Levelling the playing field through the London Network of the UK clinical trials accelerator platform.

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

Standards for the care of people with cystic fibrosis (CF); Planning for a longer life.

This is the final of four papers updating standards for the care of people with CF. That this paper "Planning a longer life" was considered necessary, highlights how much CF care has progressed over the past decade. Several factors underpin this progress, notably increased numbers of people with CF with access to CFTR modulator therapy. As the landscape for CF changes, so do the hopes and aspirations of people with CF and their families. This paper reflects the need to consider people with CF not as a "problem" to be solved, but as a success, a potential and a voice to be heard. People with CF and the wider CF community have driven this approach, reflecting many of the topics in this paper. This exercise involved wide stakeholder engagement. People with CF are keen to contribute to research priorities and be involved in all stages of research. People with CF want healthcare professionals to respect them as individuals and consider the impact of our actions on the world around us. Navigating life presents challenges to all, but for people with CF these challenges are heightened and complex. In this paper we highlight the concerns and life moments that impact people with CF, and events that the CF team should aim to support, including the challenges around having a family. People with CF and their care teams must embrace the updated standards outlined in these four papers to enjoy the full potential for a healthier life.

Genomic attributes of airway commensal bacteria and mucosa.

Microbial communities at the airway mucosal barrier are conserved and highly ordered, in likelihood reflecting co-evolution with human host factors. Freed of selection to digest nutrients, the airway microbiome underpins cognate management of mucosal immunity and pathogen resistance. We show here the initial results of systematic culture and whole-genome sequencing of the thoracic airway bacteria, identifying 52 novel species amongst 126 organisms that constitute 75% of commensals typically present in heathy individuals. Clinically relevant genes encode antimicrobial synthesis, adhesion and biofilm formation, immune modulation, iron utilisation, nitrous oxide (NO) metabolism and sphingolipid signalling. Using whole-genome content we identify dysbiotic features that may influence asthma and chronic obstructive pulmonary disease. We match isolate gene content to transcripts and metabolites expressed late in airway epithelial differentiation, identifying pathways to sustain host interactions with microbiota. Our results provide a systematic basis for decrypting interactions between commensals, pathogens, and mucosa in lung diseases of global significance.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Standards for the care of people with cystic fibrosis; establishing and maintaining health.

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy.

Perceptions surrounding the possible interaction between physical activity, pollution and asthma in children and adolescents with and without asthma.

A cornerstone of asthma management is maintaining physical activity (PA), but this may lead to increased exposure to, and deeper inhalation of, pollutants. Furthermore, children and adolescents may be more susceptible to the deleterious impacts of such exposures. Despite the recent air quality campaigns and media coverage surrounding the dangers of air pollution to respiratory health, few target children and their understanding of such issues.Using semi structured interviews, understanding of PA, air pollution and their interaction was explored with 25 youth aged 7-17 years. Utilising NVIVO 12 software, an atheoretical, inductive thematic analysis was conducted to identify key themes which were subsequently presented as pen profiles with the number of common responses within a theme indicative of its strength.The majority (88%) of youth's indicated traffic-related air pollution and global manufacturing as key sources of air pollution. Whilst all youths were aware of outdoor pollution, only 52% were aware of indoor air pollutants, of which 62% had asthma. Despite some uncertainty, all youths described pollution in a negative fashion, with 52% linking air pollution to undesirable effects on health, specifically respiratory health. PA in a polluted area was thought to be more dangerous than beneficial by 44%, although 24% suggested the benefits of PA would outweigh any detriment from pollution.Youth are aware of, and potentially compensate for, the interaction between air pollution and PA. Strategies are needed to allow youth to make more informed decisions regarding how to promote PA whilst minimising exposure to air pollution.

