease management are not usually developed specifically for seniors or created for sustained use and are primarily focused on a single disease. We created an eHealth self-management application called 'KeepWell' that supports seniors with complex care needs in their homes. It incorporates the care for two or more chronic conditions from among the most prevalent high-burden chronic diseases. METHODS AND ANALYSIS: We will evaluate the effectiveness, cost and uptake of KeepWell in a 6-month, pragmatic, hybrid effectiveness-implementation randomised controlled trial. Older adults age ≥65 years with one or more chronic conditions who are English speaking are able to consent and have access to a computer or tablet device, internet and an email address will be eligible. All consenting participants will be randomly assigned to KeepWell or control. The allocation sequence will be determined using a random number generator.Primary outcome is perceived self-efficacy at 6 months. Secondary outcomes include quality of life, health background/status, lifestyle (nutrition, physical activity, caffeine, alcohol, smoking and bladder health), social engagement and connections, eHealth literacy; all collected via a Health Risk Questionnaire embedded within KeepWell (intervention) or a survey platform (control). Implementation outcomes will include reach, effectiveness, adoption, fidelity, implementation cost and sustainability. ETHICS AND DISSEMINATION: Ethics approval has been received from the North York General Hospital Research and Ethics Board. The study is funded by the Canadian Institutes of Health Research and the Ontario Ministry of Health. We will work with our team to develop a dissemination strategy which will include publications, presentations, plain language summaries and an end-of-grant meeting. TRIAL REGISTRATION NUMBER: NCT04437238.

Changes in mammography screening in Ontario and Alberta following national guideline dissemination: an interrupted time series analysis.

Background: In November 2011, the Canadian Task Force on Preventive Health Care released guidelines for screening women at average breast cancer risk. Weak recommendations (framed using GRADE methodology) were made for screening women aged 50 to 74 years every two to three years, and for not screening women aged 40 to 49 years. Methods: We conducted an interrupted time series analysis using administrative data to examine bilateral mammography use before and after a release of a national breast screening guideline. Women aged 40 to 74 years living in Ontario or Alberta from 30th November 2008 to 30th November 2014 were included. Strata included age, region of residence, neighbourhood income quintile, immigration status, and education level. Results: In both provinces, mammography use rates were lower in the post-intervention period (527 vs. 556 and 428 vs. 465/1000 women in Ontario and Alberta, respectively). In Ontario, mammography trends decreased following guideline release to align with recommendations for women aged 40 to 74 (decrease of 2.21/1000 women, SE 0.26/1000, p<0.0001). In Alberta, mammography trends decreased for women aged 40 to 49 years (3/1000 women, SE 0.32, p<0.001) and 50 to 69 (2.9/1000 women, SE 0.79, p<0.001), but did not change for women aged 70 to 74 (0.7/1000 women, SE 1.23, p=0.553). In both provinces, trends in mammography use rates were sustained for up to three years after guideline release. Conclusions: We observed a decrease in screening for women aged 40-49. Additional research to explore whether shared decision making was used to optimize guideline-concordant screening for women aged 50-74 is needed.

Associations between polysomnography measurements and postoperative adverse respiratory events in children with neuromuscular disease.

STUDY OBJECTIVES: To determine if polysomnographic cardiorespiratory outcomes are associated with and could have the potential to predict the presence of postoperative adverse respiratory events in children with neuromuscular disease undergoing any surgical procedure. METHODS: A retrospective cohort study was conducted at a tertiary pediatric institution. The study population included individuals with neuromuscular disease admitted for a surgical intervention under general anesthetic who had undergone a polysomnogram within 1 year before surgical intervention. Polysomnographic indices and postoperative adverse respiratory events were collected through chart review. Multivariable logistic regression was used to model postoperative adverse respiratory events, where PSG results were considered primary predictors. RESULTS: Postoperative adverse respiratory events occurred in 25/61 (41%) of individuals and consisted mainly of desaturations requiring intervention 33 (73%), airway obstruction 15 (33%), and atelectasis (22%). Results from the unadjusted and adjusted logistic regression models indicated that saturation nadir and bulbar dysfunction individually were independent risk factors for postoperative adverse respiratory events with the highest areas under the receiver operating characteristic curve. A multivariable prediction model using these 2 risk factors provided an area under the receiver operating characteristic curve of 0.74 (95% confidence interval, 0.65-0.83). CONCLUSIONS: Knowing that nocturnal oxygen saturation nadir and the presence of bulbar dysfunction are potential predictors of postoperative adverse respiratory events is useful for future counseling of families and surgical planning, in an effort to improve perioperative management and reduce adverse events.

