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Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).

Abstract Objectives We systematically reviewed how investigators argued for and justified the validity of their instrumental variables (IV) in clinical studies of dementia and neurodegenerative disease. Methods We included studies using IV analysis with observational data to investigate causal effects in clinical research studies of dementia and neurodegenerative disease. We reported the subject‐matter argumentation, falsification test, and study design strategies used to satisfy the three assumptions of a valid IV: relevance, exclusion restriction, and exchangeability. Results Justification for the relevance assumption was performed in all 12 included studies, exclusion restriction in seven studies, and exchangeability in nine studies. Two subject‐matter argumentation strategies emerged from seven studies on the relevance of their IV. All studies except one provided quantitative evidence for the strength of the association between the IV and exposure variable. Four argumentation strategies emerged for exclusion restriction from six studies. Four falsification tests were performed across three studies. Three argumentation strategies emerged for exchangeability across four studies. Nine falsification tests were performed across nine studies. Two notable study design strategies were reported. Conclusion Our results reinforce IV analysis as a feasible option for clinical researchers in dementia and neurodegenerative disease by clarifying known strategies used to validate an IV.

Abstract Background In the UK, around 93,000 (0.8%) children and young people (CYP) are experiencing specific phobias that have a substantial impact on daily life. The current gold-standard treatment—multi-session cognitive behavioural therapy (CBT) – is effective at reducing specific phobia severity; however, CBT is time consuming, requires specialist CBT therapists, and is often at great cost and limited availability. A briefer variant of CBT called one session treatment (OST) has been found to offer similar clinical effectiveness for specific phobia as multi-session CBT. The aim of this study was to assess the cost-effectiveness of OST compared to multi-session CBT for CYP with specific phobias through the Alleviating Specific Phobias Experienced by Children Trial (ASPECT), a two-arm, pragmatic, multi-centre, non-inferiority randomised controlled trial. Methods CYP aged seven to 16 years with specific phobias were recruited nationally via Health and Social Care pathways, remotely randomised to the intervention group (OST) or the control group (CBT-based therapies) and analysed (n = 267). Resource use based on NHS and personal social services perspective and quality adjusted life years (QALYs) measured by EQ-5D-Y were collected at baseline and at six-month follow-up. Incremental cost-effectiveness ratio (ICER) was calculated, and non-parametric bootstrapping was conducted to capture the uncertainty around the ICER estimates. The results were presented on a cost-effectiveness acceptability curve (CEAC). A set of sensitivity analyses (including taking a societal perspective) were conducted to assess the robustness of the primary findings. Results After adjustment and bootstrapping, on average CYP in the OST group incurred less costs (incremental cost was -£302.96 (95% CI -£598.86 to -£28.61)) and maintained similar improvement in QALYs (QALYs gained 0.002 (95% CI − 0.004 to 0.008)). The CEAC shows that the probability of OST being cost-effective was over 95% across all the WTP thresholds. Results of a set of sensitivity analyses were consistent with the primary outcomes. Conclusion Compared to CBT, OST produced a reduction in costs and maintained similar improvement in QALYs. Results from both primary and sensitivity analyses suggested that OST was highly likely to be cost saving. Trial registration ISRCTN19883421 (30/11/2016).

Abstract Background Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. Methods The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. Discussion This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need. Trial registration The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 .

The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Abstract Background In proportionate or adaptive interventions, the dose or intensity can be adjusted based on individual need at predefined decision stages during the delivery of the intervention. The development of such interventions may require an evaluation of the effectiveness of the individual stages in addition to the whole intervention. However, evaluating individual stages of an intervention has various challenges, particularly the statistical design and analysis. This review aimed to identify the use of trials of proportionate interventions and how they are being designed and analysed in current practice. Methods We searched MEDLINE, Web of Science and PsycINFO for articles published between 2010 and 2015 inclusive. We considered trials of proportionate interventions in all fields of research. For each trial, its aims, design and analysis were extracted. The data synthesis was conducted using summary statistics and a narrative format. Results Our review identified 44 proportionate intervention trials, comprising 28 trial results, 13 protocols and three secondary analyses. These were mostly described as stepped care (n=37) and mainly focussed on mental health research (n=30). The other studies were aimed at finding an optimal adaptive treatment strategy (n=7) in a variety of therapeutic areas. Further terminology used included adaptive intervention, staged intervention, sequentially multiple assignment trial or a two-phase design. The median number of decision stages in the interventions was two and only one study explicitly evaluated the effect of the individual stages. Conclusions Trials of proportionate staged interventions are being used predominantly within the mental health field. However, few studies consider the different stages of the interventions, either at the design or the analysis phase, and how they may interact with one another. There is a need for further guidance on the design, analyses and reporting across trials of proportionate interventions. Trial registration Prospero, CRD42016033781. Registered on 2 February 2016.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Abstract Background In individually randomised trials we might expect interventions delivered in groups or by care providers to result in clustering of outcomes for participants treated in the same group or by the same care provider. In partially nested randomised controlled trials (pnRCTs) this clustering only occurs in one trial arm, commonly the intervention arm. It is important to measure and account for between-cluster variability in trial design and analysis. We compare analysis approaches for pnRCTs with continuous outcomes, investigating the impact on statistical inference of cluster sizes, coding of the non-clustered arm, intracluster correlation coefficient (ICCs), and differential variance between intervention and control arm, and provide recommendations for analysis. Methods We performed a simulation study assessing the performance of six analysis approaches for a two-arm pnRCT with a continuous outcome. These include: linear regression model; fully clustered mixed-effects model with singleton clusters in control arm; fully clustered mixed-effects model with one large cluster in control arm; fully clustered mixed-effects model with pseudo clusters in control arm; partially nested homoscedastic mixed effects model, and partially nested heteroscedastic mixed effects model. We varied the cluster size, number of clusters, ICC, and individual variance between the two trial arms. Results All models provided unbiased intervention effect estimates. In the partially nested mixed-effects models, methods for classifying the non-clustered control arm had negligible impact. Failure to account for even small ICCs resulted in inflated Type I error rates and over-coverage of confidence intervals. Fully clustered mixed effects models provided poor control of the Type I error rates and biased ICC estimates. The heteroscedastic partially nested mixed-effects model maintained relatively good control of Type I error rates, unbiased ICC estimation, and did not noticeably reduce power even with homoscedastic individual variances across arms. Conclusions In general, we recommend the use of a heteroscedastic partially nested mixed-effects model, which models the clustering in only one arm, for continuous outcomes similar to those generated under the scenarios of our simulations study. However, with few clusters (3–6), small cluster sizes (5–10), and small ICC (≤0.05) this model underestimates Type I error rates and there is no optimal model.

Abstract Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

Background: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke.

