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1.
Stat Methods Med Res ; : 962280220986193, 2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33509042

RESUMO

Data collected longitudinally as part of usual health care is becoming increasingly available for research, and is often available across several centres. Because the frequency of follow-up is typically determined by the patient's health, the timing of measurements may be related to the outcome of interest. Failure to account for the informative nature of the observation process can result in biased inferences. While methods for accounting for the association between observation frequency and outcome are available, they do not currently account for clustering within centres. We formulate a semi-parametric joint model to include random effects for centres as well as subjects. We also show how inverse-intensity weighted GEEs can be adapted to account for clustering, comparing stratification, frailty models, and covariate adjustment to account for clustering in the observation process. The finite-sample performance of the proposed methods is evaluated through simulation and the methods illustrated using a study of the relationship between outdoor play and air quality in children aged 2-9 living in the Greater Toronto Area.

2.
Trials ; 22(1): 15, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407719

RESUMO

BACKGROUND: Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis. METHODS/DESIGN: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms. DISCUSSION: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019.

3.
Clin Trials ; : 1740774520965173, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33231105

RESUMO

BACKGROUND/AIMS: Combinations of treatments that have already received regulatory approval can offer additional benefit over Each of the treatments individually. However, trials of these combinations are lower priority than those that develop novel therapies, which can restrict funding, timelines and patient availability. This article develops a novel trial design to facilitate the evaluation of New combination therapies. This trial design combines elements of phase II and phase III trials to reduce the burden of evaluating combination therapies, while also maintaining a feasible sample size. This design was developed for a randomised trial that compares the properties of three combination doses of ketamine and dexmedetomidine, given intranasally, to ketamine delivered intravenously for children undergoing a closed reduction for a fracture or dislocation. METHODS: This trial design uses response-adaptive randomisation to evaluate different dose combinations and increase the information collected for successful novel drug combinations. The design then uses Bayesian dose-response modelling to undertake a comparative effectiveness analysis for the most successful dose combination against a relevant comparator. We used simulation methods determine the thresholds for adapting the trial and making conclusions. We also used simulations to evaluate the probability of selecting the dose combination with the highest true effectiveness the operating characteristics of the design and its Bayesian predictive power. RESULTS: With 410 participants, five interim updates of the randomisation ratio and a probability of effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have an 83% chance of randomising the largest number of patients to the drug with the highest probability of effectiveness. Based on this adaptive randomisation procedure, the comparative effectiveness analysis has a type I error of less than 5% and a 93% chance of correcting concluding non-inferiority, when the probability of effectiveness for the optimal combination therapy is 0.9. In this case, the trial has a greater than 77% chance of meeting its dual aims of dose-finding and comparative effectiveness. Finally, the Bayesian predictive power of the trial is over 90%. CONCLUSIONS: By simultaneously determining the optimal dose and collecting data on the relative effectiveness of an intervention, we can minimise administrative burden and recruitment time for a trial. This will minimise the time required to get effective, safe combination therapies to patients quickly. The proposed trial has high potential to meet the dual study objectives within a feasible overall sample size.

4.
BMC Pediatr ; 20(1): 488, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087096

RESUMO

BACKGROUND: There is no globally accepted definition for dosing error in adult or pediatric practice. The definition of pediatric dosing error varies greatly in the literature. The objective of this study was to develop a framework, informed by a set of principles, for a clinician-based definition of drug dosing errors in critically ill children, and to identify the range that practitioners agree is a dosing error for different drug classes and clinical scenarios. METHODS: We conducted a nationwide three staged modified Delphi from May to December 2019. Expert clinicians included Canadian pediatric intensive care unit (PICU) physicians, pharmacists and nurses, with a least 5 years' experience. Outcomes were underlying principles of drug dosing, and error thresholds, as defined by proportion above and below reference range, for common PICU medications and clinical scenarios. RESULTS: Forty-four participants met eligibility, and response rates were 95, 86 and 84% for all three rounds respectively. Consensus was achieved for 13 of 15 principles, and 23 of 30 error thresholds. An over-dosed drug that is intercepted, an under-dose of a possibly life-saving medication, dosing 50% above or below target range and not adjusting for a drug interaction were agreed principles of dosing error. Altough there remained much uncertainty in defining dosing error, expert clinicians agreed that, for most medication categories and clinical scenarios, dosing over or below 10% of reference range was considered an error threshold. CONCLUSION: Dosing principles and threshold are complex in pediatric critical care, and expert clinicians were uncertain about whether many scenarios were considered in error. For most intermittent medications, dosing over 10% below or above reference range was considered a dosing error, although this was largely influenced by clinical context and drug properties. This consensus driven error threshold will help guide routine clinical dosing practice, standardized reporting and drug quality improvement in pediatric critical care.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33006611

