Clustered Treatment Assignments and Sensitivity to Unmeasured Biases in Observational Studies

Clustered treatment assignment occurs when individuals are grouped into clusters prior to treatment and whole clusters, not individuals, are assigned to treatment or control. In randomized trials, clustered assignments may be required because the treatment must be applied to all children in a classroom, or to all patients at a clinic, or to all radio listeners in the same media market. The most common cluster randomized design pairs 2S clusters into S pairs based on similar pretreatment covariates, then picks one cluster in each pair at random for treatment, the other cluster being assigned to control. Typically, group randomization increases sampling variability and so is less efficient, less powerful, than randomization at the individual level, but it may be unavoidable when it is impractical to treat just a few people within each cluster. Related issues arise in nonrandomized, observational studies of treatment effects, but in this case one must examine the sensitivity of conclusions to bias from nonrandom selection of clusters for treatment. Although clustered assignment increases sampling variability in observational studies, as it does in randomized experiments, it also tends to decrease sensitivity to unmeasured biases, and as the number of cluster pairs increases the latter effect overtakes the former, dominating it when allowance is made for nontrivial biases in treatment assignment. Intuitively, a given magnitude of departure from random assignment can do more harm if it acts on individual students than if it is restricted to act on whole classes, because the bias is unable to pick the strongest individual students for treatment, and this is especially true if a serious effort is made to pair clusters that appeared similar prior to treatment. We examine this issue using an asymptotic measure, the design sensitivity, some inequalities that exploit convexity, simulation, and an application concerned with the flooding of villages in Bangladesh

Using SVD for improved interferometric Green's function retrieval

Seismic interferometry (SI) is a technique used to estimate the Green's function (GF) between two receiver locations, as if there were a source at one of the receiver locations. However, in many applications, the requirements to recover the exact GF are not satisfied and SI yields a poor estimate of the GF. For these non-ideal cases, we improve the interferometric GFs, by applying singular value decomposition (SVD) to the cross-correlations before stacking. The SVD approach preserves energy that is stationary in the cross-correlations, which is the energy that contributes most to the GF recovery, and attenuates non-stationary energy, which leads to artefacts in the interferometric GF. We apply this method to construct virtual shot gathers (for both synthetic and field data) and demonstrate how using SVD enhances physical arrivals in these gathers. We also find that SVD is robust with respect to weakly correlated random noise, allowing a better recovery of events from noisy data, in some cases recovering energy that would otherwise be completely lost in the noise and that the standard SI technique fails to recover

Families’ roles in children’s literacy in the UK throughout the 20th century

This paper explores the changing roles of families in children’s developing literacy in the UK in the last century. It discusses how, during this time, understandings of reading and writing have evolved into the more nuanced notion of literacy. Further, in acknowledging changes in written communication practices, and shifting attitudes to reading and writ- ing, the paper sketches out how families have always played some part in the literacy of younger generations; though reading was frequently integral to the lives of many families throughout the past century, we consider in particular the more recent enhancement of children’s literacy through targeted family programmes. The paper considers policy implications for promoting young children’s literacy through work with families

Measurements of the pp → ZZ production cross section and the Z → 4ℓ branching fraction, and constraints on anomalous triple gauge couplings at √s = 13 TeV

Four-lepton production in proton-proton collisions, pp -> (Z/gamma*)(Z/gamma*) -> 4l, where l = e or mu, is studied at a center-of-mass energy of 13 TeV with the CMS detector at the LHC. The data sample corresponds to an integrated luminosity of 35.9 fb(-1). The ZZ production cross section, sigma(pp -> ZZ) = 17.2 +/- 0.5 (stat) +/- 0.7 (syst) +/- 0.4 (theo) +/- 0.4 (lumi) pb, measured using events with two opposite-sign, same-flavor lepton pairs produced in the mass region 60 4l) = 4.83(-0.22)(+0.23) (stat)(-0.29)(+0.32) (syst) +/- 0.08 (theo) +/- 0.12(lumi) x 10(-6) for events with a four-lepton invariant mass in the range 80 4GeV for all opposite-sign, same-flavor lepton pairs. The results agree with standard model predictions. The invariant mass distribution of the four-lepton system is used to set limits on anomalous ZZZ and ZZ. couplings at 95% confidence level: -0.0012 < f(4)(Z) < 0.0010, -0.0010 < f(5)(Z) < 0.0013, -0.0012 < f(4)(gamma) < 0.0013, -0.0012 < f(5)(gamma) < 0.0013

The Effect of Calcium Channel Blockers on Digital Ulcers in Systemic Sclerosis: Data From a Prospective Cohort Study