Background: The high relapse and mortality rate of small-cell lung cancer (SCLC) fuels the need for epidemiologic study to aid in its prevention. Methods: We included 24 studies from the ILCCO collaboration. Random-effects panel logistic regression and cubic spline regression were used to estimate the effects of smoking behaviors on SCLC risk and explore their non-linearity. Further, we explored whether the risk of smoking on SCLC was mediated through COPD. Findings: Significant dose–response relationships of SCLC risk were observed for all quantitative smoking variables. Smoking pack-years were associated with a sharper increase of SCLC risk for pack-years ranged 0 to approximately 50. The former smokers with longer cessation showed a 43%quit_for_5–9 years to 89%quit_for_≥20 years declined SCLC risk vs. subjects who had quit smoking

Background The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objective The objective was to determine the clinical effectiveness and cost-effectiveness of septoplasty, with or without turbinate reduction, compared with medical management, in the management of nasal obstruction associated with a deviated nasal septum. Design This was a multicentre randomised controlled trial comparing septoplasty, with or without turbinate reduction, with defined medical management; it incorporated a mixed-methods process evaluation and an economic evaluation. Setting The trial was set in 17 NHS secondary care hospitals in the UK. Participants A total of 378 eligible participants aged > 18 years were recruited. Interventions Participants were randomised on a 1: 1 basis and stratified by baseline severity and gender to either (1) septoplasty, with or without turbinate surgery (n = 188) or (2) medical management with intranasal steroid spray and saline spray (n = 190). Main outcome measures The primary outcome was the Sino-nasal Outcome Test-22 items score at 6 months (patient-reported outcome). The secondary outcomes were as follows: patient-reported outcomes – Nasal Obstruction Symptom Evaluation score at 6 and 12 months, Sino-nasal Outcome Test-22 items subscales at 12 months, Double Ordinal Airway Subjective Scale at 6 and 12 months, the Short Form questionnaire-36 items and costs; objective measurements – peak nasal inspiratory flow and rhinospirometry. The number of adverse events experienced was also recorded. A within-trial economic evaluation from an NHS and Personal Social Services perspective estimated the incremental cost per (1) improvement (of ≥ 9 points) in Sino-nasal Outcome Test-22 items score, (2) adverse event avoided and (3) quality-adjusted life-year gained at 12 months. An economic model estimated the incremental cost per quality-adjusted life-year gained at 24 and 36 months. A mixed-methods process evaluation was undertaken to understand/address recruitment issues and examine the acceptability of trial processes and treatment arms. Results At the 6-month time point, 307 participants provided primary outcome data (septoplasty, n = 152; medical management, n = 155). An intention-to-treat analysis revealed a greater and more sustained improvement in the primary outcome measure in the surgical arm. The 6-month mean Sino-nasal Outcome Test-22 items scores were −20.0 points lower (better) for participants randomised to septoplasty than for those randomised to medical management [the score for the septoplasty arm was 19.9 and the score for the medical management arm was 39.5 (95% confidence interval −23.6 to −16.4; p < 0.0001)]. This was confirmed by sensitivity analyses and through the analysis of secondary outcomes. Outcomes were statistically significantly related to baseline severity, but not to gender or turbinate reduction. In the surgical and medical management arms, 132 and 95 adverse events occurred, respectively; 14 serious adverse events occurred in the surgical arm and nine in the medical management arm. On average, septoplasty was more costly and more effective in improving Sino-nasal Outcome Test-22 items scores and quality-adjusted life-years than medical management, but incurred a larger number of adverse events. Septoplasty had a 15% probability of being considered cost-effective at 12 months at a £20,000 willingness-to-pay threshold for an additional quality-adjusted life-year. This probability increased to 99% and 100% at 24 and 36 months, respectively. Limitations COVID-19 had an impact on participant-facing data collection from March 2020. Conclusions Septoplasty, with or without turbinate reduction, is more effective than medical management with a nasal steroid and saline spray. Baseline severity predicts the degree of improvement in symptoms. Septoplasty has a low probability of cost-effectiveness at 12 months, but may be considered cost-effective at 24 months. Future work should focus on developing a septoplasty patient decision aid. Trial registration This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information. Plain language summary Septoplasty is an operation to straighten the septum, which is the partition wall between the nostrils inside the nose. Septoplasty can be used as a treatment for people who have a bent septum and symptoms of a blocked nose, such as difficulty sleeping and exercising. Medical management (a saltwater spray to clear the nose followed by a nose steroid spray) is an alternative treatment to septoplasty. The Nasal AIRway Obstruction Study (NAIROS) aimed to find out whether septoplasty or medical management is a better treatment for people with a bent septum and symptoms of a blocked nose. We recruited 378 patients with at least moderately severe nose symptoms from 17 hospitals in England, Scotland and Wales to take part in the NAIROS. Participants were randomly put into one of two groups: septoplasty or medical management. Participants’ nose symptoms were measured both when they joined the study and after 6 months, using a questionnaire called the Sino-nasal Outcome Test-22 items. This questionnaire was chosen because patients reported that it included symptoms that were important to them. Other studies have shown that a 9-point change in the Sino-nasal Outcome Test-22 items score is significant. After 6 months, on average, people in the septoplasty group improved by 25 points, whereas people in the medical management group improved by 5 points. We saw improvement after septoplasty among patients with moderate symptoms, and among those with severe symptoms. Most patients who we spoke to after a septoplasty were happy with their treatment, but some would have liked more information about what to expect after their nose surgery. In the short term, septoplasty is more costly than medical management. However, over the longer term, taking into account all the costs and benefits of treatment, suggests that septoplasty would be considered good value for money for the NHS. Scientific summary Background The indications for septoplasty are practice-based, rather than evidence-based. In addition, internationally accepted guidelines for the management of nasal obstruction associated with nasal septal deviation are lacking. Objectives The study objectives are split into three different aspects: clinical effectiveness, economic evaluation and mixed-methods process evaluation. Objective 1 was to measure clinical effectiveness according to: subjective self-reported rating of nasal airway obstruction heterogeneity of estimated treatment effect, specifically according to severity of obstruction and gender objective measures of nasal patency number of adverse events (AEs) and additional interventions required technical failure in the surgical arm how well those agreeing to enter the trial reflect those screened for eligibility. Objective 2 was to conduct an economic evaluation from the perspective of the NHS and Personal Social Services. This entailed the following processes: conducting a cost-effectiveness analysis, with outcomes reported as incremental cost per ≥ 9-point improvement in the Sino-nasal Outcome Test-22 items (SNOT-22) scores and number of AEs conducting a cost–utility analysis, with outcomes reported as incremental cost per quality-adjusted life-year (QALY) gained designing a longer-term economic model to assess costs and health consequences beyond the 12-month follow-up period. Objective 3 was to conduct a mixed-methods process evaluation of the trial and interventions, to understand: barriers to optimal recruitment, and potential solutions to address these, through integration of the Qualitative research integrated within Trials (QuinteT) Recruitment Intervention (QRI) participants’ and healthcare professionals’ experiences of trial participation and the interventions, and perceived factors likely to influence wider implementation of trial findings. Methods The Nasal AIRway Obstruction Study (NAIROS) was a multicentre, non-blinded randomised controlled trial comparing the effectiveness of septoplasty, with or without turbinate surgery, with a standardised medical management package of 6 months of intranasal steroid spray and saline spray. Participants were randomised on a 1 : 1 basis between the septoplasty (within 8 weeks) and medical management arms. The trial included an integrated health economic evaluation and a mixed-methods process evaluation incorporating a QRI. The target sample size of 378 participants allowed for 20% dropout to deliver 90% power for detecting a minimal clinically important difference of 9 points in SNOT-22 scores. This assumed a two-sided type error rate of 5% and a standard deviation of 24 points in SNOT-22 scores at 6 months. Interventions The two interventions being compared were as follows. Septoplasty, with or without inferior turbinate reduction in the contralateral nostril, performed at the discretion of the investigating clinician, preferably performed within 8 weeks of randomisation or, if not, by 12 weeks. Medical management with 6 months of mometasone furoate 50 μg per dose nasal steroid spray, suspension (Nasonex®; Merck Sharp & Dohme Limited, Hoddesdon, UK), and isotonic nasal saline spray. Participants had the option of deferred surgery after 6 or 12 months post randomisation. Setting and participants We recruited 378 patients to the main trial from 17 NHS hospitals in Great Britain. Eligible patients were identified from general ear, nose and throat referrals. Of those recruited, 188 were randomised to septoplasty and 190 were randomised to medical management. Inclusion criteria Adults aged ≥ 18 years. Baseline Nasal Obstruction Symptom Evaluation (NOSE) scale score of ≥ 30. Septal deflection visible via nasoendoscopy. Capacity to provide informed consent/complete trial questionnaires. Exclusion criteria Prior septal surgery. Systemic inflammatory disease/use of oral steroid treatment in the previous 2 weeks. Granulomatosis with polyangiitis. Nasoendoscopic evidence of unrelated associated pathology. Intranasal recreational drug use in the previous 6 months. Breastfeeding, pregnancy or intended pregnancy for duration of involvement in the trial. Bleeding diathesis. Therapeutic anticoagulation. Contraindication to general anaesthesia. Immunocompromised. External bony deformity. Measurement of clinical outcomes Primary outcome The primary outcome was patient-reported assessment of nasal and general symptoms, using the SNOT-22 questionnaire, at 6 months (−2 weeks/+4 weeks). The SNOT-22 was also assessed at baseline and 12 months (± 2 weeks). Secondary outcomes Objective measures: peak nasal inspiratory flow and rhinospirometry (maximal inhalation volume and tidal breathing) at baseline and at 6 and 12 months. Patient-reported outcomes: SNOT-22 subscales at 12 months, NOSE score and Double Ordinal Airway Subjective Scale at baseline and at 6 and 12 months. Safety measures: number and characteristics of any AEs, surgical complications and reinterventions within 12 months. Quality of life, measured using the Short Form questionnaire-36 items (SF-36) at baseline and at 6 and 12 months. Healthcare utilisation questionnaire at baseline and at 6 and 