Real-world effectiveness of airway clearance techniques in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is commonly characterised by thick respiratory mucus. From diagnosis, people with CF are prescribed daily physiotherapy, including airway clearance techniques (ACTs). ACTs consume a large proportion of treatment time, yet the efficacy and effectiveness of ACTs are poorly understood. This study aimed to evaluate associations between the quality and quantity of ACTs and lung function in children and young people with CF. METHODS: Project Fizzyo, a longitudinal observational cohort study in the UK, used remote monitoring with electronic pressure sensors attached to four different commercial ACT devices to record real-time, breath-by-breath pressure data during usual ACTs undertaken at home over 16 months in 145 children. ACTs were categorised either as conformant or not with current ACT recommendations based on breath pressure and length measurements, or as missed treatments if not recorded. Daily, weekly and monthly associations between ACT category and lung function were investigated using linear mixed effects regression models adjusting for clinical confounders. RESULTS: After exclusions, 45 224 ACT treatments (135 individuals) and 21 069 days without treatments (141 individuals) were analysed. The mean±sd age of participants was 10.2±2.9 years. Conformant ACTs (21%) had significantly higher forced expiratory volume in 1 s (FEV1) (mean effect size 0.23 (95% CI 0.19-0.27) FEV1 % pred per treatment) than non-conformant (79%) or missed treatments. There was no benefit from non-conformant or missed treatments and no significant difference in FEV1 between them (mean effect size 0.02 (95% CI -0.01-0.05) FEV1 % pred per treatment). CONCLUSIONS: ACTs are beneficial when performed as recommended, but most people use techniques that do not improve lung function. Work is needed to monitor and improve ACT quality and to increase the proportion of people doing effective airway clearance at home.

Emulated trial investigating effects of multiple treatments: estimating combined effects of mucoactive nebulisers in cystic fibrosis using registry data.

INTRODUCTION: People with cystic fibrosis (CF) are often on multiple long-term treatments, including mucoactive nebulisers. In the UK, the most common mucoactive nebuliser is dornase alfa (DNase). A common therapeutic approach for people already on DNase is to add hypertonic saline (HS). The effects of DNase and HS used alone have been studied in randomised trials, but their effects in combination have not. This study investigates whether, for people already prescribed DNase, adding HS has additional benefit for lung function or use of intravenous antibiotics. METHODS: Using UK CF Registry data from 2007 to 2018, we emulated a target trial. We included people aged 6 years and over who were prescribed DNase without HS for 2 years. We investigated the effects of combinations of DNase and HS over 5 years of follow-up. Inverse-probability-of-treatment weighting was used to control confounding. The period predated triple combination CF transmembrane conductance regulator modulators in routine care. RESULTS: 4498 individuals were included. At baseline, average age and forced expiratory volume in 1 s (FEV1%) predicted were 21.1 years and 69.7 respectively. During first year of follow-up, 3799 individuals were prescribed DNase alone; 426 added HS; 57 switched to HS alone and 216 were prescribed neither. We found no evidence that adding HS improved FEV1% at 1-5 years, or use of intravenous antibiotics at 1-4 years, compared with DNase alone. CONCLUSION: For individuals with CF prescribed DNase, we found no evidence that adding HS had an effect on FEV1% or prescription of intravenous antibiotics. Our study illustrates the emulated target trial approach using CF Registry data.

Exploring flexible polynomial regression as a method to align routine clinical outcomes with daily data capture through remote technologies.

BACKGROUND: Clinical outcomes are normally captured less frequently than data from remote technologies, leaving a disparity in volumes of data from these different sources. To align these data, flexible polynomial regression was investigated to estimate personalised trends for a continuous outcome over time. METHODS: Using electronic health records, flexible polynomial regression models inclusive of a 1st up to a 4th order were calculated to predict forced expiratory volume in 1 s (FEV1) over time in children with cystic fibrosis. The model with the lowest AIC for each individual was selected as the best fit. The optimal parameters for using flexible polynomials were investigated by comparing the measured FEV1 values to the values given by the individualised polynomial. RESULTS: There were 8,549 FEV1 measurements from 267 individuals. For individuals with > 15 measurements (n = 178), the polynomial predictions worked well; however, with < 15 measurements (n = 89), the polynomial models were conditional on the number of measurements and time between measurements. The method was validated using BMI in the same population of children. CONCLUSION: Flexible polynomials can be used to extrapolate clinical outcome measures at frequent time intervals to align with daily data captured through remote technologies.

Heterogeneous Treatment Effects after Inspiratory Muscle Training during Recovery from Postacute COVID-19 Syndrome.

