UNASSIGNED: Special educational needs (SEN) provision is designed to help pupils with additional educational, behavioural or health needs; for example, pupils with cleft lip and/or palate may be offered SEN provision to improve their speech and language skills. Our aim is to contribute to the literature and assess the impact of SEN provision on health and educational outcomes for a well-defined population.
UNASSIGNED: We will use the ECHILD database, which links educational and health records across England. Our target population consists of children identified within ECHILD to have a specific congenital anomaly: isolated cleft lip and/or palate. We will apply a trial emulation framework to reduce biases in design and analysis of observational data to investigate the causal impact of SEN provision (including none) by the start of compulsory education (Year One - age five year on entry) on the number of unplanned hospital utilisation and school absences by the end of primary education (Year Six - age ten/eleven). We will use propensity score-based estimators (inverse probability weighting (IPW) and IPW regression adjustment IPW) to compare categories of SEN provision in terms of these outcomes and to triangulate results obtained using complementary estimation methods (Naïve estimator, multivariable regression, parametric g-formula, and if possible, instrumental variables), targeting a variety of causal contrasts (average treatment effect/in the treated/in the not treated) of SEN provision.
UNASSIGNED: This study will evaluate the impact of reasonable adjustments at the start of compulsory education on health and educational outcomes in the isolated cleft lip and palate population by triangulating complementary methods under a target-trial framework.
Children born with cleft lip and/or palate have been shown to have lower academic performance compared to the general population and have also been shown to have higher attendances to hospitals. To support children with such health and education needs, special educational needs provisions such as teaching assistants can be provided. The aim of this study is to understand whether children with cleft lip and/or palate were better off on average in receiving special education needs at the start of primary school in terms of hospital usage and school absences.

UNASSIGNED: One third of children in English primary schools have additional learning support called special educational needs (SEN) provision, but children born preterm are more likely to have SEN than those born at term. We aim to assess the impact of SEN provision on health and education outcomes in children grouped by gestational age at birth.
UNASSIGNED: We will analyse linked administrative data for England using the Education and Child Health Insights from Linked Data (ECHILD) database. A target trial emulation approach will be used to specify data extraction from ECHILD, comparisons of interest and our analysis plan. Our target population is all children enrolled in year one of state-funded primary school in England who were born in an NHS hospital in England between 2003 and 2008, grouped by gestational age at birth (extremely preterm (24-<28 weeks), very preterm (28-<32 weeks), moderately preterm (32-<34 weeks), late preterm (34-<37 weeks) and full term (37-<42 weeks). The intervention of interest will comprise categories of SEN provision (including none) during year one (age five/six). The outcomes of interest are rates of unplanned hospital utilisation, educational attainment, and absences by the end of primary school education (year six, age 11). We will triangulate results from complementary estimation methods including the naïve estimator, multivariable regression, g-formula, inverse probability weighting, inverse probability weighting with regression adjustment and instrumental variables, along with a variety for a variety of causal contrasts (average treatment effect, overall, and on the treated/not treated).
UNASSIGNED: We have existing research ethics approval for analyses of the ECHILD database described in this protocol. We will disseminate our findings to diverse audiences (academics, relevant government departments, service users and providers) through seminars, peer-reviewed publications, short briefing reports and infographics for non-academics (published on the study website).
One third of all children need extra help with learning in school, such as support from a teaching assistant. Children born preterm are more likely to need extra help compared to those born at term. In England, this help is called special educational needs (SEN) provision. The aim of this study is to find out whether special educational need provision affects education and health outcomes. We will use information collected by hospitals and schools for all children who were born in England between 2003 and 2008. We will compare those with who received and did not receive extra help in school who have a similar gestational age at birth.

Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups.

UNASSIGNED: To evaluate the overall survival (OS) of patients with chronic lymphocytic leukemia (CLL) receiving either ibrutinib monotherapy as a first-line (1L) treatment or chemotherapy/chemoimmunotherapy-based (CT/CIT) regimens in 1L followed by ibrutinib in the second line (1L CT/CIT-2L ibrutinib) after disease progression by emulating a randomized trial comparing both treatment sequences.
UNASSIGNED: Patient-level data from the RESONATE-2 trial (NCT01722487) and real-world PHEDRA databases were analyzed. Three scenarios were considered using the following data sources: (1) RESONATE-2, (2) combined RESONATE-2/PHEDRA, (3) combined RESONATE-2/PHEDRA for 1L ibrutinib and PHEDRA for 1L CT/CIT-2L ibrutinib. Propensity score-based weights and inverse probability of censoring weighting were used to adjust for baseline (Scenarios 2 and 3) and time-dependent confounding (all scenarios), and to address potential biases. A weighted Cox proportional hazards model was used to estimate the OS hazard ratio (HR) and 95% confidence interval (CI) for 1L ibrutinib versus 1L CT/CIT-2L ibrutinib.
UNASSIGNED: Results from Scenario 1 showed a significantly lower risk of death with 1L ibrutinib compared with 1L chlorambucil followed by 2L ibrutinib (HR 0.35 [95% CI 0.20-0.62]). Results from Scenarios 2 and 3 demonstrated a reduced risk of death with 1L ibrutinib compared with 1L CT/CIT-2L ibrutinib (HR 0.35 [0.21-0.61] and 0.64 [0.39-1.04], respectively).
UNASSIGNED: The analyses consistently showed a reduced risk of death when ibrutinib was used as a 1L treatment in CLL compared with delaying its use until 2L after CT/CIT regimens, which suggests that initiating ibrutinib in 1L is advantageous for improving survival outcomes.