Comparative effectiveness of exercise interventions for preventing falls in older adults: A secondary analysis of a systematic review with network meta-analysis.

BACKGROUND: Systematic reviews have established that exercise reduces falls in older adults, however the most effective types of exercise are not known. This secondary analysis determined the comparative effectiveness of fall prevention exercise approaches. METHOD: All fall prevention exercise interventions for older adults were identified from an existing search from inception until April 2017. Interventions were coded using a framework of 25 exercise types. Two reviewers independently screened studies, extracted data, and appraised risk of bias. Pairwise meta-analysis and network meta-analysis (NMA) were conducted. P-scores were used to rank exercise combinations. RESULTS: One hundred and sixty-nine studies were included. NMA was conducted on 73 studies (30,697 participants) for the outcome of number of fallers. The exercise combination ranked with the greatest likelihood of being most effective relative to no exercise was: anticipatory control, dynamic stability, functional stability limits, reactive control and flexibility (p-score = 0.95). This exercise combination also significantly reduced number of fallers compared to 16 other combinations. No exercise combination had a significantly greater effect on reducing number of fallers more than this combination. CONCLUSION: This analysis identified components of effective fall prevention exercise. The results can inform evidence-informed exercise recommendations and be used to design effective programs.

Impact of a tuberculosis treatment adherence intervention versus usual care on treatment completion rates: results of a pragmatic cluster randomized controlled trial.

BACKGROUND: With the global shortage of skilled health workers estimated at 7.2 million, outpatient tuberculosis (TB) care is commonly task-shifted to lay health workers (LHWs) in many low- and middle-income countries where the shortages are greatest. While shown to improve access to care and some health outcomes including TB treatment outcomes, lack of training and supervision limit the effectiveness of LHW programs. Our objective was to refine and evaluate an intervention designed to address common causes of non-adherence to TB treatment and LHW knowledge and skills training needs. METHODS: We employed a pragmatic cluster randomized controlled trial. Participants included 103 health centres (HCs) providing TB care in four districts in Malawi, randomized 1:1 stratified by district and HC funding (Ministry of Health, non-Ministry funded). At intervention HCs, a TB treatment adherence intervention was implemented using educational outreach, a point-of-care reminder tool, and a peer support network. Clusters in the control arm provided usual care. The primary outcome was the proportion of patients with successful TB treatment (i.e., cure or treatment completion). We used a generalized linear mixed model, with district as a fixed effect and HC as a random effect, to compare proportions of patients with treatment success, among the trial arms, with adjustment for baseline differences. RESULTS: We randomized 51 HCs to the intervention group and 52 HCs to the control group. Four intervention and six control HCs accrued no eligible patients, and 371 of 1169 patients had missing outcome, HC, or demographic data, which left 74 HCs and 798 patients for analysis. Randomization group was not related to missing outcome, however, district, age, and TB type were significantly related and included in the primary analysis model. Among the 1153 patients with HC and demographic data, 297/605 (49%) and 348/548 (64%) in the intervention and control arms, respectively, had treatment success. The intervention had no significant effect on treatment success (adjusted odds ratio 1.35 [95% confidence interval 0.93-1.98]). CONCLUSION: We found no significant effect of the intervention on TB treatment outcomes with high variability in implementation quality, highlighting important challenges to both scale-up and sustainability. TRIAL REGISTRATION: ClinicalTrials.gov NCT02533089 . Registered August 20, 2015.

Spie charts for quantifying treatment effectiveness and safety in multiple outcome network meta-analysis: a proof-of-concept study.