Digital ulcers (DU) are a common, severe vascular manifestation of systemic sclerosis (SSc) with few effective treatment options. Using data from the Australian Scleroderma Cohort Study (ASCS), we sought to evaluate the effect of calcium channel blockers (CCB) on the treatment and prevention of DU.Using data from 1953 participants, with a median of 4.34 years of follow-up, we used generalised estimating equations to evaluate the clinical characteristics associated with CCB use and ascertain the risk factors for the presence of DU at subsequent study visits. A time-dependent Cox-proportional hazard model was applied to evaluate the risk of future occurrence of DU with CCB use.Sixty-six percent of participants received CCB and patients with a history of DU were more likely to be prescribed a CCB (76.76% vs 53.70%, p \u3c 0.01). CCB use was more frequent in patients with severe complications of DU including chronic DU (OR 1.47, p = 0.02), need for hospitalisation for iloprost (OR 1.30, p = 0.01) or antibiotics (OR 1.36, p = 0.04) and digital amputation (OR 1.48, p \u3c 0.01). Use of CCB was more likely in patients who experienced DU at subsequent study visits (OR 1.32, p \u3c 0.01) and was not associated with a decreased risk of the development of a first DU (HR 0.94, p = 0.65).CCB are frequently used in the management of SSc in the ASCS and their use is associated with severe peripheral vascular manifestations of SSc. However, our results suggest that CCB may not be effective in the healing or prevention of DU

Development and Initial Validation of the Novel Scleroderma Clinical Trials Consortium Activity Index

OBJECTIVE Accurate measurement of disease activity in systemic sclerosis (SSc) remains a significant clinical challenge. The Scleroderma Clinical Trials Consortium (SCTC) convened an Activity Index Working Group (WG) to develop a novel measure of disease activity (SCTC-AI). METHODS Using consensus methodology, we developed a conceptual definition of disease activity. Literature review and expert consensus generated provisional SCTC-AI items, which were reduced by Delphi survey. Provisional items were weighted against a combined endpoint of morbidity and mortality, using time-dependent Cox proportional hazards regression analysis of the Australian Scleroderma Cohort Study (ASCS) (n=1,254). External validation of the SCTC-AI was performed using data collected from 1,103 Canadian Scleroderma Research Group Study participants. RESULTS Disease activity in SSc was defined using consensus methodology as 'aspects of disease that are reversible, or can be arrested, with time and, or effective therapy'. One-hundred and forty-one provisional SCTC-AI items were generated and reduced using 3 rounds of Delphi survey and statistical reduction and weighting, against mortality and quality of life measures, yielding a final 24-item index with a maximum possible score of 140. Survival analysis in an external cohort showed a graded relationship between disease activity scores and survival (p<0.01). CONCLUSION We present a novel instrument to quantify the burden of disease activity in SSc. We have employed a rigorous consensus-based process in combination with data-driven methods, to develop an instrument that has face, content and criterion validity. Further work is required to fully validate and confirm the construct and discriminative validity of the SCTC-AI

Clinical Characteristics and Survival of Pulmonary Arterial Hypertension With or Without Interstitial Lung Disease in Systemic Sclerosis

Objectives To describe the clinical phenotype and prognosis of people in the Australian Scleroderma (SSc) Cohort Study with pulmonary arterial hypertension (PAH) with or without interstitial lung disease (ILD). Methods Participants meeting ACR/EULAR criteria for SSc were divided into four mutually exclusive groups: those meeting criteria for PAH (PAH-only), ILD (ILD-only), concurrent PAH and ILD (PAH-ILD) or neither PAH nor ILD (SSc-only). Logistic or linear regression analyses were used for associations between clinical features, health-related quality of life (HRQoL) and physical function. Survival analysis was performed using Kaplan–Meier estimates and Cox-regression modelling. Results Of 1561 participants, 7% fulfilled criteria for PAH-only, 24% ILD-only, 7% PAH-ILD and 62% SSc-only. People with PAH-ILD were more frequently male, with diffuse skin involvement, higher inflammatory markers, older age of SSc onset and higher frequency of extensive ILD than the cohort overall (p \u3c 0.001). People of Asian race more frequently developed PAH-ILD (p \u3c 0.001). People with PAH-ILD or PAH-only had worse WHO functional class and 6-min-walk-distance than ILD-only (p \u3c 0.001). HRQoL scores were worst in those with PAH-ILD (p \u3c 0.001). Survival was reduced in the PAH-only and PAH-ILD groups (p \u3c 0.01). Multivariable hazard modelling demonstrated the worst prognosis in extensive ILD and PAH (HR = 5.65 95% CI 3.50–9.12 p \u3c 0.01), followed by PAH-only (HR = 4.21 95% CI 2.89–6.13 p \u3c 0.01) and PAH with limited ILD (HR = 2.46 95% CI 1.52–3.99 p \u3c 0.01). Conclusions The prevalence of concurrent PAH-ILD in the ASCS is 7%, with poorer survival in those patients with PAH-ILD compared to ILD or SSc alone. The presence of PAH confers a poorer overall prognosis than even extensive ILD; however, further data are required to better understand the clinical outcomes of this high-risk patient group