12 months. Time and travel questionnaire at 12 months. Measurement of health economic outcomes To compare costs incurred by the NHS and Personal Social Services (PSS) with those incurred by participants in the management of a deviated septum. To compare QALYs, based on responses to the SF-36 administered at baseline and at 6 and 12 months, converted to Short Form questionnaire-6 Dimensions (SF-6D) utility scores, derived using the area under the curve method. To compare the cost-effectiveness of septoplasty with that of medical management at 12 months, measured in terms of the incremental: cost per improvement (of ≥ 9 points) in SNOT-22 scores cost per AE avoided cost per QALY gained. To compare the cost-effectiveness of septoplasty with that of medical management at 24 and 36 months in terms of the incremental cost per QALY gained (costs and QALYs were extrapolated using an economic model). Mixed-methods process evaluation outcomes The objectives for the mixed-methods process evaluation were addressed through observations of training and NAIROS meetings, interviews with health professionals and participants, audio-recording of recruitment discussions and review of screening logs. The QRI initiated with a ‘pre-recruitment’ phase to raise awareness about common recruitment issues/solutions learnt from previous trials. Phase 1 of the QRI investigated sources of recruitment difficulty that were specific to the NAIROS, informing ‘actions’ to optimise recruitment as the trial was under way (phase 2). Statistical analysis The primary statistical analysis was carried out on an intention-to-treat (ITT) basis, retaining patients in their randomised treatment groups. Multivariable linear regression models were used to compare the 6-month SNOT-22 scores between the treatment groups, adjusting any treatment effect by baseline SNOT-22 score and stratification factors at randomisation [(1) gender and (2) severity at baseline (according to three NOSE categories reported in the literature: 30–50, moderate; 55–75, severe; and 80–100, extreme)]. Sensitivity analyses, including a per-treatment and a per-protocol analysis, were also undertaken. Secondary outcomes were analysed in a way that was similar to the primary outcome analysis. Economic analysis The cost-effectiveness of septoplasty, compared with medical management, was evaluated by estimating the total costs incurred by the NHS and PSS to manage a deviated septum and averaging these costs across participants in each study arm. Both within-trial and model-based analyses were undertaken. The within-trial analysis estimated costs and effects over 12 months. Three different measures of effects were used: improvement (of ≥ 9 points) in SNOT-22 scores, number of AEs and QALYs. QALYs were derived from responses to the SF-36, which we converted into SF-6D scores (utilities) using a standardised algorithm and the area under the curve approach. An economic model was designed to extrapolate costs and benefits beyond the 12-month study follow-up period. Mixed-methods process evaluation analysis QuinteT Recruitment Intervention: thematic and content analyses were undertaken of interviews and audio-recorded consultations, and descriptive analyses of screening log data were undertaken. Qualitative process evaluation: a thematic analysis was undertaken using a coding framework, informed by normalisation process theory. Results Primary outcomes The ITT analysis found that, at 6 months, participants randomised to the septoplasty arm (n = 152) had SNOT-22 scores that were, on average, 20.0 points lower (i.e. better) than those of participants randomised to medical management (n = 155) [95% confidence interval (CI) −23.6 to −16.4 points; p < 0.0001]. This strong signal was confirmed by both sensitivity analyses and analysis of secondary outcomes. The mean SNOT-22 scores at 6 months were 19.9 points for the septoplasty arm and 39.5 points for the medical management arm. At 12 months, the adjusted mean difference for SNOT-22 scores between the two arms had reduced to −10.1 points (95% CI −14.5 to −5.6 points; p < 0.0001). This diminished effect at 12 months was predominantly due to SNOT-22 scores tending to reduce over time among those randomised to medical management. Overall, the improvement in SNOT-22 score in the surgical arm was both notably faster and greater, and was sustained over the trial period. Increased baseline severity of nasal obstruction was associated with greater improvements in the primary outcome. Gender had no impact on outcome improvement. Approximately 45 out of 190 (24%) participants discontinued allocated medical management treatment and had non-trial surgery, and 22 out of 188 (12%) of those randomised to septoplasty did not receive the surgical intervention. The per-protocol (treatment effect −19.7, 95% CI −23.4 to −16.0) and per-treatment analyses (treatment effect −19.3, 95% CI −23.3 to −15.3) confirmed a statistically significant greater improvement in the surgical arm. Secondary outcomes All secondary outcome measures, both patient-reported and objective measures, showed a greater improvement in the surgical arm. Turbinate reduction did not appear to add additional benefit in comparison with septoplasty alone. At 6 months, 80% of patients reported improvement in nasal breathing (74% at 12 months). Six out of 166 patients undergoing septoplasty were recommended to consider revision septoplasty. Adverse events Overall, there were 227 AEs: 132 in the surgical arm and 95 in the medical management arm. Fourteen serious adverse events occurred in the surgical arm and nine in the medical arm. At 6 months, 7 out of 174 (4%) participants experienced hospital re-admission with nasal bleeding, none of whom required operative reintervention. Twenty out of 172 (12%) participants reported infection requiring antibiotic treatment, 19 out of 171 (11%) participants reported decreased sense of smell, 18 out of 171 (11%) participants reported numbness of the upper teeth and 17 out of 171 (10%) participants reported change in appearance of the nose. Six nasal septal perforations (3%) and seven intranasal adhesions (4%) were noted at 6 and 12 months’ follow-up. Economic evaluation On average, septoplasty was more costly and more effective in terms of improvements in SNOT-22 score and QALYs than medical management. The incremental cost per improvement (of ≥ 9 points) in SNOT-22 score was £4855. The incremental cost per QALY gained was £27,114 and septoplasty had a 15% probability of being considered cost-effective at a £20,000 willingness-to-pay threshold for an additional QALY. This probability increased to 68% at a £30,000 threshold. Septoplasty was dominated by medical management when AEs were the outcome of interest, as it was more costly and associated with a greater number of AEs. The economic model estimated the incremental cost per QALY gained at 24 months (£13,221) and 36 months (£7368). Septoplasty had a 99% (at 24 months) and a 100% (at 36 months) probability of being considered cost-effective, compared with medical management, at a £20,000 threshold for an additional QALY. Mixed-methods process evaluation QuinteT Recruitment Intervention findings Data sources included 19 interviews with recruiters, 108 audio-recorded discussions and regular scrutiny of screening logs. Despite recruiters’ commitment to the NAIROS, there were challenges operationalising recruitment processes into routine clinical care, which restricted identification of potentially eligible patients. Analysis of recorded consultations revealed evidence of recruiters operationalising the pre-recruitment training, but also illuminated unanticipated challenges around explaining the trial arms, which undermined equipoise. Tailored actions were implemented in phase 2 to address these issues, through feedback/training for individuals/groups, ‘recruitment workshops’ with sites, and written guidance and webinars for professionals who interacted with patients throughout the clinical pathway. The recruitment target was reached successfully without a funding extension and without the need to open additional sites. Qualitative process evaluation Nine surgeons and five research nurses working on the NAIROS trial were interviewed and 39 interviews were conducted with 31 participants. Prior to the NAIROS, decisions regarding the appropriateness of surgery for individual patients were made on the basis of a complex and largely subjective combination of symptoms, history and patient anatomy. Surgeons indicated that they would welcome clearer criteria to guide decision-making. However, although some surgeons embraced a role for standardised outcome measures such as the NOSE and the SNOT-22 in decision-making, others were more reluctant; this could be a barrier to the implementation of trial findings. Although trial findings show that, as a group, participants in the surgical arm experienced more improvement than those in the medical management arm, the qualitative study demonstrated that individual experiences were varied. Although some patients in the medical management arm achieved little or no benefit from treatment, others did report positive effects, with a possible mechanism of action being a reduction in turbinate size. Patients undergoing medical management might benefit from individual advice regarding application of the sprays, taking into account distorted anatomy, to maximise effectiveness and reduce side effects. Although most participants were able to incorporate spray use into their daily routines, long-term spray use was perceived by some to be burdensome. Despite the large number of participants who perceived septoplasty to be effective in reducing their symptoms, there were still some participants who felt that they received little to no benefit from the operation. Participants reported being underprepared for the immediate post-surgery period. Limitations COVID-19 had a major impact on the study, resulting in the cessation of clinical measurements and objective outcomes from March 2020. From that time, all patient-reported outcomes were collected by post or online, or transcribed over the telephone. The ITT analysis is likely to offer an overestimate of the true impact of medical management in improving outcomes as 22% of participants in that arm received septoplasty before the 12-month outcome point. Conclusions Septoplasty, with or without turbinate reduction, is a clinically effective intervention. Participants with a deviated nasal septum with a moderate, severe or extreme baseline severity of nasal obstruction symptoms had an improvement in patient-reported outcomes at 6 and 12 months. This improvement surpassed that of standardised medical management. The results suggest that surgery has a low probability of being cost-effective at 12 months but may be considered cost-effective at 24 months. Impact on health services The NAIROS clearly demonstrates that adults presenting with nasal obstruction associated with a deviated nasal septum, in the absence of clinical evidence of a coexistent nasal/sinus disease and with a baseline NOSE score of > 30, can reliably be offered surgery in the knowledge that improvements in patient-reported outcomes are superior to improvements when treated with a nasal steroid/saline spray combination. Recommendations for research The most important research priority to emerge from the NAIROS is the need to develop a patient decision aid to explore management of a deviated nasal septum. The place of medical treatment in the management of nasal obstruction associated with a deviated nasal septum needs to be explored further. A prospective randomised trial would be required to examine the place of turbinate reduction surgery in nasal obstruction. Study registration This trial is registered as ISRCTN16168569 and EudraCT 2017-000893-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 14/226/07) and is published in full in Health Technology Assessment; Vol. 28, No. 10. See the NIHR Funding and Awards website for further award information.