RESUMO

OBJECTIVE: Infection is a leading cause of death in the SLE population. Low immunoglobulin levels might be a potential risk for infection. We aimed to assess whether acquired low levels of any type of immunoglobulin increase the risk of clinically relevant infection in adult patients with SLE. METHODS: We compared adult SLE patients who had acquired any low immunoglobulin levels (IgA, IgM or IgG) for 2 years with patients with normal or high levels with respect to clinically relevant infection (defined as infections requiring intravenous or oral antibiotics) in a prospective cohort study. Group balance was achieved using propensity score adjustment, matching and inverse probability weighting. Primary analysis was time to event using Cox-regression modelling adjusting for potential confounders. Sensitivity analyses were conducted to examine several exposure and outcome definitions. RESULTS: Patients with hypogammaglobulinaemia had longer disease duration, more lupus nephritis history, higher proteinuria and more accumulated damage. Low IgA level was associated with increased risk of clinically relevant infection [hazard ratio (HR): 2.24, 95% CI: 1.61, 3.12] while low IgG (HR: 1.15, 95% CI: 0.84, 1.59) or low IgM (HR: 0.95, 95% CI: 0.73, 1.23) was not. Low immunoglobulin recovery in the first year was 2.5% (11), second year 8.2% (36), third year 10.1% (44) and fourth year 18.4% (80), and 60% (263) of acquired hypogammaglobulinaemia recovered over 4 years. CONCLUSION: The majority of acquired hypogammaglobulinaemia in adult patients with SLE is transient. Only low acquired IgA was associated with increased risk of infection among adult patients with SLE. Whether immunoglobulin replacement provides additional protective effect requires further investigation.

6.
J Rheumatol ; 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32739897

RESUMO

OBJECTIVE: To evaluate the feasibility of studying creatine in juvenile dermatomyositis (JDM). Secondary objectives were to determine the effect of creatine on muscle function and metabolism, aerobic capacity, fatigue, physical activity and quality of life, as well as its safety. METHODS: We conducted a 6-month double-blind, randomized, multiple-baseline design; patients were assigned to creatine or placebo. Feasibility was assessed using attended study visits, completed study procedures, and adherence. Muscle function, aerobic capacity and muscle strength were assessed with standardized exercise tests. Muscle metabolism was assessed using a 31-Phosphorus Magnetic Resonance Spectroscopy protocol. Fatigue, physical activity and quality of life were assessed by questionnaires. Statistical significance was estimated using a randomization (permutation) test. Changes in outcome measures taken at baseline and end-of-study were calculated using paired t tests. RESULTS: Median (range) adherence to the study drug was 88.5% (20.5-95.5%) and the proportion of subjects with 80% adherence or higher was 76.9%. There were no missed study visits. There were no statistically significant changes in muscle function, strength, aerobic capacity, disease activity, fatigue, physical activity or quality of life while subjects were on creatine compared to placebo. There were statistically significant adaptations in muscle metabolism (e.g., decrease in change in muscle pH following exercise, and decrease in Phosphate/Phosphocreatine ratio) at the end-of-study, compared to baseline. There were no significant adverse effects. CONCLUSION: Creatine supplementation in children with JDM is feasible to study, and is safe and well-tolerated; it may lead to improvements in muscle metabolism.

