Two-stage estimation to adjust for treatment switching in randomised trials: a simulation study investigating the use of inverse probability weighting instead of re-censoring.

BACKGROUND: Treatment switching is common in randomised trials of oncology treatments, with control group patients switching onto the experimental treatment during follow-up. This distorts an intention-to-treat comparison of the treatments under investigation. Two-stage estimation (TSE) can be used to estimate counterfactual survival times for patients who switch treatments - that is, survival times that would have been observed in the absence of switching. However, when switchers do not die during the study, counterfactual censoring times are estimated, inducing informative censoring. Re-censoring is usually applied alongside TSE to resolve this problem, but results in lost longer-term information - a major concern if the objective is to estimate long-term treatment effects, as is usually the case in health technology assessment. Inverse probability of censoring weights (IPCW) represents an alternative technique for addressing informative censoring but has not before been combined with TSE. We aim to determine whether combining TSE with IPCW (TSEipcw) represents a valid alternative to re-censoring. METHODS: We conducted a simulation study to compare TSEipcw to TSE with and without re-censoring. We simulated 48 scenarios where control group patients could switch onto the experimental treatment, with switching affected by prognosis. We investigated various switching proportions, treatment effects, survival function shapes, disease severities and switcher prognoses. We assessed the alternative TSE applications according to their estimation of control group restricted mean survival (RMST) that would have been observed in the absence of switching up to the end of trial follow-up. RESULTS: TSEipcw performed well when its weights had a low coefficient of variation, but performed poorly when the coefficient of variation was high. Re-censored analyses usually under-estimated control group RMST, whereas non-re-censored analyses usually produced over-estimates, with bias more serious when the treatment effect was high. In scenarios where TSEipcw performed well, it produced low bias that was often between the two extremes associated with the re-censoring and non-recensoring options. CONCLUSIONS: Treatment switching adjustment analyses using TSE should be conducted with re-censoring, without re-censoring, and with IPCW to explore the sensitivity in results to these application options. This should allow analysts and decision-makers to better interpret the results of adjustment analyses.

Assessing causal treatment effect estimation when using large observational datasets.

BACKGROUND: Recently, there has been a heightened interest in developing and evaluating different methods for analysing observational data. This has been driven by the increased availability of large data resources such as Electronic Health Record (EHR) data alongside known limitations and changing characteristics of randomised controlled trials (RCTs). A wide range of methods are available for analysing observational data. However, various, sometimes strict, and often unverifiable assumptions must be made in order for the resulting effect estimates to have a causal interpretation. In this paper we will compare some common approaches to estimating treatment effects from observational data in order to highlight the importance of considering, and justifying, the relevant assumptions prior to conducting an observational analysis. METHODS: A simulation study was conducted based upon a small cohort of patients with chronic obstructive pulmonary disease. Two-stage least squares instrumental variables, propensity score, and linear regression models were compared under a range of different scenarios including different strengths of instrumental variable and unmeasured confounding. The effects of violating the assumptions of the instrumental variables analysis were also assessed. Sample sizes of up to 200,000 patients were considered. RESULTS: Two-stage least squares instrumental variable methods can yield unbiased treatment effect estimates in the presence of unmeasured confounding provided the sample size is sufficiently large. Adjusting for measured covariates in the analysis reduces the variability in the two-stage least squares estimates. In the simulation study, propensity score methods produced very similar results to linear regression for all scenarios. A weak instrument or strong unmeasured confounding led to an increase in uncertainty in the two-stage least squares instrumental variable effect estimates. A violation of the instrumental variable assumptions led to bias in the two-stage least squares effect estimates. Indeed, these were sometimes even more biased than those from a naïve linear regression model. CONCLUSIONS: Instrumental variable methods can perform better than naïve regression and propensity scores. However, the assumptions need to be carefully considered and justified prior to conducting an analysis or performance may be worse than if the problem of unmeasured confounding had been ignored altogether.

Further studies to evaluate methods of leucoreduction to prevent alloimmune platelet refractoriness and induce tolerance in a dog platelet transfusion model.