Background Social skills interventions are commonly recommended to help children and young people with autism spectrum disorder develop social skills, but some struggle to engage in these interventions. LEGO® (LEGO System A/S, Billund, Denmark) based therapy, a group social skills intervention, aims to be more interesting and engaging. Objective To evaluate the clinical effectiveness of LEGO® based therapy on the social and emotional skills of children and young people with autism spectrum disorder in school settings compared with usual support. Secondary objectives included evaluations of cost-effectiveness, acceptability and treatment fidelity. Design A cluster randomised controlled trial randomly allocating participating schools to either LEGO® based therapy and usual support or usual support only. Setting Mainstream schools in the north of England. Participants Children and young people (aged 7–15 years) with autism spectrum disorder, their parent/guardian, an associated teacher/teaching assistant and a facilitator teacher/teaching assistant (intervention schools only). Intervention Schools randomised to the intervention arm delivered 12 weekly sessions of LEGO® based therapy, which promotes collaborative play and encourages social problem-solving in groups of three children and young people with a facilitator (trained teacher or teaching assistant). Participants received usual support from school and community services. Participants in the control arm received usual support only. Research assistants and statisticians were blind to treatment allocation. Main outcome measure The social skills subscale of the Social Skills Improvement System (SSIS), completed by the children and young people’s unblinded teacher pre randomisation and 20 weeks post randomisation. The SSIS social skills subscale measures social skills including social communication, co-operation, empathy, assertion, responsibility and self-control. Participants completed a number of other pre- and post-randomisation measures of emotional health, quality of life, loneliness, problem behaviours, academic competence, service resource utilisation and adverse events. Results A total of 250 children and young people from 98 schools were randomised: 127 to the intervention arm and 123 to the control arm. Intention-to-treat analysis of the main outcome measure showed a modest positive difference of 3.74 points (95% confidence interval –0.16 to 7.63 points, standardised effect size 0.18; p = 0.06) in favour of the intervention arm. Statistical significance increased in per-protocol analysis, with a modest positive difference (standardised effect size 0.21; p = 0.036). Cost-effectiveness of the intervention was found in reduced service use costs and a small increase in quality-adjusted life-years. Intervention fidelity and acceptability were positive. No intervention-related adverse events or effects were reported. Conclusions The primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes of between 0.15 and 0.21. There were positive health economics and qualitative findings, corroborated by the difference between arms for the majority of secondary outcomes, which were not statistically significant but favoured the intervention arm. Post hoc additional analysis was exploratory and was not used in drawing this conclusion. Given the small positive change, LEGO® based therapy for children and young people with autism spectrum disorder in schools should be considered. Limitations The primary outcome measure was completed by an unblinded teacher (rather than by the facilitator). Future work The study team recommends future research into LEGO® based therapy, particularly in school environments. Trial registration This trial is registered as ISRCTN64852382. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary Autism spectrum disorder is characterised by difficulties with social relationships and communication, which can make it difficult to make friends. Social skills training is commonly used to help children and young people learn different social skills, but some children and young people do not enjoy these therapies. LEGO® (LEGO System A/S, Billund, Denmark) based therapy takes a new approach by focusing on making the process interesting and fun. This research investigated the effect of LEGO® based therapy groups in schools on the social and emotional abilities of children and young people with autism spectrum disorder. It was a randomised controlled trial, so each school that was taking part was randomly chosen to provide either usual support (from the school or NHS services) or 12 sessions of LEGO® based therapy with a trained school staff member as well as usual support. Children and young people played one of three roles – the ‘engineer’ (gives instructions), the ‘supplier’ (finds the pieces) or the ‘builder’ (builds the model) – and worked together. Questionnaires completed by children and young people, their parents/guardians and teachers were used to look at the intervention’s effects. The main objective was to see if there was a change in social skills measured by a teacher-completed questionnaire. Results showed that the social skills of children and young people in the LEGO® based therapy groups did improve a little. We found that the intervention is not very costly for schools to run. Many parents/guardians and teachers thought that the intervention was beneficial and that the children and young people enjoyed it. Scientific summary Background Autism spectrum disorder (ASD) is a neurodevelopmental condition currently estimated to affect 1.00–1.16% of children and young people (CYP) in the UK. Autistic CYP typically experience developmental differences in social communication and may have strong specific interests/preferences and repetitive behaviours. Impacts are often seen in social functioning, general mental health and long-term social and educational outcomes into adulthood. Social learning through friendships is an important part of a child or young person’s development. It is an area in which many autistic CYP struggle because they tend to initiate and engage in social interactions differently from typically developing peers. They may prefer solitary activities with structured rules and less co-operative play and emotional exchange, which may mean that they find social interactions more challenging. Over time, autistic CYP may feel socially isolated. A number of social interventions aim to help autistic CYP to develop these skills. CYP often find it difficult to transfer skills learnt in one context to other areas of their lives. LEGO® (LEGO System A/S, Billund, Denmark) based therapy is a group social skills intervention designed for autistic CYP to facilitate the learning and flexible practising of social skills with peers. It is designed to make social interactions interesting by using a structured and predictable toy with which CYP are often already familiar and intrinsically motivated to play. The use of LEGO® based therapy in the UK is increasing following reported potential benefits. However, the evidence base for LEGO® based therapy is limited, with only a small number of studies assessing its use for autistic CYP. Among these, only one small study used a randomised controlled trial design to compare LEGO® based therapy with a similar social skills intervention, the Social Use of Language Programme (SULP). This study had several limitations, including a small sample size and a lack of fully randomised allocation. A scoping review of the research in this area conducted in 2017 concluded that more robustly designed studies with larger sample sizes and standardised outcome measures are needed to properly evaluate the effectiveness of LEGO® based therapy in this population. Objectives Primary objective To examine the clinical effectiveness of LEGO® based therapy groups on the social and emotional competence (specifically perceived social skills) of autistic CYP in schools, compared with usual support for autistic CYP, at 20 weeks after randomisation. Secondary objectives To examine the clinical effectiveness of LEGO® based therapy groups on the perceived social isolation of autistic CYP in schools, compared with usual support for, at 20 and 52 weeks. To examine the clinical effectiveness of LEGO® based therapy groups on the academic competence of autistic CYP in schools, compared with usual support for autistic CYP, at 20 and 52 weeks. To examine the clinical effectiveness of LEGO® based therapy groups on assertion, social control, externalising and internalising in autistic CYP in the school setting, compared with usual support for autistic CYP, at 20 and 52 weeks. To examine the cost-effectiveness of LEGO® based therapy groups, compared with usual support for autistic CYP, at 52 weeks. To examine the emotional and behavioural symptoms in those receiving LEGO® based therapy, compared with usual support for autistic CYP, at 20 and 52 weeks. To determine if the impact of LEGO® based therapy is sustainable into the next academic year by comparing effectiveness on social and emotional competence (specifically perceived social skills) at 52 weeks after randomisation. To examine the acceptability of the intervention at follow-up points using a purpose-designed questionnaire and telephone interviews at 20 weeks. To examine treatment fidelity through independent observation of treatment sessions across schools and a self-report measure completed by the facilitator [i.e. a trained teacher or teaching assistant (TA)] after each session. Setting The setting was mainstream primary and secondary schools in the north of England. Participants Participants were CYP in mainstream schools between the ages of 7 and 15 years with a diagnosis of ASD, a parent or guardian of the CYP and a teacher or TA in the child or young person’s school who knew them well (i.e. an associated teacher). Another school staff member was recruited in schools allocated to the intervention arm to run the LEGO® based therapy sessions (i.e. a facilitator teacher). Participants were recruited by contact with mainstream primary and secondary schools following meetings to explain the study and confirmation of eligible CYP in their schools. Participants were included if they met study inclusion criteria and provided fully informed consent to participate. Methods The trial used a pragmatic cluster randomised controlled trial design. Remote randomisation of each school using stratified randomisation lists was provided by a blinded statistician from the Clinical Trials Research Unit, School of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK. All participants completed a set of baseline questionnaires. Once baseline measures were completed for all participants in a school, the school was randomly allocated to one of two trial arms. Participating CYP in schools allocated to the intervention arm received 12 sessions of LEGO® based therapy in addition to usual support from their school, their general practitioner and other professionals. In schools allocated to the control arm, participating CYP received usual support only. Training was provided for intervention school staff by members of the study team and experienced local authority members trained by experts in the field. All participants were followed up 20 and 52 weeks after their school was randomised and were asked to complete similar questionnaires to those completed at baseline and questionnaires around their health resource use. Acceptability of the interventions was assessed using a purpose-designed questionnaire and telephone interviews with parents and facilitators. Fidelity was assessed using questionnaires and video-recordings when possible. The study team ensured the involvement of patients and the public throughout the study, including a parent of an autistic child and groups such as the Young Dynamos research advisory group (Bradford District Care NHS Foundation Trust, Shipley, UK) and the National Autistic Society (London, UK) in initial study design and specific discussions throughout the study. Intervention LEGO® based therapy LEGO® based therapy is a social skills intervention designed to support CYP with social communication difficulties, such as autistic CYP, by offering playful opportunities to practise social skills. It was created by Daniel LeGoff, who observed that autistic CYP may be particularly drawn to LEGO bricks, perhaps because of their interests and strengths in systemising. In the intervention, CYP, usually in groups of three, build LEGO sets. The CYP take turns to play one of three roles: the ‘engineer’, who has the instructions and communicates them to the group; the ‘supplier’, who finds the correct bricks; and the ‘builder’, who builds the model. CYP then progress to collaborative ‘freestyle’ building, in which they build models of their own design together. Sessions aim to be CYP led, following their interests as far as possible. Many skills are practised throughout, including communication, joint attention, problem-solving, emotion regulation and compromise. The intervention uses a naturalistic play setting, meaning that CYP learn how to collaborate with others through doing, rather than through didactic teaching. Sessions are facilitated by an adult, who aims to guide the CYP rather than direct them explicitly. Adults are encouraged to allow CYP to solve their own challenges and to promote social problem-solving skills, stepping in to prompt through open questions when needed. CYP are encouraged to practise and role-play new social strategies discovered in the sessions. The adult’s role is also to praise and highlight the positive things happening in a session, using rewards such as stickers and certificates as motivation. Procedure The intervention was provided in school by teachers or TAs, termed ‘facilitators’, who were provided with a 3-hour face-to-face training session on how to deliver the intervention. Training was provided by members of the study team and experienced professionals from each recruiting site’s local authority who had been ‘trained to train’ school staff members by co-applicant Gina Gomez de la Cuesta and expert colleagues. Facilitators were also provided with a brief guide specifically designed for this study, which describes the essential elements of the intervention and how to facilitate sessions successfully. Schools were given all materials needed to run their sessions, including a range of LEGO sets with instructions and freestyle bricks, funded by the research. Groups were also given ‘brick club’ materials, including group rules, role cards (i.e. supplier, builder or engineer), free-play building ideas and a points system chart, all of which they were encouraged to use. Schools were asked to run 12 sessions of LEGO® based therapy over a 12-week period. It was recommended that sessions were run for 1 hour once per week for the 12-week period; however, multiple sessions in 1 week due to illness and time constraints were acceptable. Sessions less than 1 hour in duration were also acceptable, but facilitators were encouraged to run groups for at least 45 minutes. Fidelity Intervention fidelity was assessed via two methods: (1) completion of the self-report fidelity checklist after each session of LEGO® based therapy by all facilitators and (2) video-recording of a subset of sessions where consent to be video-recorded was obtained. Video-recordings were stratified to include sessions from three time points: early intervention sessions (sessions 1–4), mid-point intervention sessions (sessions 5–8) and later intervention sessions (sessions 9–12). The self-report fidelity checklist was designed by experts on the team and mapped onto the main components of the intervention identified in the manual and previous publications. It asked the facilitator to identify which components of the intervention had taken place. Video-recordings were completed in schools where all participating CYP, their parents/guardians and the facilitator consented to the recording. These were then independently reviewed and assessed for fidelity to the intended intervention delivery method against the fidelity checklist. Sixteen sessions were double rated to ensure rating accuracy. Results The clinical effectiveness of LEGO® based therapy for autistic CYP was analysed using intention-to-treat (ITT) analysis of the teacher-completed social skills subscale of the Social Skills Improvement System (SSIS) at 20 weeks. A total of 250 participants were consented and randomised to the trial, and the primary outcome ITT analysis comprised 217 CYP (86.8%) with complete baseline and primary outcome data, with 116 in the intervention arm (91.3%) and 101 in the control arm (82.1%). The SSIS is a behaviour rating scale widely used in national portfolio studies and has been shown to be sensitive to change. A modest positive difference on this scale of 3.74 points [95% confidence interval (CI) –0.16 to 7.63 points, p = 0.06; standardised effect size 0.18] was found for CYP in the intervention arm compared with the control arm. A per-protocol analysis, which included CYP in the intervention arm who had attended six or more intervention sessions, was also carried out and showed a slightly greater, statistically significant, difference (4.23 points, 95% CI 0.27 to 8.19 points; p = 0.036). Between-group differences in both analyses did not reach the pre-specified minimum clinically important difference (MCID) of a 9- to 10-point increase on the social skills subscale of the SSIS. The health economics analysis showed cost-effectiveness of the intervention through both reduced service use costs and a small but significant increase in quality-adjusted life years (QALYs). There was a small reduction in school-based intervention costs and intervention costs on the whole (with reduced NHS child mental health service costs) in the intervention arm compared with the control arm. Mean QALYs as reported by parents/guardians and CYP were shown to be marginally higher (by 0.03 QALYs) in the intervention arm than in the control arm. Fidelity to the intended intervention delivery method was measured via self-report and independent reviewers. Levels of self-reported fidelity were very good, with 99% of the core content of the intervention delivered and 91% of all content being reported as delivered. Levels of fidelity assessed by independent reviewers using video-recordings were good, with 83% of core content and 77% of all content being rated as delivered. Qualitative analysis showed good levels of acceptability of the intervention by CYP, parents/guardians and facilitators, with many schools continuing to run the intervention after the study ended. Discussion Limitations of the study included the fact that the primary outcome measure was completed by a teacher who did not deliver the intervention but who was not necessarily blind to the intervention. Although we obtained qualitative data from parents/carers and educators/facilitators, we had no direct impressions from the CYP themselves, although the adults consistently reported high levels of satisfaction on the part of the CYP. Analysis of the primary outcome showed modest positive improvements in social skills, although this analysis and sensitivity analyses did not show large enough changes in social skills scores for CYP in the intervention arm to reach the pre-specified MCID. However, the primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes between 0.15 and 0.21, and there were positive health economics and qualitative findings. This is corroborated to some extent by the fact that the difference between arms for the majority of secondary outcomes, although not statistically significant, favoured the intervention arm. The post hoc additional analysis was exploratory and was not used in drawing this overall conclusion. Conclusions Given the positive findings of the health economics and qualitative analyses, and the presence of a small yet positive change in social skills, consideration should be given to LEGO® based therapy and its contribution to the social skills of autistic CYP when run in a school setting. The study team recommends future research into LEGO® based therapy, particularly when run in school environments. Additional analysis showed possible avenues for exploration, including whether or not there is a greater impact of the intervention for autistic CYP in secondary schools, or for those with less severe ASD symptomatology, and when there is more than one autistic child or young person in each therapy session. Trial registration This trial is registered as ISRCTN64852382. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Introduction Observational studies represent an alternative to estimate real-world causal effects in the absence of available randomised controlled trials (RCTs). Target trial emulation is a framework for the application of RCT design principles to emulate a hypothetical open-label RCT (the hypothetical target trial) using existing observational data as the primary data source as opposed to the prospective recruitment and measurement of randomised units. The aim of this systematic review is to investigate the practices of studies applying the target trial emulation framework to evaluate the effectiveness of interventions.Methods and analysis We will systematically search in Medline (via Ovid), Embase (via Ovid, entries from medRxiv are included), PsycINFO (via Ovid), SCOPUS, Web of Science, Cochrane Library, the ISRCTN registry and ClinicalTrials.gov for all study reports and protocols which used the trial emulation framework (without time restriction). We will extract information concerning study design, data source, analysis, results, interpretation and dissemination. Two reviewers will perform study selection, data extraction and quality assessment. Disagreements between reviewers will be resolved by a third reviewer. A narrative approach will be used to synthesise and report qualitative and quantitative data. Reporting of the review will be informed by Preferred Reporting Items for Systematic Review and Meta-Analysis guidance (PRISMA).Ethics and dissemination Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations.