7.
Br J Psychiatry ; : 1-8, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641181

RESUMO

BACKGROUND: Children with autism spectrum disorder (ASD) have increased susceptibility to anxiety disorders. Variation in a common ASD symptom, insistence on sameness behaviour, may predict future anxiety symptoms. AIMS: To describe the joint heterogeneous longitudinal trajectories of insistence on sameness and anxiety in children with ASD and to characterise subgroups at higher risk for anxiety. METHOD: In a longitudinal ASD cohort (n = 421), insistence on sameness behaviour was measured using the Autism Diagnostic Interview-Revised at approximately ages 3, 6 and 11 years. Anxiety was quantified at 8 time points between ages 3 and 11 years using the Child Behavior Checklist (CBCL) (parent report). Clusters of participants following similar trajectories were identified using group-based and joint trajectory modelling. RESULTS: Three insistence on sameness trajectories were identified: (a) 'low-stable' (41.7% of participants), (b) 'moderate-increasing' (52.0%) and (c) 'high-peaking' (i.e. increasing then stabilising/decreasing behaviour) (6.3%). Four anxiety trajectories were identified: (a) 'low-increasing' (51.0%), (b) 'moderate-decreasing' (16.2%), (c) 'moderate-increasing' (19.6%) and (d) 'high-stable' (13.1%). Of those assigned to the 'high-peaking' insistence on sameness trajectory, 95% jointly followed an anxiety trajectory that surpassed the threshold for clinical concern (T-score >65) by middle childhood (anxiety trajectories 3 or 4). Insistence on sameness and anxiety trajectories were similar in severity and direction for 64% of the sample; for 36%, incongruous patterns were seen (e.g. decreasing anxiety and increasing insistence on sameness). CONCLUSIONS: The concurrent assessment of insistence on sameness behaviour and anxiety in ASD may help in understanding current symptom profiles and anticipating future trajectories. High preschool insistence on sameness in particular may be associated with elevated current or future anxiety symptoms.

8.
J Rheumatol ; 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32611674

RESUMO

Observational studies allow researchers to understand the natural history of rheumatic conditions, risk factors for disease development, and factors affecting important disease-related outcomes, and to estimate treatment effect from real-world data. However, this design carries a risk of confounding bias. A propensity score (PS) is a balancing score that aims to minimize the difference between study groups and consequently potential confounding effects. The score can be applied in 1 of 4 methods in observational research: matching, stratification, adjustment, and inverse probability weighting. Systemic lupus erythematosus (SLE) is a rare disease characterized by a relatively small sample size and/or low event rates. In this article, we review the PS methods. We demonstrate application of the PS methods to achieve study group balance in a rare disease using an example of risk of infection in SLE patients with hypogammaglobulinemia.

9.
Stat Med ; 39(23): 3074-3104, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32706130

RESUMO

The EQ-5D, a widely used multiattribute utility instrument, is commonly used in health economic evaluations where the goal is to decide on which treatments to reimburse. Like other instruments, value sets of the EQ-5D are constructed using valuation studies typically valuing a subset of the health states and using predicted values from a regression model for the unvalued health states. In current practice the prediction errors associated with the value sets are substantial. The goal of this work is 2-fold. First, derive a formula of the mean squared error (MSE) of a value set assuming that the value set is estimated using a linear mixed model with either an independent or a Gaussian spatial correlation on the model misspecification error. Second, explore the effect of the number of health states directly valued, the number of participants and the correlation structure on the MSE. Keeping the total number of participants and the total number of valuations fixed, valuing all 242 health states of the EQ-5D-3L was found to reduce the MSE considerably compared with the common practice of valuing only 42 health states. Furthermore, an independent correlation structure with 3773 participants valuing 42 health states produced the MSE that can be achieved with less than 600 participants valuing all 242 health states under a Gaussian spatial correlation structure. Based on the comparison of the MSE values of some of the well-known designs our suggestion is to value more health states and to use a model with spatially correlated misspecification errors.