BACKGROUND: Network meta-analysis (NMA) simultaneously synthesises direct and indirect evidence on the relative efficacy and safety of at least three treatments. A decision maker may use the coherent results of an NMA to determine which treatment is best for a given outcome. However, this evidence must be balanced across multiple outcomes. This study aims to provide a framework that permits the objective integration of the comparative effectiveness and safety of treatments across multiple outcomes. METHODS: In the proposed framework, measures of each treatment's performance are plotted on its own pie chart, superimposed on another pie chart representing the performance of a hypothetical treatment that is the best across all outcomes. This creates a spie chart for each treatment, where the coverage area represents the probability a treatment ranks best overall. The angles of each sector may be adjusted to reflect the importance of each outcome to a decision maker. The framework is illustrated using two published NMA datasets comparing dietary oils and fats and psoriasis treatments. Outcome measures are plotted in terms of the surface under the cumulative ranking curve. The use of the spie chart was contrasted with that of the radar plot. RESULTS: In the NMA comparing the effects of dietary oils and fats on four lipid biomarkers, the ease of incorporating the lipids' relative importance on spie charts was demonstrated using coefficients from a published risk prediction model on coronary heart disease. Radar plots produced two sets of areas based on the ordering of the lipids on the axes, while the spie chart only produced one set. In the NMA comparing psoriasis treatments, the areas inside spie charts containing both efficacy and safety outcomes masked critical information on the treatments' comparative safety. Plotting the areas inside spie charts of the efficacy outcomes against measures of the safety outcome facilitated simultaneous comparisons of the treatments' benefits and harms. CONCLUSIONS: The spie chart is more optimal than a radar plot for integrating the comparative effectiveness or safety of a treatment across multiple outcomes. Formal validation in the decision-making context, along with statistical comparisons with other recent approaches are required.

Development and Pilot Evaluation of an Educational Tool for the FLACC Pain Scale.

BACKGROUND: The FLACC (Face, Legs, Activity, Cry, Consolability) pain scale is commonly used for pediatric pain assessment; however, no online educational tool exists to facilitate the use of the scale. AIMS: This study aimed to develop an online educational tool and evaluate its effect on nurse knowledge, user confidence, and scoring accuracy. DESIGN AND METHODS: In phase 1, semistructured interviews were conducted to identify preferred educational features and content. Eight informants were interviewed in phase 1. Recommendations informed the development of the educational tool. Data were analyzed via conventional content analysis. Phase 2 involved a pre-post evaluation of the tool through online surveys. Posteducational data were collected immediately after the tool was completed. Wilcoxon signed rank and McNemar-Bowker tests were used to compare pre- and post-training knowledge, confidence, and FLACC scores. Scoring accuracy was examined using percentage agreement and consensus analysis. RESULTS: Thirty-four nurses participated in phase 2. The educational tool significantly improved knowledge (p < .0001) and increased user confidence, although not to a significant level (p = .06). There was a significant improvement in correct assessment of moderate pain (p = .04). Almost all nurses correctly assessed severe pain before and after education (91%). However, there was a decrease in accurate assessment of mild pain (p = .01). CONCLUSIONS: Because the intervention improved knowledge, user confidence, and assessment accuracy of moderate pain, it would be useful to implement such a tool as part of clinician education. However, further modifications will be needed to improve assessment of mild pain.

MultiCenter Interrupted Time Series Analysis: Incorporating Within and Between-Center Heterogeneity.

BACKGROUND: Segmented regression (SR) is the most common statistical method used in the analysis of interrupted time series (ITS) data. However, this modeling strategy is indicated to produce spurious results when applied to aggregated data. For multicenter ITS studies, data at a given time point are often aggregated across different participants and settings; thus, conventional segmented regression analysis may not be an optimal approach. Our objective is to provide a robust method for analysis of ITS data, while accounting for two sources of heterogeneity, between participants and across sites. METHODS: We present a methodological framework within the segmented regression modeling strategy, where we introduced weights to account for between-participant variation and the differences across multiple sites. We empirically compared the proposed weighted segmented regression (wSR) with the conventional SR as well as with a previously published pooled analysis method using data from the Mobility of Vulnerable Elders in Ontario (MOVE-ON) project, a multisite ITS study. RESULTS: Overall, the wSR produced the most precise estimates, where they had the narrowest 95% CI, while the conventional SR method resulted in the least precise estimates. Our method also resulted in increased power. The pooled analysis method and the wSR had comparable results when there were ≤4 sites included in the overall analysis and when there was moderate to high between-site heterogeneity as measured by the I 2 statistic. CONCLUSION: Incorporating participant-level and site-level variability led to estimates that were more precise and accurate in determining the magnitude of the effect of an intervention and led to increased statistical power. This underscores the importance of accounting for the inherent variability in aggregated data. Extensive simulations are required to further assess the methods in a wide range of scenarios and outcome types.

