Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia B.

INTRODUCTION: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used. AIM: To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results. METHODS: Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons. RESULTS: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators. CONCLUSIONS: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.

Matching-adjusted indirect treatment comparison of chimeric antigen receptor T-cell therapies for third-line or later treatment of relapsed or refractory large B-cell lymphoma: lisocabtagene maraleucel versus tisagenlecleucel.

BACKGROUND: There are no head-to-head clinical studies comparing chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed or refractory aggressive large B-cell lymphomas. Naive, indirect comparisons may be inappropriate, as the study designs and patient populations could differ substantially. Matching-adjusted indirect comparisons (MAIC) can reduce many biases associated with indirect comparisons between studies. To determine the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) to tisagenlecleucel, we describe an unanchored MAIC of the pivotal studies TRANSCEND NHL 001 (TRANSCEND; NCT02631044; liso-cel) and JULIET (NCT02445248; tisagenlecleucel). METHODS: Individual patient data (IPD) from TRANSCEND were available to the authors; for the JULIET pivotal study, summary-level data from the published study were used. To balance the populations between two studies, IPD from TRANSCEND were adjusted to match the marginal distribution (e.g., mean, variance) of clinical factors among patients from JULIET. RESULTS: Results from the primary MAIC showed liso-cel had statistically significant greater efficacy than tisagenlecleucel (objective response rate: odds ratio [OR] = 2.78, 95% confidence interval [CI]: 1.63‒4.74; complete response rate: OR = 2.01, 95% CI: 1.22‒3.30; progression-free survival: hazard ratio [HR] = 0.65, 95% CI: 0.47‒0.91; overall survival: HR = 0.67, 95% CI: 0.47‒0.95). MAIC of safety outcomes showed lower ORs for all-grade and grade ≥ 3 cytokine release syndrome, and grade ≥ 3 prolonged cytopenia for liso-cel when compared with tisagenlecleucel; there were no statistically significant differences detected for other safety outcomes. CONCLUSIONS: Overall, this MAIC of two CAR T-cell therapies indicates liso-cel had favorable efficacy and a comparable or better safety profile relative to tisagenlecleucel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02631044 and NCT02445248.

Incidence and Resolution Strategies for Early-Onset Postoperative Leg Pain Following Lumbar Total Disc Replacement.

BACKGROUND: Lumbar total disc replacement (TDR) has produced results similar or superior to fusion in treating symptomatic disc degeneration. Some patients have reported onset of leg pain early after surgery. Little information is available specifically on this problem. The purpose of this study was to investigate the incidence of early-onset postoperative leg pain following lumbar TDR and to describe strategies for its treatment. METHODS: The study was based on a post hoc analysis of prospectively collected adverse event data from 283 patients in the activL Food and Drug Administration investigational device exemption study. Early-onset leg pain was defined as occurring between 0 and 4 weeks postprocedure, and the baseline visual analog scale score in the affected leg(s) was <25 (of 100). The treatment types these patients received were analyzed. RESULTS: Among 283 patients, 26 (9.2%) had an early-onset leg pain event. The majority of these events resolved (20/26, 76.9%). Of those resolving, 55% (11/20) did so within 3 months. Most patients received at least 1 drug treatment for leg pain (92.3%). Of those receiving drug therapy, the most common type was neurogenic (61.5%), followed by narcotics (46.2%). Steroid use was prescribed in 30.8%. The majority of resolved cases were not on narcotics and resolved with neurogenic drugs. Three patients went on to have surgery, none of whom benefited from it. Age, body mass index, and baseline disability scores were predictive of time to resolution. CONCLUSION: Early-onset postoperative leg pain occurred in approximately 10% of lumbar TDR patients. The majority of events resolved, often within 3 months. Treatment with conservative care, including medication(s), was more effective in resolving symptoms rather than surgery. CLINICAL RELEVANCE: This study provides useful information for providers and patients on the incidence, treatment, and resolution of leg pain with onset after lumbar TDR and not related to direct neural compression identified by imaging. LEVEL OF EVIDENCE: 2.