Background: Up to 10% of children and young people have a specific phobia that can significantly affect their mental health, development and daily functioning. Cognitive–behavioural therapy-based interventions remain the dominant treatment, but limitations to their provision warrant investigation into low-intensity alternatives. One-session treatment is one such alternative that shares cognitive–behavioural therapy principles but has a shorter treatment period. Objective: This research investigated the non-inferiority of one-session treatment to cognitive–behavioural therapy for treating specific phobias in children and young people. The acceptability and cost-effectiveness of one-session treatment were examined. Design: A pragmatic, multicentre, non-inferiority randomised controlled trial, with embedded economic and qualitative evaluations. Settings: There were 26 sites, including 12 NHS trusts. Participants: Participants were aged 7–16 years and had a specific phobia defined in accordance with established international clinical criteria. Interventions: Participants were randomised 1 : 1 to receive one-session treatment or usual-care cognitive–behavioural therapy, and were stratified according to age and phobia severity. Outcome assessors remained blind to treatment allocation. Main outcome measures: The primary outcome measure was the Behavioural Avoidance Task at 6 months’ follow-up. Secondary outcomes included the Anxiety Disorder Interview Schedule, Child Anxiety Impact Scale, Revised Children’s Anxiety and Depression Scale, a goal-based outcome measure, Child Health Utility 9D, EuroQol-5 Dimensions Youth version and resource usage. Treatment fidelity was assessed using the Cognitive Behaviour Therapy Scale for Children and Young People and the One-Session Treatment Rating Scale. Results: A total of 274 participants were recruited, with 268 participants randomised to one-session treatment (n = 134) or cognitive–behavioural therapy (n = 134). A total of 197 participants contributed some data, with 149 participants in the intention-to-treat analysis and 113 in the per-protocol analysis. Mean Behavioural Avoidance Task scores at 6 months were similar across treatment groups when both intention-to-treat and per-protocol analyses were applied [cognitive–behavioural therapy: 7.1 (intention to treat), 7.4 (per protocol); one-session treatment: 7.4 (intention to treat), 7.6 (per protocol); on the standardised scale adjusted mean difference for cognitive–behavioural therapy compared with one-session treatment –0.123, 95% confidence interval –0.449 to 0.202 (intention to treat), mean difference –0.204, 95% confidence interval –0.579 to 0.171 (per protocol)]. These findings were wholly below the standardised non-inferiority limit of 0.4, which suggests that one-session treatment is non-inferior to cognitive–behavioural therapy. No between-group differences in secondary outcome measures were found. The health economics evaluation suggested that, compared with cognitive–behavioural therapy, one-session treatment marginally decreased the mean service use costs and maintained similar mean quality-adjusted life-year improvement. Nested qualitative evaluation found one-session treatment to be considered acceptable by those who received it, their parents/guardians and clinicians. No adverse events occurred as a result of phobia treatment. Limitations: The COVID-19 pandemic meant that 48 children and young people could not complete the primary outcome measure. Service waiting times resulted in some participants not starting therapy before follow-up. Conclusions: One-session treatment for specific phobia in UK-based child mental health treatment centres is as clinically effective as multisession cognitive–behavioural therapy and highly likely to be cost-saving. Future work could involve improving the implementation of one-session treatment through training and commissioning of improved care pathways. Trial registration: This trial is registered as ISRCTN19883421. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 42. See the NIHR Journals Library website for further project information.