Methods, Applications and Challenges in the Analysis of Interrupted Time Series Data: A Scoping Review.

OBJECTIVE: Interrupted time series (ITS) designs are robust quasi-experimental designs commonly used to evaluate the impact of interventions and programs implemented in healthcare settings. This scoping review aims to 1) identify and summarize existing methods used in the analysis of ITS studies conducted in health research, 2) elucidate their strengths and limitations, 3) describe their applications in health research and 4) identify any methodological gaps and challenges. DESIGN: Scoping review. DATA SOURCES: Searches were conducted in MEDLINE, JSTOR, PUBMED, EMBASE, CINAHL, Web of Science and the Cochrane Library from inception until September 2017. STUDY SELECTION: Studies in health research involving ITS methods or reporting on the application of ITS designs. DATA EXTRACTION: Screening of studies was completed independently and in duplicate by two reviewers. One reviewer extracted the data from relevant studies in consultations with a second reviewer. Results of the review were presented with respect to methodological and application areas, and data were summarized using descriptive statistics. RESULTS: A total of 1389 articles were included, of which 98.27% (N=1365) were application papers. Segmented linear regression was the most commonly used method (26%, N=360). A small percentage (1.73%, N=24) were methods papers, of which 11 described either the development of novel methods or improvement of existing methods, 7 adapted methods from other areas of statistics, while 6 provided comparative assessment of conventional ITS methods. CONCLUSION: A significantly increasing trend in ITS use over time is observed, where its application in health research almost tripled within the last decade. Several statistical methods are available for analyzing ITS data. Researchers should consider the types of data and validate the required assumptions for the various methods. There is a significant methodological gap in ITS analysis involving aggregated data, where analyses involving such data did not account for heterogeneity across patients and hospital settings.

Variation in lung function and nutritional decline in cystic fibrosis by genotype: An analysis of the Canadian cystic fibrosis registry.

BACKGROUND: This study aimed to improve our understanding of the natural history of cystic fibrosis (CF) by comparing lung function and body mass index z-score (zBMI) between patients with different genotypes and identify a genotype with outcomes most comparable to homozygous ΔF508 patients. METHODS: Data was obtained from the Canadian CF Registry between January 1st 2007-January 1st 2016. Patients were categorized into one of five groups based on their genotype. A mixed-effects model was conducted with adjustments for age, sex, age of diagnosis, and baseline clinical measures. RESULTS: Among 2612 patients, those with non-mild forms of CF, and particularly adult patients with the same functional allele classification were found to have a lung function trajectory comparable to individuals with the homozygous ∆F508 genotype (annual change in percent predicted forced expiratory volume in 1 s of -0.83, 95% CI: -0.93, -0.73). The rates of zBMI change over the study period were not significantly different between the genotype groups. CONCLUSION: This population-based study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. The finding that there are different genotypes with comparable rates of lung function decline to patients of the homozygous ∆F508 group supports the use of multiple comparison groups to assess the long-term efficacy of emerging CF therapies.

Scaling-up implementation in community hospitals: a multisite interrupted time series design of the Mobilization of Vulnerable Elders (MOVE) program in Alberta.

BACKGROUND: As the population ages, older hospitalized patients are at increased risk for hospital-acquired morbidity. The Mobilization of Vulnerable Elders (MOVE) program is an evidence-informed early mobilization intervention that was previously evaluated in Ontario, Canada. The program was effective at improving mobilization rates and decreasing length of stay in academic hospitals. The aim of this study was to scale-up the program and conduct a replication study evaluating the impact of the evidence-informed mobilization intervention on various units in community hospitals within a different Canadian province. METHODS: The MOVE program was tailored to the local context at four community hospitals in Alberta, Canada. The study population was patients aged 65 years and older who were admitted to medicine, surgery, rehabilitation and intensive care units between July 2015 and July 2016. The primary outcome was patient mobilization measured by conducting visual audits twice a week, three times a day. The secondary outcomes included hospital length of stay obtained from hospital administrative data, and perceptions of the intervention assessed through a qualitative assessment. Using an interrupted time series design, the intervention was evaluated over three time periods (pre-intervention, during, and post-intervention). RESULTS: A total of 3601 patients [mean age 80.1 years (SD = 8.4 years)] were included in the overall analysis. There was a significant increase in mobilization at the end of the intervention period compared to pre-intervention, with 6% more patients out of bed (95% confidence interval (CI) 1, 11; p-value = 0.0173). A decreasing trend in median length of stay was observed, where patients on average stayed an estimated 3.59 fewer days (95%CI -15.06, 7.88) during the intervention compared to pre-intervention period. CONCLUSIONS: MOVE is a low-cost, effective and adaptable intervention that improves mobilization in older hospitalized patients. This intervention has been replicated and scaled up across various units and hospital settings.