OBJECTIVES: Three leucoreduction filters were evaluated - when used alone or combined with centrifuge leucoreduction (C-LR) - to prevent alloimmune platelet refractoriness in a dog platelet transfusion model. MATERIALS AND METHODS: Donor platelet-rich plasma (PRP) or buffy coat (BC) platelets were either filter leucoreduced (F-LR) or F-LR/C-LR, (51) Cr radiolabelled and transfused. Weekly transfusions were given for up to 8 weeks or until platelet refractoriness. Recipients who accepted treated transfusions were then given non-leucoreduced (non-LR) platelets to determine whether donor-specific tolerance had been induced. RESULTS: Acceptance of F-LR PRP transfusions ranged from 29% to 66%. F-LR/C-LR transfusions prepared from PRP were accepted by 92%, from BC by 63% and from pooled PRP by 75% of recipients (p=NS); overall acceptance rate of F-LR/C-LR transfusions was 83%. Tolerance to subsequent non-LR transfusions occurred in 45% of the F-LR-/C-LR-accepting recipients unrelated to DR-B compatibility between donors and recipients (P = 0·18). CONCLUSION: In a dog platelet transfusion model, acceptance of donor platelets required combining F-LR with C-LR as apparently each process removes different immunizing WBCs.

Developing a Natural History Model for Duchenne Muscular Dystrophy.

BACKGROUND: The aim of this study was to pool multiple data sets to build a patient-centric, data-informed, natural history model (NHM) for Duchenne muscular dystrophy (DMD) to estimate disease trajectory across patient lifetime under current standard of care in future economic evaluations. The study was conducted as part of Project HERCULES, a multi-stakeholder collaboration to develop tools to support health technology assessments of new treatments for DMD. METHODS: Health states were informed by a review of NHMs for DMD and input from clinicians, patients and caregivers, and defined using common outcomes in clinical trials and real-world practice. The primary source informing the NHM was the Critical Path Institute Duchenne Regulatory Science Consortium (D-RSC) database. This was supplemented with expert input obtained via an elicitation exercise, and a systematic literature review and meta-analysis of mortality data. RESULTS: The NHM includes ambulatory, transfer and non-ambulatory phases, which capture loss of ambulation, ability to weight bear and upper body and respiratory function, respectively. The NHM estimates patients spend approximately 9.5 years in ambulatory states, 1.5 years in the transfer state and the remainder of their lives in non-ambulatory states. Median predicted survival is 34.8 years (95% CI 34.1-35.8). CONCLUSION: The model includes a detailed disease pathway for DMD, including the clinically and economically important transfer state. The NHM may be used to estimate the current trajectory of DMD in economic evaluations of new treatments, facilitating inclusion of a lifetime time horizon, and will help identify areas for further research.

Dynamic modulation of spatially structured polarization fields for real-time control of ultrafast laser-material interactions.

The polarization state of an ultrafast laser is dynamically controlled using two Spatial Light Modulators and additional waveplates. Consequently, four states of polarization, linear horizontal and vertical, radial and azimuthal, all with a ring intensity distribution, were dynamically switched at a frequency ν = 12.5 Hz while synchronized with a motion control system. This technique, demonstrated here for the first time, enables a remarkable level of real-time control of the properties of light waves and applied to real-time surface patterning, shows that highly controlled nanostructuring is possible. Laser ablation of Induced Periodic Surface Structures is used to directly verify the state of polarization at the focal plane.

Validation of the Patient Global Impression scales for use in detrusor overactivity: secondary analysis of the RELAX study.