Patients who undergo primary tumor resection (PTR) reportedly have significantly higher overall survival (OS) than those who do not undergo this procedure. However, this result is only evident in past retrospective studies, and clinical trial results did not show the same trend. Thus, it remains unclear whether primary tumor resection effectively increases survival in patients with metastatic colorectal cancer (mCRC) across different study designs. We compared the OS of patients with asymptomatic unresectable mCRC who underwent PTR with that of those who did not. This retrospective cohort study was designed to be a target trial emulation of a randomized controlled trial (RCT) that would have compared the effectiveness of PTR versus non-PTR in patients with asymptomatic unresectable mCRC from 2009 to 2017. A systematic review and meta-analysis were conducted to compare the efficacy of PTR and non-PTR in patients with mCRC, and corresponding results were compared. This cohort included 1,132 patients for a per-protocol analysis. The PTR group had non-significantly longer survival (adjusted hazard ratio: 0.70, 95% confidence interval: 0.62-1.01) than the non-PTR group in our cohort. A meta-analysis including five RCTs (1,016 patients) and our cohort found that the PTR group did not have a significantly lower mortality rate than the non-PTR group. The results of this cohort study and previous RCTs suggest that PTR is not associated with improved survival compared to systemic chemotherapy combined with targeted therapy among asymptomatic unresectable mCRC patients. Therefore, routine PTR is not recommended in these patients.

Direct oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large-scale outcome trials. What role can non-randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT-DUPLICATIVE Initiative emulated the design of eight DOAC randomized clinical trials (RCT) using non-randomized claims database studies. RCT study design parameters and measurements were closely emulated by the database studies and produced highly concordant results. The results of the single database study that did not meet all agreement metrics with the specific RCT it was emulating were aligned with a meta-analysis of six trials studying similar questions, suggesting the trial result was an outlier. Well-designed database studies using fit-for-purpose data came to the same conclusions as DOAC trials, illustrating how database studies could complement RCTs for Factor XI inhibitors-by accelerating insights in underrepresented populations, demonstrating effectiveness and safety in clinical practice, and testing broader indications.

BACKGROUND: High rates of negative intrusive thoughts have been reported among cancer patients. Prevalent users of beta-blocker therapy have reported lower levels of cancer related intrusive thoughts than non-user. The aim of this study is to investigate if initiation of beta-blocker therapy reduces the prevalence and severity of intrusive thoughts (co-primary endpoints) and the prevalence of anxiety, depressed mood, and low quality of life (secondary endpoints) in cancer survivors.
METHODS: Data on patient-reported outcomes from three cohort studies of Swedish patients diagnosed with colon, prostate or rectal cancer were combined with data on beta-blocker prescriptions retrieved from the Swedish Prescribed Drug Register. Two randomized controlled trials were emulated. Trial 1 had follow-up 1 year after diagnosis, trial 2 had follow-up 2 years after diagnosis, baseline in both trials was 12 months before follow-up. Those who initiated beta-blocker therapy between baseline and follow-up was assigned Active group, those who did not was assigned Control group. All endpoints were analysed using Bayesian ordered logistic regression.
RESULTS: Trial 1 consisted of Active group, n = 59, and Control group, n = 3936. Trial 2 consisted of Active group, n = 87, and Control group, n = 3132. The majority of participants were men, 83% in trial 1 and 94% in trial 2. The prevalence and severity of intrusive thoughts were lower in the Active group in trial 1, but no significant differences between groups were found in either trial. The prevalence of depressed mood, worse quality of life and periods of anxiety were higher in the Active group in both trials with significant differences for quality of life in trial 1 and anxiety in trial 2.
CONCLUSIONS: The emulated trials demonstrated no evidence of a protective effect of beta-blocker therapy against intrusive thoughts. The Active group had reduced quality of life and elevated anxiety compared to the Control group.
BACKGROUND: The three cohort studies were registered at isrctn.com/clinicaltrials.gov (ISRCTN06393679, NCT02530593 and NCT01477229).