10.
JAMA Surg ; 155(9): e201985, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697298

RESUMO

Importance: Results of previous studies are mixed regarding the economic implications of a Roux-en-Y gastric bypass (RYGB). Objective: To assess the 5-year incremental health care use and expenditures after RYGB. Design, Setting, and Participants: This population-based cohort study conducted in Ontario, Canada, used a difference-in-differences approach to compare health care use and expenditures between patients who underwent a publicly funded RYGB from March 1, 2010, to March 31, 2013, and propensity score-matched control individuals who did not undergo a surgical bariatric procedure. The study period allowed for a minimum 60 months of follow-up because, at that time, the most recent date for which administrative data on health care and expenditures were available was March 31, 2018. Data sources included the Ontario Bariatric Registry linked to several Ontario health administrative databases and the Electronic Medical Record Administrative Data Linked Database. Health care use and expenditures data for 5 years before and 5 years after the index date (procedure date for RYGB group; random date for controls) were analyzed. Data analyses were performed March 12, 2019, to March 10, 2020. Intervention: RYGB procedure. Main Outcomes and Measures: The primary outcome was total health care expenditures. Results: The final propensity score-matched cohorts comprised 1587 individuals in the RYGB group (mean [SD] age, 47 [10.2] years) and 1587 controls (mean [SD] age, 47 [12.2] years); each group had 1228 women (77.4%) and a mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 46. Mean total health care expenditures (2017 Canadian dollars) per patient in the RYGB group increased from CAD $15 594 (95% CI, CAD $14 743 to CAD $16 614) (US $12 008 [95% CI, US $11 353 to US $12 794]) in the 5 years before the procedure to CAD $30 389 (95% CI, CAD $28 789 to CAD $32 232) (US $23 401 [95% CI, US $22 169 to US $24 821]) over the 5 years after the procedure, a difference of CAD $14 795 (95% CI, CAD $13 172 to CAD $16 480) (US $11 393 [95% CI, US $10 143 to US $12 691]). For the control group, mean total health care expenditures per individual increased from CAD $16 109 (95% CI, CAD $14 727 to CAD $17 591) (US $12 405 [95% CI, US $11 341 to US $13 546]) 5 years before the index date to CAD $20 073 (95% CI, CAD $18 147 to CAD $22 169) (US $15 457 [95% CI, US $13 974 to US $17 071]) 5 years after the date, a difference of CAD $3964 (95% CI, CAD $2250 to CAD $5875) (US $3053 [95% CI, US $1733 to US $4524]). Overall, the difference-in-differences estimate of the net cost of RYGB was CAD $10 831 (95% CI, CAD $8252 to CAD $13 283) (US $8341 [95% CI, $6355 to $10 229]) over the 5-year period. This amount excluded the mean (SD) cost associated with the index date: CAD $6501 (CAD $1087) (US $5006 [US $837]) for the RYGB cohort and CAD $9 (CAD $72) (US $7 [US $55]) for the controls. The cost differential was primarily associated with increased hospitalizations in the first months immediately after RYGB. Expenditures leveled off in year 3 after the index date; differences in total expenditures between the RYGB and control cohorts were not statistically significantly different in years 4 and 5. Conclusions and Relevance: Health care expenditures in the 3 years after publicly funded RYGB were higher in patients who underwent the procedure than in control individuals, but the costs were similar thereafter. This finding suggests the need to decrease hospital and emergency department readmissions after surgical bariatric procedures because such use is associated with increased spending.