OBJECTIVE: To assess construct validity of the Patient Global Impression scales (Severity [PGI-S], Bother [PGI-B] and Improvement [PGI-I]) for symptoms of detrusor overactivity (DO). DESIGN: Secondary analysis of a randomised trial of onabotulinum toxin A. SETTING: Eight UK urogynaecology departments. POPULATION: A total of 240 women with DO refractory to medical treatment randomised to receive 200 iu onabotulinum toxin A or placebo in the RELAX trial and followed up for 6 months. MAIN OUTCOME MEASURES: Urinary diaries and disease-specific quality of life (QoL) questionnaires were completed at baseline and during follow up. Discriminatory ability of the PGI-S, PGI-B and PGI-I scales to identify symptom severity and change in severity was assessed by comparing mean diary and QoL outcomes across the response categories, analysed by one-way analysis of variance. RESULTS: Data were available from 237 women (98.8%) for validation of PGI-S and PGI-B at baseline, and 192 women (80%) at 6 weeks follow up for validation of PGI-I. Leakage episodes (P = 0.01), urgency episodes (P = 0.019), urgency severity (P = 0.012), and QoL scores (all P < 0.001) were greater in women with more severe problems on PGI-S. Similar results were seen for PGI-B: leakage (P = 0.051), urgency episodes (P < 0.001), urgency severity (P < 0.001), and QoL scores (all P < 0.001). PGI-I responses demonstrated significant relationships with size of change of all variables (P < 0.001). The generic instrument EQ-5D had weaker relationships (PGI-S, P = 0.09; PGI-B, P = 0.004; PGI-I, P = 0.06), suggesting that it was less sensitive. CONCLUSIONS: The PGI scales are robust and valid instruments to assess disease severity, bother and improvement after treatment in women with detrusor overactivity.

What lies beneath: molecular phylogenetics and ancestral state reconstruction of the ancient subterranean Australian Parabathynellidae (Syncarida, Crustacea).

The crustacean family Parabathynellidae is an ancient and significant faunal component of subterranean ecosystems. Molecular data were generated in order to examine phylogenetic relationships amongst Australian genera and assess the species diversity of this group within Australia. We also used the resultant phylogenetic framework, in combination with an ancestral state reconstruction (ASR) analysis, to explore the evolution of two key morphological characters (number of segments of the first and second antennae), previously used to define genera, and assess the oligomerization principle (i.e. serial appendage reduction over time), which is commonly invoked in crustacean systematics. The ASR approach also allowed an assessment of whether there has been convergent evolution of appendage numbers during the evolution of Australian parabathynellids. Sequence data from the mtDNA COI and nDNA 18S rRNA genes were obtained from 32 parabathynellid species (100% of described genera and ~25% of described species) from key groundwater regions across Australia. Phylogenetic analyses revealed that species of each known genus, defined by traditional morphological methods, were monophyletic, suggesting that the commonly used generic characters are robust for defining distinct evolutionary lineages. Additionally, ancestral state reconstruction analysis provided evidence for multiple cases of convergent evolution for the two morphological characters evaluated, suggesting that caution needs to be shown when using these characters for elucidating phylogenetic relationships, particularly when there are few morphological characters available for reconstructing relationships. The ancestral state analysis contradicted the conventional view of parabathynellid evolution, which assumes that more simplified taxa (i.e. those with fewer-segmented appendages and setae) are derived and more complex taxa are primitive.

Perfusion Scotoma: A Potential Core Underestimation in CT Perfusion in the Delayed Time Window in Patients with Acute Ischemic Stroke.

With the growing rise in utilization of CT perfusion for selecting patients for thrombectomy in acute ischemic stroke from large vessel occlusion, some potential pitfalls are becoming more commonly seen particularly when it comes to estimating the core infarct size on CT perfusion. Ghost infarct core has been described to account for overestimating core infarct size in the early time period (<3 hours). Herein, we describe the phenomenon of underestimating core infarct size on CT perfusion in the later time period (>6 hours), which we have termed perfusion scotoma.

Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.

Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m(2) , p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

Esophageal stents for benign refractory strictures: a meta-analysis.