The randomized controlled trial (RCT) forms the basis for drug approval by regulatory agencies. Observational studies using existing data from healthcare databases now also provide real-world evidence (RWE) in regulatory decision-making. Several initiatives are assessing the value of RWE by conducting observational studies that emulate published RCTs. While many RCTs are straightforward to emulate, others are challenging. We describe three RCT design aspects that pose challenges for observational studies. First are trials that enrol already treated subjects who must discontinue these treatments at the time of randomization, which can distort the comparison with observational studies. Second is the inclusion of a run-in phase, especially to exclude non-compliant subjects from the trial. Third are trials that evaluate the effect of weaning off treatment. In conclusion, future randomized trials that aim to be emulated by observational studies could consider study designs that allow emulation and thus provide valid and complementary RWE.

UNASSIGNED: There is no real-world evidence regarding the association between beta-blocker use and mortality or cardiovascular outcomes in patients with obstructive sleep apnoea (OSA). We aimed to investigate the impact of beta-blocker use on all-cause mortality and cardiovascular diseases (CVDs) in patients with OSA.
UNASSIGNED: We conducted a target trial emulation study of 37,581 patients with newly diagnosed OSA from 1st January 2000 to 30th November 2021 using the IMRD-UK database (formerly known as the THIN database). We compared the treatment strategies of initiating beta-blocker treatment within one year versus non-beta-blocker treatment through the method of clone-censor-weight. Covariates, including patients\' demographics, lifestyle, comorbidities, and recent medications, were measured and controlled. Patients were followed up for all-cause mortality or composite CVD outcomes (angina, myocardial infarction, stroke/transient ischaemic attack, heart failure, or atrial fibrillation). We estimated the five-year absolute risks, risk differences and risk ratio with 95% confidence intervals (CIs) with standardised, weighted pooled logistic regression, which is a discrete-time hazard model for survival analysis. Several sensitivity analyses were performed, including multiple imputation addressing the missing data.
UNASSIGNED: The median follow-up time was 4.1 (interquartile range, 1.9-7.8) years. The five-year absolute risk of all-cause mortality and CVD outcomes were 4.9% (95% CI, 3.8-6.0) and 13.0% (95% CI, 11.4-15.0) among beta-blocker users, and 4.0% (95% CI, 3.8-4.2) and 9.4% (95% CI, 9.1-9.7) among non-beta-blocker users, respectively. The five-year absolute risk difference and risk ratio between the two groups for all-cause mortality and CVD outcomes were 0.9% (95% CI, -0.2 to 2.1) and 1.22 (95% CI, 0.96-1.54), and 3.5% (95% CI, 2.1-5.5) and 1.37 (95% CI, 1.22-1.62), respectively. Findings were consistent across the sensitivity analyses.
UNASSIGNED: Beta-blocker treatment was associated with an increased risk of CVD and a trend for an increased risk of mortality among patients with OSA. Further studies are needed to confirm our findings.
UNASSIGNED: Innovation and Technology Commission of the Hong Kong Special Administration Region Government.

When conducting randomised controlled trials is impractical, an alternative is to carry out an observational study. However, making valid causal inferences from observational data is challenging because of the risk of several statistical biases. In 2016 Hernán and Robins put forward the \'target trial framework\' as a guide to best design and analyse observational studies whilst preventing the most common biases. This framework consists of (1) clearly defining a causal question about an intervention, (2) specifying the protocol of the hypothetical trial, and (3) explaining how the observational data will be used to emulate it.
The aim of this scoping review was to identify and review all explicit attempts of trial emulation studies across all medical fields. Embase, Medline and Web of Science were searched for trial emulation studies published in English from database inception to February 25, 2021. The following information was extracted from studies that were deemed eligible for review: the subject area, the type of observational data that they leveraged, and the statistical methods they used to address the following biases: (A) confounding bias, (B) immortal time bias, and (C) selection bias.
The search resulted in 617 studies, 38 of which we deemed eligible for review. Of those 38 studies, most focused on cardiology, infectious diseases or oncology and the majority used electronic health records/electronic medical records data and cohort studies data. Different statistical methods were used to address confounding at baseline and selection bias, predominantly conditioning on the confounders (N = 18/49, 37%) and inverse probability of censoring weighting (N = 7/20, 35%) respectively. Different approaches were used to address immortal time bias, assigning individuals to treatment strategies at start of follow-up based on their data available at that specific time (N = 21, 55%), using the sequential trial emulations approach (N = 11, 29%) or the cloning approach (N = 6, 16%).
Different methods can be leveraged to address (A) confounding bias, (B) immortal time bias, and (C) selection bias. When working with observational data, and if possible, the \'target trial\' framework should be used as it provides a structured conceptual approach to observational research.