PURPOSE: The objective of this study is to investigate whether heterogeneous treatment effects occur for changes in inspiratory muscle strength, perceived dyspnea, and health-related quality of life after 8 wk of unsupervised home-based inspiratory muscle training (IMT) in adults with postacute coronavirus disease 2019 (COVID-19) syndrome. METHODS: In total, 147 adults with self-reported prior COVID-19 either completed an 8-wk home-based IMT intervention ( n = 111, 92 females, 48 ± 11 yr, 9.3 ± 3.6 months postacute COVID-19 infection) or acted as "usual care" wait list controls ( n = 36, 34 females, 49 ± 12 yr, 9.4 ± 3.2 months postacute COVID-19 infection). RESULTS: Applying a Bayesian framework, we found clear evidence of heterogeneity of treatment response for inspiratory muscle strength: the estimated difference between standard deviations (SD) of the IMT and control groups was 22.8 cm H 2 O (75% credible interval (CrI), 4.7-37.7) for changes in maximal inspiratory pressure (MIP) and 86.8 pressure time units (75% CrI, 55.7-116.7) for sustained MIP (SMIP). Conversely, there were minimal differences in the SD between the IMT and the control group for changes in perceived dyspnea and health-related quality of life, providing no evidence of heterogeneous treatment effects. Higher cumulative power during the IMT intervention was related to changes in MIP ( ß = 10.9 cm H 2 O (95% CrI, 5.3-16.8) per 1 SD) and SMIP ( ß = 63.7 (32.2-95.3) pressure time units per 1 SD), clearly indicating an IMT dose response for changes in inspiratory muscle strength. Older age (>50 yr), a longer time postacute COVID-19 (>3 months), and greater severity of dyspnea at baseline were also associated with smaller improvements in inspiratory muscle strength. CONCLUSIONS: Heterogeneous individual responses occurred after an 8-wk home-based IMT program in people with postacute COVID-19 syndrome. Consistent with standard exercise theory, larger improvements in inspiratory muscle strength are strongly related to a greater cumulative dose of IMT.

Causal inference in survival analysis using longitudinal observational data: Sequential trials and marginal structural models.

Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

A DELPHI study priority setting the remaining challenges for the use of routinely collected data in trials: COMORANT-UK.

BACKGROUND: Researchers are increasingly seeking to use routinely collected data to support clinical trials. This approach has the potential to transform the way clinical trials are conducted in the future. The availability of routinely collected data for research, whether healthcare or administrative, has increased, and infrastructure funding has enabled much of this. However, challenges remain at all stages of a trial life cycle. This study, COMORANT-UK, aimed to systematically identify, with key stakeholders across the UK, the ongoing challenges related to trials that seek to use routinely collected data. METHODS: This three-step Delphi method consisted of two rounds of anonymous web-based surveys and a virtual consensus meeting. Stakeholders included trialists, data infrastructures, funders of trials, regulators, data providers and the public. Stakeholders identified research questions or challenges that they considered were of particular importance and then selected their top 10 in the second survey. The ranked questions were taken forward to the consensus meeting for discussion with representatives invited from the stakeholder groups. RESULTS: In the first survey, 66 respondents yielded over 260 questions or challenges. These were thematically grouped and merged into a list of 40 unique questions. Eighty-eight stakeholders then ranked their top ten from the 40 questions in the second survey. The most common 14 questions were brought to the virtual consensus meeting in which stakeholders agreed a top list of seven questions. We report these seven questions which are within the following domains: trial design, Patient and Public Involvement, trial set-up, trial open and trial data. These questions address both evidence gaps (requiring further methodological research) and implementation gaps (requiring training and/or service re-organisation). CONCLUSION: This prioritised list of seven questions should inform the direction of future research in this area and should direct efforts to ensure that the benefits in major infrastructure for routinely collected data are achieved and translated. Without this and future work to address these questions, the potential societal benefits of using routinely collected data to help answer important clinical questions will not be realised.

Future therapies for cystic fibrosis.

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

Incidence determinants and serological correlates of reactive symptoms following SARS-CoV-2 vaccination.