Background: Mental disorders have become a public health crisis. Early prevention is key. Parenting programmes are effective for children aged ≥ 3 years; however, there is a lack of evidence of their effectiveness for children aged ≤ 2 years. Objectives: To establish if the model named Enhancing Social–Emotional Health and Well-being in the Early Years (E-SEE) Steps can (1) enhance child social emotional well-being and establish whether or not it is cost-effective at 20 months of age when compared with services as usual; and (2) be delivered as a proportionate universal model with fidelity. Design: A pragmatic two-arm randomised controlled trial and economic appraisal, with an embedded process evaluation to examine the outcomes, implementation and cost-effectiveness of the intervention, and intervention uptake, compared with services as usual. The study had an external pilot phase (which was originally planned as an internal pilot). Setting: The intervention was delivered in community settings by early years children’s services and/or public health staff in four sites. Participants: A total of 341 parents of infants aged ≤ 8 weeks were randomised in a ratio of 5 : 1 (intervention, n = 285; control, n = 56). The target sample was 606 parents. Intervention: Two Incredible Years® parenting programmes (i.e. infant and toddler) delivered in a proportionate universal model with three levels [one universal (book) and two targeted group-based parenting programmes]. Main outcome measures: Child social and emotional well-being (primary outcome) was assessed using the Ages and Stages Questionnaire: Social and Emotional, 2nd edition, at 2, 9 and 18 months after randomisation. Parent depression (secondary key outcome) was assessed using the Patient Health Questionnaire-9 items. Both questionnaires were eligibility screeners for targeted groups. Results: The primary outcome analysis provided no evidence that the E-SEE Steps model was effective in enhancing child social and emotional well-being. The adjusted mean difference was 3.02 on the original Ages and Stages Questionnaire: Social and Emotional, 2nd edition, in favour of the control [95% confidence interval –0.03 to 6.08; p = 0.052; N = 321 (intervention, n = 268; control, n = 53)]. Analysis of the key secondary outcome (i.e. parent depression levels as assessed by the Patient Health Questionnaire-9 items) provided weak evidence on the Patient Health Questionnaire-9 items in favour of the intervention (adjusted mean difference –0.61, 95% confidence interval –1.34 to 0.12; p = 0.1). Other secondary outcomes did not differ between arms. The economic analysis showed that the E-SEE Steps model was associated with higher costs and was marginally more effective (0.031 quality-adjusted life-years gained from E-SEE Steps compared with SAU, 95% confidence interval –0.008 to 0.071) than services as usual, resulting in an incremental cost-effectiveness ratio of approximately £20,062 per quality-adjusted life-year compared with services as usual. Overall take-up of the targeted parenting programmes was low. Sites, although enthusiastic, identified barriers to delivering the intervention. Limitations: The target sample size was not met and the study was not powered to explore the effectiveness of each level of intervention. Most parents in the sample were well educated and, therefore, the results are unlikely to be generalisable, particularly to those at greatest risk of poor social and emotional well-being. Conclusions: The E-SEE Steps proportionate universal model did not enhance child social and emotional well-being, but generated non-significant improvements in parent health outcomes, resulting in considerable uncertainty around the cost-effectiveness of the intervention. The primary and key secondary outcome gave inconsistent signals. Although, with system changes, increased resources and adaptations to the intervention, the model could be implemented, evidence for positive outcomes from the E-SEE Steps model is poor. Future work: The universal-level E-SEE Step data (i.e. the Incredible Years book) from the external pilot will be pooled with the main trial data for further exploration up to follow-up 1, which is the time point at which most change was seen. Trial registration: This trial is registered as ISRCTN11079129. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.