11.
Med Decis Making ; 40(4): 483-497, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32517541

RESUMO

Introduction. The EQ-5D-5L valuation protocol contains both time tradeoff (TTO) tasks and discrete choice experiments (DCE), raising the question of how to best use these in creating a value set. The hybrid model, which combines TTO and DCE data, has emerged as a commonly used approach. However, this model assumes independence among responses from the same individual, a linear relationship between TTO and DCE utilities, and, in many implementations, homoscedastic residuals. The aims of this study are to examine alternatives to these assumptions and determine the impact of misspecification on value sets. Methods. We performed a simulation study, parameterized using the US EQ-5D-5L valuation study, to assess the impact of model misspecification. We simulated TTO and DCE data with nonlinear relationships between TTO and DCE utilities, heteroscedastic errors, and correlated responses. Simulated data were analyzed using hybrid models with and without heteroscedasticity, Tobit models with and without heteroscedasticity, a latent class model, and a mixed model. Results. Mean absolute errors (MAEs) for correctly specified models were <0.05, whereas models that incorrectly assumed a linear relationship between TTO and DCE utilities or homoscedasticity of TTO responses featured states with an MAE >0.1. When a linear relationship between TTO and DCE utilities held, using both TTO and DCE data under correct specification yielded smaller MAEs compared with using TTO data alone but yielded larger MAEs when a linear relationship did not hold. Mistakenly assuming homoscedasticity led to increased MAEs, whereas ignoring dependence did not. Conclusions. Because heteroscedasticity in TTO utilities and nonlinear associations between DCE and TTO utilities have been noted, we recommend careful assessment of scedasticity and linearity to ascertain the suitability of a hybrid model.

12.
Med Decis Making ; 40(3): 339-347, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32428427

RESUMO

Background. Scoring algorithms of multi-attribute utility instruments (MAUI) are developed in valuation studies and are hence estimated subject to uncertainty. Valuation studies need to be designed to achieve reasonable accuracy. We aim to provide the first closed-form mathematical formula for the mean square error (MSE) of an additive MAUI as a function of sample size that acknowledges that the MAUI model for the mean utility is not a perfect fit. Methods. Based on the design of the EQ-5D valuation study, we derived our closed-form formula in terms of sample size and number of directly valued health states overall and per subject. We validated our formula by conducting a simulation study using the US EQ-5D-3L valuation data set and examined the effect of using a random-effects versus an ordinary least-squares model and the effect of heteroscedasticity. We explored the effect of sample size and number of valued health states. Results. The simulation study validated our MSE-based closed-form formula regardless of whether assuming a random-effects model versus an ordinary least squares model or heteroscedasticity versus homoscedasticity. As the sample size approaches infinity, the MSE does not approach zero but levels off asymptotically. The improvement based on increasing sample is more prominent when the sample is small. When the sample size is greater than 300 to 500, further increases do not meaningfully improve the MSE, while increasing the number of health states can further improve the MSE. Conclusion. We have derived a closed-form formula to calculate the MSE of an additive MAUI scoring algorithm based on sample size and number of health states, which will enable the developers of MAUI valuation studies to calculate the required sample size for their desired predictive precision.

13.
BMC Med Res Methodol ; 20(1): 135, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471357

RESUMO

BACKGROUND: Observational longitudinal data often feature irregular, informative visit times. We propose descriptive measures to quantify the extent of irregularity to select an appropriate analytic outcome approach. METHODS: We divided the study period into bins and calculated the mean proportions of individuals with 0, 1, and > 1 visits per bin. Perfect repeated measures features everyone with 1 visit per bin. Missingness leads to individuals with 0 visits per bin while irregularity leads to individuals with > 1 visit per bin. We applied these methods to: 1) the TARGet Kids! study, which invites participation at ages 2, 4, 6, 9, 12, 15, 18, 24 months, and 2) the childhood-onset Systemic Lupus Erythematosus (cSLE) study which recommended at least 1 visit every 6 months. RESULTS: The mean proportions of 0 and > 1 visits per bin were above 0.67 and below 0.03 respectively in the TARGet Kids! study, suggesting repeated measures with missingness. For the cSLE study, bin widths of 6 months yielded mean proportions of 1 and > 1 visits per bin of 0.39, suggesting irregular visits. CONCLUSIONS: Our methods describe the extent of irregularity and help distinguish between protocol-driven visits and irregular visits. This is an important step in choosing an analytic strategy for the outcome.