Prospective population-based studies investigating associations between reactive symptoms following SARS-CoV-2 vaccination and serologic responses to vaccination are lacking. We therefore conducted a study in 9003 adults from the UK general population receiving SARS-CoV-2 vaccines as part of the national vaccination programme. Titres of combined IgG/IgA/IgM responses to SARS-CoV-2 spike (S) glycoprotein were determined in eluates of dried blood spots collected from all participants before and after vaccination. 4262 (47.3%) participants experienced systemic reactive symptoms after a first vaccine dose. Factors associating with lower risk of such symptoms included older age (aOR per additional 10 years of age 0.85, 95% CI: 0.81-0.90), male vs. female sex (0.59, 0.53-0.65) and receipt of an mRNA vaccine vs. ChAdOx1 nCoV-19 (0.29, 0.26-0.32 for BNT162b2; 0.06, 0.01-0.26 for mRNA-1273). Higher risk of such symptoms was associated with SARS-CoV-2 seropositivity and COVID-19 symptoms prior to vaccination (2.23, 1.78-2.81), but not with SARS-CoV-2 seropositivity in the absence of COVID-19 symptoms (0.94, 0.81-1.09). Presence vs. absence of self-reported anxiety or depression at enrolment associated with higher risk of such symptoms (1.24, 1.12-1.39). Post-vaccination anti-S titres were higher among participants who experienced reactive symptoms after vaccination vs. those who did not (P < 0.001). We conclude that factors influencing risk of systemic symptoms after SARS-CoV-2 vaccination include demographic characteristics, pre-vaccination SARS-CoV-2 serostatus and vaccine type. Participants experiencing reactive symptoms following SARS-CoV-2 vaccination had higher post-vaccination titres of IgG/A/M anti-S antibodies. Improved public understanding of the frequency of reactogenic symptoms and their positive association with vaccine immunogenicity could potentially increase vaccine uptake.

Estimating the contribution of respiratory pathogens to acute exacerbations of COPD using routine data.

OBJECTIVES: To characterise microbiology testing and results associated with emergency admissions for acute exacerbation of COPD (AECOPD), and determine the accuracy of ICD-10 codes in retrospectively identifying laboratory-confirmed respiratory pathogens in this setting. METHODS: Using person-level data from the Secure Anonymised Information Linkage Databank in Wales, we extracted emergency admissions for COPD from 1/12/2016 to 30/11/2018 and undertook linkage of admissions data to microbiology data to identify laboratory-confirmed infection. We further used these data to assess the accuracy of pathogen-specific ICD-10 codes. RESULTS: We analysed data from 15,950 people who had 25,715 emergency admissions for COPD over the two-year period. 99.5% of admissions could be linked to a laboratory test within 7 days of admission date. Sputum was collected in 5,013 (19.5%) of admissions, and respiratory virus testing in 1,219 (4.7%). Where respiratory virus testing was undertaken, 46.7% returned any positive result. Influenza was the virus most frequently detected, in 21.5% of admissions where testing was conducted. ICD-10 codes exhibited low sensitivity in detecting laboratory-confirmed respiratory pathogens. CONCLUSIONS: In people admitted to hospital with AECOPD, increased testing for respiratory viruses could enable more effective antibiotic stewardship and isolation of cases. Linkage with microbiology data achieves more accurate and reliable case definitions.

Defining clinical subtypes of adult asthma using electronic health records: Analysis of a large UK primary care database with external validation.

INTRODUCTION: Asthma is one of the commonest chronic conditions in the world. Subtypes of asthma have been defined, typically from clinical datasets on small, well-characterised subpopulations of asthma patients. We sought to define asthma subtypes from large longitudinal primary care electronic health records (EHRs) using cluster analysis. METHODS: In this retrospective cohort study, we extracted asthma subpopulations from the Optimum Patient Care Research Database (OPCRD) to robustly train and test algorithms, and externally validated findings in the Secure Anonymised Information Linkage (SAIL) Databank. In both databases, we identified adults with an asthma diagnosis code recorded in the three years prior to an index date. Train and test datasets were selected from OPCRD using an index date of Jan 1, 2016. Two internal validation datasets were selected from OPCRD using index dates of Jan 1, 2017 and 2018. Three external validation datasets were selected from SAIL using index dates of Jan 1, 2016, 2017 and 2018. Each dataset comprised 50,000 randomly selected non-overlapping patients. Subtypes were defined by applying multiple correspondence analysis and k-means cluster analysis to the train dataset, and were validated in the internal and external validation datasets. RESULTS: We defined six asthma subtypes with clear clinical interpretability: low inhaled corticosteroid (ICS) use and low healthcare utilisation (30% of patients); low-to-medium ICS use (36%); low-to-medium ICS use and comorbidities (12%); varied ICS use and comorbid chronic obstructive pulmonary disease (4%); high (10%) and very high ICS use (7%). The subtypes were replicated with high accuracy in internal (91-92%) and external (84-86%) datasets. CONCLUSION: Asthma subtypes derived and validated in large independent EHR databases were primarily defined by level of ICS use, level of healthcare use, and presence of comorbidities. This has important clinical implications towards defining asthma subtypes, facilitating patient stratification, and developing more personalised monitoring and treatment strategies.