Empirical evaluation of SUCRA-based treatment ranks in network meta-analysis: quantifying robustness using Cohen's kappa.

OBJECTIVE: To provide a framework for quantifying the robustness of treatment ranks based on Surface Under the Cumulative RAnking curve (SUCRA) in network meta-analysis (NMA) and investigating potential factors associated with lack of robustness. METHODS: We propose the use of Cohen's kappa to quantify the agreement between SUCRA-based treatment ranks estimated through NMA of a complete data set and a subset of it. We illustrate our approach using five published NMA data sets, where robustness was assessed by removing studies one at a time. RESULTS: Overall, SUCRA-based treatment ranks were robust to individual studies in the five data sets we considered. We observed more incidences of disagreement between ranks in the networks with larger numbers of treatments. Most treatments moved only one or two ranks up or down. The lowest quadratic weighted kappa estimate observed across all networks was in the network with the smallest number of treatments (4), where weighted kappa=40%. In the network with the largest number of treatments (12), the lowest observed quadratic weighted kappa=89%, reflecting a small shift in this network's treatment ranks overall. Preliminary observations suggest that a study's size, the number of studies making a treatment comparison, and the agreement of a study's estimated treatment effect(s) with those estimated by other studies making the same comparison(s) may explain the overall robustness of treatment ranks to studies. CONCLUSIONS: Investigating robustness or sensitivity in an NMA may reveal outlying rank changes that are clinically or policy-relevant. Cohen's kappa is a useful measure that permits investigation into study characteristics that may explain varying sensitivity to individual studies. However, this study presents a framework as a proof of concept and further investigation is required to identify potential factors associated with the robustness of treatment ranks using more extensive empirical evaluations.

Can the effects of the mobilization of vulnerable elders in Ontario (MOVE ON) implementation be replicated in new settings: an interrupted time series design.

BACKGROUND: Bed rest for older hospitalized patients places them at risk for hospital-acquired morbidity. We previously evaluated an early mobilization intervention and found it to be effective at improving mobilization rates and decreasing length of stay on internal medicine units. The aim of this study was to conduct a replication study evaluating the impact of the evidence-informed mobilization intervention on surgery, psychiatry, medicine, and cardiology inpatient units. METHODS: A multi-component early mobilization intervention was tailored to the local context at seven hospitals in Ontario, Canada. The primary outcome was patient mobilization measured by conducting visual audits twice a week, three times a day. Secondary outcomes were hospital length of stay and discharge destination, which were obtained from hospital decision support data. The study population was patients aged 65 years and older who were admitted to surgery, psychiatry, medicine, and cardiology inpatient units between March and August 2014. Using an interrupted time series design, the intervention was evaluated over three time periods-pre-intervention, during, and post-intervention. RESULTS: A total of 3098 patients [mean age 78.46 years (SD 8.38)] were included in the overall analysis. There was a significant increase in mobility immediately after the intervention period compared to pre-intervention with a slope change of 1.91 (95% confidence interval [CI] 0.74-3.08, P-value = 0.0014). A decreasing trend in median length of stay was observed in the majority of the participating sites. Overall, a median length of stay of 26.24 days (95% CI 23.67-28.80) was observed pre-intervention compared to 23.81 days (95% CI 20.13-27.49) during the intervention and 24.69 days (95% CI 22.43-26.95) post-intervention. The overall decrease in median length of stay was associated with the increase in mobility across the sites. CONCLUSIONS: MOVE increased mobilization and these results were replicated across surgery, psychiatry, medicine, and cardiology inpatient units.