14.
Contemp Clin Trials Commun ; 18: 100561, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32300671

RESUMO

Background/Aims: Non-inferiority trials investigate whether a novel intervention, which typically has other benefits (i.e., cheaper or safer), has similar clinical effectiveness to currently available treatments. In situations where interim evidence in a non-inferiority trial suggests that the novel treatment is truly inferior, ethical concerns with continuing randomisation to the "inferior" intervention are raised. Thus, if interim data indicate that concluding non-inferiority at the end of the trial is unlikely, stopping for futility should be considered. To date, limited examples are available to guide the development of stopping rules for non-inferiority trials. Methods: We used a Bayesian predictive power approach to develop a stopping rule for futility for a trial collecting binary outcomes. We evaluated the frequentist operating characteristics of the stopping rule to ensure control of the Type I and Type II error. Our case study is the Intranasal Ketamine for Procedural Sedation trial (INK trial), a non-inferiority trial designed to assess the sedative properties of ketamine administered using two alternative routes. Results: We considered implementing our stopping rule after the INK trial enrols 140 patients out of 560. The trial would be stopped if 12 more patients experience a failure on the novel treatment compared to standard care. This trial has a type I error rate of 2.2% and a power of 80%. Conclusions: Stopping for futility in non-inferiority trials reduces exposure to ineffective treatments and preserves resources for alternative research questions. Futility stopping rules based on Bayesian predictive power are easy to implement and align with trial aims. Trial registration: ClinicalTrials.gov NCT02828566 July 11, 2016.

15.
Res Pract Thromb Haemost ; 4(2): 318-325, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32110763

RESUMO

Background: Standard of care for persons with severe hemophilia A includes regular replacement of factor VIII (FVIII). Prophylaxis regimens using standard half-life (SHL) FVIII concentrates, while effective, are costly and require frequent intravenous infusions. Aim: This study evaluated the adherence of 56 boys with severe hemophilia A to tailored, frequency-escalated prophylaxis with an SHL recombinant FVIII concentrate. Methods: We reviewed the factor infusion and bleeding logs of study subjects. Adherence to the prescribed regimen was calculated on a weekly basis, and bleeding rates were determined from self/proxy-reported bleeding logs. The primary outcome was adherence to the prescribed prophylaxis regimen. Results: The median (range of values [ROV]) weekly adherence to prophylaxis was 85.7% (37.4%-99.8%). The median (ROV) adherent weeks on steps 1 (weekly), 2 (twice weekly), and 3 (alternate-day) were 92.9% (50%-100%), 80.3 (32%-96%), and 72.6% (14%-98%); relative to step 1, subjects were less likely to be adherent on steps 2 and 3 (P < 0.00). On step 1, our cohort had higher adherence than previously reported rates. The median (ROV) adherence to the breakthrough bleeding protocol was 47.1% (0%-100%). At any given time, bleeding risk was reduced by 15% for each 10% increase in adherence during the preceding 12 weeks (hazard ratio, 0.85; 95% confidence interval, 0.81-0.90). Conclusion: This cohort had high rates of adherence to the prescribed prophylaxis regimen. Initiating prophylaxis with once-weekly infusions facilitated adherence to the prophylaxis regimen in this cohort of boys with severe hemophilia A started on primary prophylaxis at a very young age.

16.
Stat Methods Med Res ; 29(9): 2507-2519, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31994451

RESUMO

Constructing causal inference methods to handle longitudinal data in observational studies is of high interest. In an observational setting, treatment assignment at each clinical visit follows a decision strategy where the treating clinician selects treatment based on current and past clinical measurements as well as treatment histories. These time-dependent structures, coupled with inherent correlations between and within each visit, add on to the data complexity. Despite recent interest in Bayesian causal methods, only a limited literature has explored approaches to handle longitudinal data and no method handles repeatedly measured outcomes. In this paper, we extended two Bayesian approaches: Bayesian estimation of marginal structural models and two-stage Bayesian propensity score analysis to handle a repeatedly measured outcome. Our proposed methods permit causal estimation of treatment effects at each visit. Time-dependent inverse probability of treatment weights are obtained from the Markov chain Monte Carlo samples of the posterior treatment assignment model for each follow-up visit. We use a simulation study to validate and compare the proposed methods and illustrate our approaches through a study of intravenous immunoglobulin therapy in treating newly diagnosed juvenile dermatomyositis.