Matching-adjusted indirect treatment comparison of liso-cel versus axi-cel in relapsed or refractory large B cell lymphoma.

BACKGROUND: In the absence of randomized studies directly comparing chimeric antigen receptor T cell therapies, this study used matching-adjusted indirect comparisons (MAIC) to evaluate the comparative efficacy and safety of lisocabtagene maraleucel (liso-cel) versus axicabtagene ciloleucel (axi-cel) in patients with relapsed or refractory large B cell lymphoma (LBCL). METHODS: Primary data sources included individual patient data from the TRANSCEND NHL 001 study (TRANSCEND [NCT02631044]; N = 256 for efficacy set, N = 269 for safety set) for liso-cel and summary-level data from the ZUMA-1 study (NCT02348216; N = 101 for efficacy set, N = 108 for safety set) for axi-cel. Inter-study differences in design, eligibility criteria, baseline characteristics, and outcomes were assessed and aligned to the extent feasible. Clinically relevant prognostic factors were adjusted in a stepwise fashion by ranked order. Since bridging therapy was allowed in TRANSCEND but not ZUMA-1, the initial efficacy and safety analyses included bridging therapy use as a matching factor (TRANSCEND patients who received bridging therapy were removed). Subsequent sensitivity analyses excluded this matching factor. RESULTS: The initial analysis showed similar MAIC-weighted efficacy outcomes between TRANSCEND and ZUMA-1 for overall and complete response rates (odds ratio [95% confidence interval (CI)], 1.40 [0.56-3.49] and 1.21 [0.56-2.64], respectively) and for overall survival and progression-free survival (hazard ratio [95% CI], 0.81 [0.44-1.49] and 0.95 [0.58-1.57], respectively). MAIC-weighted safety outcomes favored liso-cel, with significantly lower odds of all-grade and grade ≥ 3 cytokine release syndrome (odds ratio [95% CI], 0.03 [0.01-0.07] and 0.08 [0.01-0.67], respectively) and study-specific neurological events (0.16 [0.08-0.33] and 0.05 [0.02-0.15], respectively). Efficacy and safety outcomes remained similar in sensitivity analyses, which did not include use of bridging therapy as a matching factor. CONCLUSIONS: After matching and adjusting for clinically relevant prognostic factors, liso-cel demonstrated comparable efficacy and a more favorable safety profile compared with axi-cel in patients with third- or later-line relapsed or refractory LBCL. TRIAL REGISTRATION: NCT02631044 and NCT02348216.

Applying GRADE to a network meta-analysis of antidepressants led to more conservative conclusions.

OBJECTIVE: To explore the impact of applying the Grading of Recommendations and Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence in a published network meta-analysis (NMA) of antidepressant therapies. STUDY DESIGN AND SETTINGS: We applied the GRADE approach to rate the certainty of the evidence for two outcomes, efficacy and acceptability, in each of the 66 paired comparisons within a previously published NMA assessing the relative efficacy and acceptability of 12 new-generation antidepressants. RESULTS: For the outcome of efficacy, of the 25 comparisons in which the 95% CrI of OR excluded 1, 18 had certainty of evidence rated high or moderate. For the outcome of acceptability, of the 13 comparisons whose 95% CrI excluded 1, 10 had certainty of evidence rated high or moderate. Of the 11 comparisons involving sertraline, the antidepressants that the authors of the NMA suggested to be best, only 3 demonstrated it to be more effective and only 3 showed better tolerance, based on a 95% CrI excluding 1 and a high or moderate rating of certainty. CONCLUSIONS: In this example, application of GRADE highlighted varying evidence certainty, led to more conservative conclusions, and potentially avoided unwarranted strong inferences based on low certainty evidence.

Comparative Efficacy of Angiotensin II Antagonists in Essential Hypertension: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials.