BACKGROUND AND AIMS: Fully covered self-expanding removable stents (SERS) have been considered a viable alternative to serial bougienage. The primary aim of this meta-analysis was to determine the efficacy of SERS for refractory esophageal strictures. METHODS: Medline, Embase, and PubMed databases were searched using the keywords "esophageal stricture," "esophageal stents," "benign stricture," "dysphagia," "caustic," "peptic stricture," "anastomotic," "radiation," and "dysphagia" for the period from January 1965 to June 2010. Articles were selected for review independently by two authors (T. T. and J. M.) on the basis of predefined inclusion criteria, and the data collected. A meta-analysis using a random effects model was done. RESULTS: Eight studies with a total of 199 patients were included in the final analysis (104-males, average age 56 years, range: 49 - 68 years). Overall, 46.2 % of patients (95 %CI: 38.3 % - 54.1 %) had dysphagia improvement at an average follow up of 74 weeks. There was a significant difference ( P = 0.019) in dysphagia improvement for patients with Polyflex stents (55.3 %; 95 %CI: 44.4 % - 65.9 %) versus nitinol stents (21.8 %; 95 %CI: 13.7 % - 33.7 %). On meta-regression, patient sex ( P = 0.80), patient age ( P = 0.725), corrosive etiology ( P = 0.30), stricture location ( P = 0.273), stricture length ( P = 0.32), time of removal ( P = 0.056), and duration of follow-up (0.35) had no significance influence on the outcome. The migration rate was 26.4 % (95 %CI: 25.3 % - 39.3 %). CONCLUSIONS: Although the efficacy of SERS placement in benign refractory strictures is 46.2 %, it is associated with migration rate of 26.4 %. Nevertheless, the use of these temporary stents, which can be successfully removed in 87 % of patients, is an alluring prospect for treating patients with this difficult condition.

Searching for the right outcome? A systematic review and meta-analysis of controlled trials using carotid intima-media thickness or pulse wave velocity to infer antiatherogenic properties of thiazolidinediones.

INTRODUCTION: Recent meta-analyses cast doubt over purported beneficial effects of Peroxisome Proliferator Activated Receptor-Gamma (PPAR-gamma) receptor agonists. Thiazolidinedione (TZD) trials using surrogate outcomes to postulate an antiatherogenic paradigm have been criticised as misinformative. We conducted an independent systematic review and meta-analysis of controlled TZD studies incorporating carotid intima-media thickness (CIMT) or pulse wave velocity (PWV) as primary outcome measures. The aim was to provide an evidence-based overview of TZD intervention studies using markers prospectively linked to vascular outcome in type 2 diabetes. METHODS: Systematic search of known databases for TZD intervention trials using mean thickness CIMT(n = 9) and ankle-brachial PWV(n = 6) as primary outcome measures was performed. CIMT and PWV pooled weighted mean difference was calculated using a random effects model accounting for heterogeneity and publication bias. An indirect meta-analysis provided a comparison of rosiglitazone and pioglitazone effects. RESULTS: A composite of combined placebo and comparator controlled trials demonstrated a significant weighted mean difference of-0.06 mm for CIMT (95% CI-0.09 to-0.02, p = 0.001) and-0.72 ms(-1) for PWV (95% CI-1.28 to-0.16, p = 0.011) in favour of thiazolidiendione treatment. No TZD intraclass variation in CIMT (p = 0.96) or PWV (p = 0.33) change was observed. CONCLUSION: TZDs exhibit significant beneficial effects on aorto-carotid atherosclerosis when assessed using prospectively validated non-invasive techniques. Inferring clinical benefit in the absence of confirmatory outcome trials is questionable and caution should be exercised when interpreting intervention data with surrogate endpoints. TZD-induced congestive cardiac failure or other unknown PPAR-gamma adverse effects are plausible explanations for the conflicting results of intervention trials using markers of atherosclerosis and clinical event outcomes.

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes.

Human chorionic gonadotrophin (hCG) is largely used to confirm pregnancy. Yet evidence shows that longitudinal hCG profiles are distinguishable between healthy and failing pregnancies. We retrospectively fitted a joint longitudinal-survival model to data from 127 (85 healthy and 42 failing pregnancies) US women, aged 18-45, who were attempting to conceive, to quantify the association between longitudinally measured urinary hCG and early miscarriage. Using subject-specific predictions, obtained uniquely from the joint model, we investigated the plausibility of adaptively monitoring early pregnancy outcomes based on updating hCG measurements. Volunteers collected daily early morning urine samples for their menstrual cycle and up to 28 days post day of missed period. The longitudinal submodel for log hCG included a random intercept and slope and fixed linear and quadratic time terms. The survival submodel included maternal age and cycle length covariates. Unit increases in log hCG corresponded to a 63.9% (HR 0.36, 95% CI 0.16, 0.47) decrease in the risk of miscarriage, confirming a strong association between hCG and miscarriage. Outputted conditional survival probabilities gave individualised risk estimates for the early pregnancy outcomes in the short term. However, longer term monitoring would require a larger sample size and prospectively followed up data, focusing on emerging extensions to the joint model, which allow assessment of the specificity and sensitivity.