BackgroundEvidence for parenting programs to improve wellbeing in children under three is inconclusive. We investigated the fidelity, impact, and cost-effectiveness of two parenting programs delivered within a longitudinal proportionate delivery model ('E-SEE Steps').MethodsEligible parents with a child ≤ 8 weeks were recruited into a parallel two-arm, assessor blinded, randomized controlled, community-based, trial with embedded economic and process evaluations. Post-baseline randomization applied a 5:1 (intervention-to-control) ratio, stratified by primary (child social-emotional wellbeing (ASQ:SE-2)) and key secondary (maternal depression (PHQ-9)) outcome scores, sex, and site. All intervention parents received the Incredible Years® Baby Book (IY-B), and were offered the targeted Infant (IY-I)/Toddler (IY-T) program if eligible, based on ASQ:SE-2/PHQ-9 scores. Control families received usual services. Fidelity data were analysed descriptively. Primary analysis applied intention to treat. Effectiveness analysis fitted a marginal model to outcome scores. Cost-effectiveness analysis involved Incremental Cost-Effectiveness Ratios (ICERs).ResultsThe target sample (N = 606) was not achieved; 341 mothers were randomized (285:56), 322 (94%) were retained to study end. Of those eligible for the IY-I (n = 101), and IY-T (n = 101) programs, 51 and 21 respectively, attended. Eight (of 14) groups met the 80% self-reported fidelity criteria. No significant differences between arms were found for adjusted mean difference scores; ASQ:SE-2 (3.02, 95% CI: -0.03, 6.08, p = 0.052), PHQ-9 (-0.61; 95% CI: -1.34, 0.12, p = 0.1). E-SEE Steps had higher costs, but improved mothers' Health-related Quality of Life (0.031 Quality Adjusted Life Year (QALY) gain), ICER of £20,062 per QALY compared to control. Serious adverse events (n = 86) were unrelated to the intervention.ConclusionsE-SEE Steps was not effective, but was borderline cost-effective. The model was delivered with varying fidelity, with lower-than-expected IY-T uptake. Changes to delivery systems and the individual programs may be needed prior to future evaluation.Trial registrationInternational Standard Randomized Controlled Trial Number: ISRCTN11079129.