BACKGROUND: Evidence on the long-term clinical benefits of individual members of angiotensin II receptor blockers is limited given the lack of head-to-head studies. We conducted a network meta-analysis to determine the comparative efficacy of different members within this drug class with respect to outcomes of (i) blood pressure reduction (at 24 and 52 weeks) and (ii) prevention of cardiovascular disease (>104 weeks). METHODS: A systematic literature review was conducted - Protocol registration: (PROSPERO - CRD42014007067) - to identify relevant literature from the following databases: Cochrane Library, PubMed, Medline and EMBASE; searched from inception to July 2016. Randomised controlled trials (RCTs) were included if they reported long-term effectiveness relating to blood pressure, mortality, myocardial infarction or stroke. Eligible studies included those with placebo or specific active-treatment comparators (either another angiotensin II receptor blockers or hydrochlorothiazide). A Bayesian random-effects network model was used to combine direct within-trial comparisons between treatment groups with indirect evidence from other trials. RESULTS: Thirty-six studies were identified, representing 28 unique trials. Blood pressure reduction, based on 12 studies (n=807) with fixed dosing regimen, was found to be similar amongst members of the angiotensin receptor blocker drug class at both 24 and 52 weeks. A network meta-analysis of five studies (n=16,716) with a treat-to-target approach found that prevention of all-cause mortality, stroke and myocardial infarction was similar across the angiotensin-receptor blockers therapies initiated. CONCLUSIONS: Current evidence is insufficient to show differences in any members within the angiotensin II receptor blocker drug class with respect to blood pressuring lowering effects or a reduction in cardiovascular diseases.

Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis.

This article describes conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence (confidence in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic review authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: (1) consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, (2) there is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, (3) we should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and (4) in the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.

The effects of various diets on glycemic outcomes during pregnancy: A systematic review and network meta-analysis.

AIMS: Evidence to support dietary modifications to improve glycemia during pregnancy is limited, and the benefits of diet beyond limiting gestational weight gain is unclear. Therefore, a systematic review and network meta-analysis of randomized trials was conducted to compare the effects of various common diets, stratified by the addition of gestational weight gain advice, on fasting glucose and insulin, hemoglobin A1c (HbA1c), and homeostatic model assessment for insulin resistance (HOMA-IR) in pregnant women. METHODS: MEDLINE, EMBASE, Cochrane database, and reference lists of published studies were searched through April 2017. Randomized trials directly comparing two or more diets for ≥2-weeks were eligible. Bayesian network meta-analysis was performed for fasting glucose. Owing to a lack of similar dietary comparisons, a standard pairwise meta-analysis for the other glycemic outcomes was performed. The certainty of the pooled effect estimates was assessed using the GRADE tool. RESULTS: Twenty-one trials (1,865 participants) were included. In general, when given alongside gestational weight gain advice, fasting glucose improved in most diets compared to diets that gave gestational weight gain advice only. However, fasting glucose increased in high unsaturated or monounsaturated fatty acids diets. In the absence of gestational weight gain advice, fasting glucose improved in DASH-style diets compared to standard of care. Although most were non-significant, similar trends were observed for these same diets for the other glycemic outcomes. Dietary comparisons ranged from moderate to very low in quality of evidence. CONCLUSION/INTERPRETATION: Alongside with gestational weight gain advice, most diets, with the exception of a high unsaturated or a high monounsaturated fatty acid diet, demonstrated a fasting glucose improvement compared with gestational weight gain advice only. When gestational weight gain advice was not given, the DASH-style diet appeared optimal on fasting glucose. However, a small number of trials were identified and most dietary comparisons were underpowered to detect differences in glycemic outcomes. Further studies that are high in quality and adequately powered are needed to confirm these findings. REGISTRATION: PROSPERO CRD42015026008.

Modified Early Warning Score (MEWS) Identifies Critical Illness among Ward Patients in a Resource Restricted Setting in Kampala, Uganda: A Prospective Observational Study.