17.
JPEN J Parenter Enteral Nutr ; 44(3): 507-515, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31267545

RESUMO

BACKGROUND: Accurate measurement of energy expenditure is not widely available. Patient and clinical factors associated with energy expenditure have been poorly explored, leading to errors in estimation formulae. The objective of this study was to determine clinical factors associated with measured energy expenditure (MEE), expressed in kcal/kg/d, in critically ill children. METHODS: This was a retrospective study at 2 Canadian pediatric intensive care units (ICUs). Patients were mechanically ventilated children who had 1 or more MEE using indirect calorimetry. Associations between MEE and 28 clinical factors were evaluated in univariate regression and 16 factors in a multivariate regression model accounting for repeated measurements. RESULTS: Data from 239 patients (279 measurements) were analyzed. Median (Q1, Q3) MEE was 34.8 (26.8, 46.2) kcal/kg/d. MEE was significantly associated with weight, heart rate, diastolic blood pressure, ICU day of indirect calorimetry (P = 0.004), minute ventilation, vasoactive inotropic score (P = 0.004), opioids, chloral hydrate, dexmedetomidine, inhaled salbutamol (P = 0.02), and propofol dose (all P < 0.0001 unless otherwise specified) in the final multivariate regression model. CONCLUSIONS: This study demonstrated association between MEE (kcal/kg/d) and factors not previously explored in pediatric critical illness. Further evaluation of these factors to confirm associations and more precisely quantify the magnitude of effect is required to support refinement of formulae to estimate energy expenditure.

18.
J Am Acad Child Adolesc Psychiatry ; 59(7): 890-899.e3, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31541676

RESUMO

OBJECTIVE: A significant proportion of children with autism spectrum disorder (ASD) will develop an anxiety disorder during childhood. Restricted and repetitive behavior severity in ASD positively correlates with anxiety severity in cross-sectional surveys. The longitudinal relationship between restricted/repetitive behavior and future anxiety symptoms is unclear. METHOD: In a longitudinal cohort of children with ASD (n = 421), restricted/repetitive behavior severity at enrollment (age 2-5 years) was categorized as "mild," "moderate," or "severe" using the Autism Diagnostic Interview-Revised. Elevated anxiety symptoms were defined by a Child Behavior Checklist (parent report) Anxiety subscale T-score of >65 at ages 8 to 11 years. Multivariable logistic regression with multiple imputation for missing data was used to examine the association between restricted/repetitive behavior severity and elevated anxiety symptoms while adjusting for age, sex, adaptive functioning, baseline anxiety, income, and parenting stress, generating adjusted odds ratios (aORs) and 95% CIs. RESULTS: Approximately 58% of children with severe restricted/repetitive behavior at enrollment had elevated anxiety symptoms by age 11, compared to 41% of those with moderate, and 20% of those with mild restricted/repetitive behavior, respectively. Moderate and severe restricted/repetitive behavior were both associated with increased odds of elevated anxiety (moderate aOR: 2.5 [1.2-5.3]; severe aOR: 3.2 (1.4-7.5]). CONCLUSION: Restricted/repetitive behavior severity at time of ASD diagnosis indicates risk for future anxiety symptoms. This finding increases our understanding of which children with ASD will develop anxiety disorders and may guide research concerning early interventions and etiological mechanisms.