Immunomodulatory effects of mixed hematopoietic chimerism: immune tolerance in canine model of lung transplantation.

Long-term survival after lung transplantation is limited by acute and chronic graft rejection. Induction of immune tolerance by first establishing mixed hematopoietic chimerism (MC) is a promising strategy to improve outcomes. In a preclinical canine model, stable MC was established in recipients after reduced-intensity conditioning and hematopoietic cell transplantation from a DLA-identical donor. Delayed lung transplantation was performed from the stem cell donor without pharmacological immunosuppression. Lung graft survival without loss of function was prolonged in chimeric (n = 5) vs. nonchimeric (n = 7) recipients (p < or = 0.05, Fisher's test). There were histological changes consistent with low-grade rejection in 3/5 of the lung grafts in chimeric recipients at > or =1 year. Chimeric recipients after lung transplantation had a normal immune response to a T-dependent antigen. Compared to normal dogs, there were significant increases of CD4+INFgamma+, CD4+IL-4+ and CD8+ INFgamma+ T-cell subsets in the blood (p < 0.0001 for each of the three T-cell subsets). Markers for regulatory T-cell subsets including foxP3, IL10 and TGFbeta were also increased in CD3+ T cells from the blood and peripheral tissues of chimeric recipients after lung transplantation. Establishing MC is immunomodulatory and observed changes were consistent with activation of both the effector and regulatory immune response.

Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials.

PURPOSE: Tumour necrosis factor (TNF) plays an important role in inflammation and may affect tumour growth control. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, a meta-analysis was performed using individual patient data from randomised controlled trials (RCT) in patients with rheumatoid arthritis (RA). METHODS: A search was conducted of bibliographic databases, abstracts from annual meetings and any unpublished studies on file with manufacturers of etanercept to December 2006. Only RCT of etanercept used for 12 weeks or more in patients with RA were included. Nine trials met the inclusion criteria. To adjudicate endpoints, the case narratives of potential cases were reviewed. Patient-level data were extracted from the clinical trials databases. RESULTS: The nine trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years of follow-up) and 1072 who received control therapy (1051 person-years). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.47/1000 person-years) and seven patients in the control group (IR 6.66/1000 person-years). A Cox's proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI 0.79 to 4.28) for the etanercept group compared with the control group. CONCLUSIONS: In this analysis, the point estimate of malignancy risk was higher in etanercept-treated patients, although the results were not statistically significant. The approach of obtaining individual patient data of RCT in cooperation with trial sponsors allowed important insights into the methodological advantages and challenges of sparse adverse event data meta-analysis.

Protection of macaques against SIV infection by subunit vaccines of SIV envelope glycoprotein gp160.

Simian immunodeficiency virus (SIV) is a primate lentivirus related to human immunodeficiency viruses and is an etiologic agent for acquired immunodeficiency syndrome (AIDS)-like diseases in macaques. To date, only inactivated whole virus vaccines have been shown to protect macaques against SIV infection. Protective immunity was elicited by recombinant subunit vaccines. Four Macaca fascicularis were immunized with recombinant vaccinia virus expressing SIVmne gp160 and were boosted with gp160 produced in baculovirus-infected cells. All four animals were protected against an intravenous challenge of the homologous virus at one to nine animal-infectious doses. These results indicate that immunization with viral envelope antigens alone is sufficient to elicit protective immunity against a primate immunodeficiency virus. The combination immunization regimen, similar to one now being evaluated in humans as candidate human immunodeficiency virus (HIV)-1 vaccines, appears to be an effective way to elicit such immune responses.