INTRODUCTION: Providing optimal critical care in developing countries is limited by lack of recognition of critical illness and lack of essential resources. The Modified Early Warning Score (MEWS), based on physiological parameters, is validated in adult medical and surgical patients as a predictor of mortality. The objective of this study performed in Uganda was to determine the prevalence of critical illness on the wards as defined by the MEWS, to evaluate the MEWS as a predictor of death, and to describe additional risk factors for mortality. METHODS: We conducted a prospective observational study at Mulago National Referral Teaching Hospital in Uganda. We included medical and surgical ward patients over 18 years old, excluding patients discharged the day of enrolment, obstetrical patients, and patients who self-discharged prior to study completion. Over a 72-hour study period, we collected demographic and vital signs, and calculated MEWS; at 7-days we measured outcomes. Patients discharged prior to 7 days were assumed to be alive at study completion. Descriptive and inferential statistical analyses were performed. RESULTS: Of 452 patients, the median age was 40.5 (IQR 29-54) years, 53.3% were male, 24.3% were HIV positive, and 45.1% had medical diagnoses. MEWS ranged from 0 to 9, with higher scores representing hemodynamic instability. The median MEWS was 2 [IQR 1-3] and the median length of hospital stay was 9 days [IQR 4-24]. In-hospital mortality at 7-days was 5.5%; 41.4% of patients were discharged and 53.1% remained on the ward. Mortality was independently associated with medical admission (OR: 7.17; 95% CI: 2.064-24.930; p = 0.002) and the MEWS ≥ 5 (OR: 5.82; 95% CI: 2.420-13.987; p<0.0001) in the multivariable analysis. CONCLUSION: There is a significant burden of critical illness at Mulago Hospital, Uganda. Implementation of the MEWS could provide a useful triage tool to identify patients at greatest risk of death. Future research should include refinement of MEWS for low-resource settings, and development of appropriate interventions for patients identified to be at high risk of death based on early warning scores.

Sensitivity subgroup analysis based on single-center vs. multi-center trial status when interpreting meta-analyses pooled estimates: the logical way forward.

OBJECTIVES: Prior studies regarding whether single-center trial estimates are larger than multi-center are equivocal. We examined the extent to which single-center trials yield systematically larger effects than multi-center trials. STUDY DESIGN AND SETTING: We searched the 119 core clinical journals and the Cochrane Database of Systematic Reviews for meta-analyses (MAs) of randomized controlled trials (RCTs) published during 2012. In this meta-epidemiologic study, for binary variables, we computed the pooled ratio of ORs (RORs), and for continuous outcomes mean difference in standardized mean differences (SMDs), we conducted weighted random-effects meta-regression and random-effects MA modeling. Our primary analyses were restricted to MAs that included at least five RCTs and in which at least 25% of the studies used each of single trial center (SC) and more trial center (MC) designs. RESULTS: We identified 81 MAs for the odds ratio (OR) and 43 for the SMD outcome measures. Based on our analytic plan, our primary analysis (core) is based on 25 MAs/241 RCTs (binary outcome) and 18 MAs/173 RCTs (continuous outcome). Based on the core analysis, we found no difference in magnitude of effect between SC and MC for binary outcomes [RORs: 1.02; 95% confidence interval (CI): 0.83, 1.24; I(2) 20.2%]. Effect sizes were systematically larger for SC than MC for the continuous outcome measure (mean difference in SMDs: -0.13; 95% CI: -0.21, -0.05; I(2) 0%). CONCLUSIONS: Our results do not support prior findings of larger effects in SC than MC trials addressing binary outcomes but show a very similar small increase in effect in SC than MC trials addressing continuous outcomes. Authors of systematic reviews would be wise to include all trials irrespective of SC vs. MC design and address SC vs. MC status as a possible explanation of heterogeneity (and consider sensitivity analyses).

Adiposity and immune-muscle crosstalk in South Asians &Europeans: A cross-sectional study.