Rebound in asthma exacerbations following relaxation of COVID-19 restrictions: a longitudinal population-based study (COVIDENCE UK).

BACKGROUND: The imposition of restrictions on social mixing early in the COVID-19 pandemic was followed by a reduction in asthma exacerbations in multiple settings internationally. Temporal trends in social mixing, incident acute respiratory infections (ARI) and asthma exacerbations following relaxation of COVID-19 restrictions have not yet been described. METHODS: We conducted a population-based longitudinal study in 2312 UK adults with asthma between November 2020 and April 2022. Details of face covering use, social mixing, incident ARI and severe asthma exacerbations were collected via monthly online questionnaires. Temporal changes in these parameters were visualised using Poisson generalised additive models. Multilevel logistic regression was used to test for associations between incident ARI and risk of asthma exacerbations, adjusting for potential confounders. RESULTS: Relaxation of COVID-19 restrictions from April 2021 coincided with reduced face covering use (p<0.001), increased frequency of indoor visits to public places and other households (p<0.001) and rising incidence of COVID-19 (p<0.001), non-COVID-19 ARI (p<0.001) and severe asthma exacerbations (p=0.007). Incident non-COVID-19 ARI associated independently with increased risk of asthma exacerbation (adjusted OR 5.75, 95% CI 4.75 to 6.97) as did incident COVID-19, both prior to emergence of the omicron variant of SARS-CoV-2 (5.89, 3.45 to 10.04) and subsequently (5.69, 3.89 to 8.31). CONCLUSIONS: Relaxation of COVID-19 restrictions coincided with decreased face covering use, increased social mixing and a rebound in ARI and asthma exacerbations. Associations between incident ARI and risk of severe asthma exacerbation were similar for non-COVID-19 ARI and COVID-19, both before and after emergence of the SARS-CoV-2 omicron variant. STUDY REGISTRATION NUMBER: NCT04330599.

Trajectories of early growth and subsequent lung function in cystic fibrosis: An observational study using UK and Canadian registry data.

BACKGROUND: Understanding the pulmonary impact of changes in early life nutritional status over time in a paediatric CF population may help inform how to use nutritional assessment to guide clinical care. National registry data provides an opportunity to study patterns of weight gain over time at the level of the individual, and thus to gain detailed understanding of the relationship between early weight trajectories and later lung function in children with Cystic Fibrosis (CF). METHODS: Using data from the United Kingdom (UK) and Canadian CF Registries, a mixed effects linear regression model was used to describe children's weight and BMI z-score trajectories from age 1 to 5 years. The intercept (weight-for-age at age 1) and slope (weight-for-age trajectory) from this model were then used as covariates in a linear regression of first lung function measurement at age 6 years. RESULTS: In both the UK and Canadian data, greater weight-for-age z-score at age 1 year and greater change in weight-for-age over time were associated with higher FEV1% predicted. A greater weight-for-age z-score at age 1 year was associated with a higher FEV1% predicted (UK: 3.78% (95% CI: 1.76; 4.70); Canada: 3.20% (95%CI: 1.76, 4.70)). These associations were reproduced for BMI z-scores and FVC% predicted. CONCLUSIONS: Early weight-for-age, specifically at age 1 year, and weight-for-age trajectories across early childhood are associated with later lung function. This relationship persists after adjustment for potential confounders. Current guidelines may need to be updated to place less emphasis on a specific cut-off (such as the 10th percentile) and encourage tracking of weight-for-age over time.