Many studies in the biomedical research literature report analyses that fail to recognise important data dependencies from multilevel or complex experimental designs. Statistical inferences resulting from such analyses are unlikely to be valid and are often potentially highly misleading. Failure to recognise this as a problem is often referred to in the statistical literature as a unit of analysis (UoA) issue. Here, by analysing two example datasets in a simulation study, we demonstrate the impact of UoA issues on study efficiency and estimation bias, and highlight where errors in analysis can occur. We also provide code (written in R) as a resource to help researchers undertake their own statistical analyses.

BACKGROUND:Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS:We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS:Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p

Manuscripts should include all the experimental and statistical details that are needed to replicate the experiments and analyses reported in them.

Lack of reproducibility is an ongoing problem in some areas of the biomedical sciences. Poor experimental design and a failure to engage with experienced statisticians at key stages in the design and analysis of experiments are two factors that contribute to this problem. The RIPOSTE (Reducing IrreProducibility in labOratory STudiEs) framework has been developed to support early and regular discussions between scientists and statisticians in order to improve the design, conduct and analysis of laboratory studies and, therefore, to reduce irreproducibility. This framework is intended for use during the early stages of a research project, when specific questions or hypotheses are proposed. The essential points within the framework are explained and illustrated using three examples (a medical equipment test, a macrophage study and a gene expression study). Sound study design minimises the possibility of bias being introduced into experiments and leads to higher quality research with more reproducible results.