South Asians (SA) are at higher risk of cardiometabolic disorders than Europeans (EU), yet the potential determinants of this risk are poorly understood. We tested the hypotheses that 1) South Asians (SA) have greater muscle inflammation compared to Europeans (EU) at similar fat mass 2) differential regional adiposity in SA compared to EU is associated with enhanced muscle inflammation in SA. This cross-sectional study was conducted at a tertiary academic center in Hamilton, Ontario, Canada. The study included 29 EU and 26 SA. Quantitative real-time PCR and western blot were used to measure muscle inflammation. Statistical analysis was done using a General Linear Model. Despite having similar macrophage content to EU, SA muscle had lower levels of chemokine CCL2 compared to EU at gene expression (ß -1.099, SE ß 0.521, p-value 0.04) and protein (0.84 ± 0.69 versus 1.10 ± 0.60, p-value 0.052) levels. SA had more pronounced abdominal and hepatic adiposity, with smaller Intramyocellular lipid particles compared to EU (0.26 ± 0.12 µm(2) versus 0.15 ± 0.06 µm(2), p-value 0.02). In conclusion, CCL2 downregulation in SA may be an attempt to protect muscle against macrophage infiltration, and defects in fatty acid partitioning to muscle may lead to the disproportionate adiposity and adverse cardiometabolic profile in SA.

Network meta-analysis using R: a review of currently available automated packages.

Network meta-analysis (NMA)--a statistical technique that allows comparison of multiple treatments in the same meta-analysis simultaneously--has become increasingly popular in the medical literature in recent years. The statistical methodology underpinning this technique and software tools for implementing the methods are evolving. Both commercial and freely available statistical software packages have been developed to facilitate the statistical computations using NMA with varying degrees of functionality and ease of use. This paper aims to introduce the reader to three R packages, namely, gemtc, pcnetmeta, and netmeta, which are freely available software tools implemented in R. Each automates the process of performing NMA so that users can perform the analysis with minimal computational effort. We present, compare and contrast the availability and functionality of different important features of NMA in these three packages so that clinical investigators and researchers can determine which R packages to implement depending on their analysis needs. Four summary tables detailing (i) data input and network plotting, (ii) modeling options, (iii) assumption checking and diagnostic testing, and (iv) inference and reporting tools, are provided, along with an analysis of a previously published dataset to illustrate the outputs available from each package. We demonstrate that each of the three packages provides a useful set of tools, and combined provide users with nearly all functionality that might be desired when conducting a NMA.

Testing for associations between systolic blood pressure and single-nucleotide polymorphism profiles obtained from sparse principal component analysis.

BACKGROUND: Hypertension is a prevalent condition linked to major cardiovascular conditions and multiple other comorbidities. Genetic information can offer a deeper understanding about susceptibility and the underlying disease mechanisms. The Genetic Analysis Workshop 18 (GAW18) provides abundant genotype data to determine genetic associations for being hypertensive and for the underlying trait of systolic blood pressure (SBP). The high-dimensional nature of this data promotes dimension reduction techniques to remove excess noise and also synthesize genetic information for complex, polygenic traits. METHODS: For both measured and simulated phenotype data from GAW18, we use sparse principal component analysis to obtain sparse genetic profiles that represent the underlying data structures. We then detect associations between the obtained sparse principal components (PCs) and SBP, a major indicator of hypertension, following up by investigating the sparse PCs for genetic structure to gain insight into new patterns. RESULTS: After adjusting for multiple testing, 27 of 122 PCs were significantly associated with measured SBP, offering a large number of components to investigate. Considering the top 3 PCs, linked genetic regions have been identified; these may act in unison while associated with SBP. Simulated data offered similar results. CONCLUSIONS: Sparse PCs can offer a new data-driven approach to structuring genotype data and understanding the genetic mechanics behind complex, polygenic traits such as hypertension.

Response to Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis for Function and Pain is Affected by Rheumatoid Factor.