19.
J Oncol Pharm Pract ; 26(2): 379-385, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31156051

RESUMO

OBJECTIVES: We evaluated adherence of human epidermal growth factor receptor-2 testing using immunohistochemistry and fluorescence in situ hybridization, as well as adjuvant trastuzumab treatment according to Canadian guidelines, and predictors of trastuzumab use in early-stage breast cancer in Ontario. METHODS: Retrospective cohort of early-stage breast cancer patients identified in the Ontario Cancer Registry. Human epidermal growth factor receptor-2 test type, sequence, result(s), tumor grade, and hormone receptor status were abstracted from Ontario Cancer Registry pathology reports. Trastuzumab treatment was determined from provincial cancer agency records. Other variables were determined from administrative data sources. Logistic regression models were used to estimate adjusted odds ratios for factors associated with guideline adherence. RESULTS: The first human epidermal growth factor receptor-2 test result was the strongest predictor of confirmatory testing (p < 0.05). Human epidermal growth factor receptor-2 testing by immunohistochemistry accounted for the majority of documented first tests (94%; n = 8249). Overall, 27% (n = 2360) of tested patients received a second test by fluorescence in situ hybridization (46%) or immunohistochemistry (49%) assay. Most human epidermal growth factor receptor-2 equivocal patients (89%; n = 784) received a confirmatory test. Among human epidermal growth factor receptor-2-positive patients, only 57% (n = 385) received trastuzumab treatment within the study period. Human epidermal growth factor receptor-2 status was the strongest predictor of trastuzumab use. Younger patients (<70 years at diagnosis) and negative hormone receptor status had higher odds of trastuzumab treatment (p < 0.05) compared to older and positive hormone receptor status patients. CONCLUSIONS: Immunohistochemistry use as a first test was largely consistent with Canadian guidelines; however, immunohistochemistry was frequently used as a confirmatory test, which is not guideline-concordant. Monitoring these testing and treating patterns is necessary to optimize health outcomes associated with trastuzumab.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/administração & dosagem , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Ontário , Estudos Retrospectivos
20.
Influenza Other Respir Viruses ; 14(1): 28-36, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702876

RESUMO

BACKGROUND: We investigated whether influenza vaccination reduces symptom severity among children who develop laboratory-confirmed influenza, and whether this association differed between influenza vaccine formulations. METHODS: We performed a retrospective cohort study using data from two blinded cluster randomized control trials of influenza vaccines in Hutterite colonies. In trial 1, children received trivalent inactivated influenza vaccine (TIV) or hepatitis A vaccine. In trial 2, children received trivalent live attenuated (TLAIV) or TIV. We assessed four outcomes (total number of symptoms, number of respiratory symptoms, number of systemic symptoms, and duration of symptoms) among children with PCR-confirmed influenza. We utilized two-sample t tests to quantify the relationship between vaccine group and outcome. We performed multivariable strain-specific analyses, controlling for age and season. RESULTS: TIV vs. Hep A vaccine: Among vaccinated children, 200 confirmed influenza infections were observed across 3014 person-seasons. Vaccine type (TIV vs. Hep A vaccine) did not significantly affect the number of respiratory or systemic symptoms, nor duration of symptoms (P > .05). TLAIV vs. TIV: Among 1186 children who received a study vaccine, 166 confirmed influenza infections were observed. TLAIV recipients experienced fewer total, respiratory, and systemic symptoms compared to TIV recipients (P < .05 for all). TLAIV-associated attenuation of symptom severity was observed in influenza B or A/H1N1 infections, but not H3. CONCLUSIONS: Seasonal influenza vaccine did not consistently attenuate symptom severity in the context of vaccine failure; however, TLAIV offered superior severity attenuation compared to TIV. Our results challenge the dictum that influenza vaccine reduces the severity of symptoms even when the vaccine fails to prevent influenza.


Assuntos
Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Adolescente , Alberta , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/fisiologia , Vírus da Influenza B/genética , Vírus da Influenza B/imunologia , Vírus da Influenza B/fisiologia , Influenza Humana/diagnóstico , Influenza Humana/virologia , Masculino , Estudos Retrospectivos , Estações do Ano , Vacinação , Vacinas de Produtos Inativados/administração & dosagem
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