OBJECTIVES: To investigate differences in response to tumor necrosis factor inhibitor treatment (TNFi) in seropositive (rheumatoid factor positive; RF+) versus seronegative (RF-) patients with established RA as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) and pain. METHODS: RA patients from an established RA cohort were studied according to rheumatoid factor (RF) status for change in HAQ-DI and pain (0-3 VAS) one year after starting treatment with a TNFi. RESULTS: There were 238 patients treated with TNFi who had follow-up data (178 RF+ and 60 RF-). Disease duration was longer in RF+ vs RF- (12+8 vs 8+8 years) but the proportion of females (82% vs 72%, P=0.7), baseline HAQ-DI (1.44+0.63 vs 1.41+0.63, P=0.8) and pain (1.92+0.67 vs 1.93+0.67, P=0.9) were not different. The mean duration of treatment of first TNFi was 2.8 vs 2.3 years, P=0.1 and 68% of RF+ vs 62% of RF- were still receiving first TNFi at last visit (P=0.5). For patients with data at baseline and one year, the one-year HAQ-DI change was significantly greater in 90 RF+ patients (-0.356) versus 38 RF- patients (-0.126; P=0.04). The mean pain improvement was also greater in 77 RF+ vs 32 RF- patients (-0.725 vs -0.332 respectively; P=0.03). Numbers are small, data are missing and comorbidities, DAS28 and anti-CCP were not collected. CONCLUSION: Despite limitations in the data, in established RA after failure of DMARDs, RF+ patients may be more responsive to TNFi therapy as measured by changes in HAQ-DI and pain. INNOVATION: There may be a better response to TNFi in RA if RF positive for function and pain.

The effectiveness of opioid substitution treatments for patients with opioid dependence: a systematic review and multiple treatment comparison protocol.

BACKGROUND: Opioids are psychoactive analgesic drugs prescribed for pain relief and palliative care. Due to their addictive potential, effort and vigilance in controlling prescriptions is needed to avoid misuse and dependence. Despite the effort, the prevalence of opioid use disorder continues to rise. Opioid substitution therapies are commonly used to treat opioid dependence; however, there is minimal consensus as to which therapy is most effective. Available treatments include methadone, heroin, buprenorphine, as well as naltrexone. This systematic review aims to assess and compare the effect of all available opioid substitution therapies on the treatment of opioid dependence. METHODS/DESIGN: The authors will search Medline, EMBASE, PubMed, PsycINFO, Web of Science, Cochrane Library, Cochrane Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform Search Portal, and the National Institutes for Health Clinical Trials Registry. The title, abstract, and full-text screening will be completed in duplicate. When appropriate, multiple treatment comparison Bayesian meta-analytic methods will be performed to deduce summary statistics estimating the effectiveness of all opioid substitution therapies in terms of retention and response to treatment (as measured through continued opioid abuse). DISCUSSION: Using evidence gained from this systematic review, we anticipate disseminating an objective review of the current available literature on the effectiveness of all opioid substitution therapies for the treatment of opioid use disorder. The results of this systematic review are imperative to the further enhancement of clinical practice in addiction medicine. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013006507.

Applications of machine learning and data mining methods to detect associations of rare and common variants with complex traits.

Machine learning methods (MLMs), designed to develop models using high-dimensional predictors, have been used to analyze genome-wide genetic and genomic data to predict risks for complex traits. We summarize the results from six contributions to our Genetic Analysis Workshop 18 working group; these investigators applied MLMs and data mining to analyses of rare and common genetic variants measured in pedigrees. To develop risk profiles, group members analyzed blood pressure traits along with single-nucleotide polymorphisms and rare variant genotypes derived from sequence and imputation analyses in large Mexican American pedigrees. Supervised MLMs included penalized regression with varying penalties, support vector machines, and permanental classification. Unsupervised MLMs included sparse principal components analysis and sparse graphical models. Entropy-based components analyses were also used to mine these data. None of the investigators fully capitalized on the genetic information provided by the complete pedigrees. Their approaches either corrected for the nonindependence of the individuals within the pedigrees or analyzed only those who were independent. Some methods allowed for covariate adjustment, whereas others did not. We evaluated these methods using a variety of metrics. Four contributors conducted primary analyses on the real data, and the other two research groups used the simulated data with and without knowledge of the underlying simulation model. One group used the answers to the simulated data to assess power and type I errors. Although the MLMs applied were substantially different, each research group concluded that MLMs have advantages over standard statistical approaches with these high-dimensional data.

Effects of income and dental insurance coverage on need for dental care in Canada.

OBJECTIVE: To estimate the strength of the associations among income, dental insurance coverage and need for dental care (both urgent and nonurgent) in Canada. METHODS: Multinomial logistic models were fit to data from the 2009 Canadian Health Measures Survey to test unadjusted associations among household income, dental insurance coverage and the need for urgent and nonurgent dental care. Adjusted associations, controlling for socio-demographic variables (age, sex, immigration status, education and province of residence) and oral health habits (brushing, flossing and visits to the dentist) were also evaluated. RESULTS: In the unadjusted model, need for treatment was lower among people with dental insurance than among those without insurance coverage (for urgent treatment: odds ratio [OR] 0.76, 95% confidence interval [CI] 0.66-0.89; for nonurgent treatment: OR 0.59, 95% CI 0.50-0.70). In addition, there was an income gradient, whereby people with higher income had less need for dental treatment (for urgent treatment: OR 0.99, 95% CI 0.99-1.00; for nonurgent treatment: OR 0.99, 95% CI 0.98-0.99). Controlling for socio-demographic and oral health variables decreased the magnitude of the association between dental insurance coverage and need for treatment (for urgent treatment: OR 0.80, 95% CI 0.68-0.95; for nonurgent treatment: OR 0.76, 95% CI 0.63-0.92). An interaction term between dental coverage and income was significant in relation to the need for nonurgent treatment: among lower-income individuals, having insurance slightly decreased the odds of needing nonurgent treatment, with this decrease in odds becoming greater for middle-income earners and even greater for high-income earners. CONCLUSION: Income-related inequality in need for dental care exists even in the presence of dental insurance coverage and good dental hygiene habits. These findings highlight the need for increased access to dental care for low-income populations and families living in poverty.

Determining best practices in early rheumatoid arthritis by comparing differences in treatment at sites in the Canadian Early Arthritis Cohort.

OBJECTIVE: To determine site variation by comparing outcomes across sites in an early rheumatoid arthritis cohort. METHODS: Sites from the Canadian Early Arthritis Cohort database with at least 40 patients were studied. Comparisons were made among sites in change in 28-joint Disease Activity Score (DAS28), proportion of patients in DAS28 remission, and treatment strategies. RESULTS: The study included 1138 baseline patients at 8 sites, with baseline (SD) age 52 years (16.9); 72% women; 23% erosions; 54% ever smokers; 51% rheumatoid factor-positive; 37% anticitrullinated protein antibody-positive; disease duration 187 (203) days; DAS28 4.5 (1.4). Site had an effect on outcomes when adjusting for confounders. At 6 and 12 months, sites B and H, the 2 largest sites, had the best changes in DAS28 (-1.82 and -2.09, respectively, at 6 mos, and -2.27 for both at 12 mos; p < 0.001). Site H had the most patients in DAS28 remission at 6 months [64.5% compared to other sites that had from 34.1% to 51.7% (p < 0.001)], and at the last followup, sites B and H had the most in remission. Subcutaneous methotrexate was used more overall and earlier at sites B and H. Those sites used less steroid therapy, and site B had the second-highest use of triple disease-modifying antirheumatic drugs at any visit. Medications were increased more in 2 of the 3 smallest sites. Biologics were used by 9 months most in the smallest (50.0%) and then largest (19.6%) sites. CONCLUSION: Sites in an early inflammatory arthritis cohort yielded different outcomes. Better outcomes up to 12 months may result from initial treatment with early combination therapy and/or subcutaneous methotrexate.