Preserved ratio impaired spirometry (PRISm) is defined as a FEV
of less than 80% predicted and a FEV
/forced vital capacity (FVC) ratio of 0·70 or higher. Previous research has indicated that PRISm ...is associated with respiratory symptoms and is a precursor of chronic obstructive pulmonary disease (COPD). However, these findings are based on relatively small selective cohorts with short follow-up. We aimed to determine the prevalence, risk factors, clinical implications, and mortality of PRISm in a large adult general population.
For this cohort analysis, we used data from the UKBiobank to assess PRISm prevalence, risk factors and associated symptoms, and associated comorbidities in a large adult population. Participants with spirometry deemed acceptable by an investigator (best measure FEV
and FVC values) at baseline were included. Participants were excluded if they did not have acceptable spirometry or were missing data on body-mass index or smoking status. Control spirometry was defined as a FEV
of 80% or more predicted and a FEV
/FVC ratio of 0·70 or higher. Airflow obstruction was defined as a FEV
/FVC ratio of less than 0·70. We used multivariable regression to determine risk factors for PRISm and associated comorbidities. Individuals who lived within close proximity to an assessment centre were invited for follow-up, with repeat spirometry. Only participants who had been included at baseline were examined in follow-up. This allowed for a longitudinal analysis of PRISm over time and risk factors for transition to airflow obstruction. We also did the survival analysis for a 12-year period.
Participants were recruited by UK Biobank between Dec 19, 2006, and Oct 10, 2010. We included 351 874 UK Biobank participants (189 247 women and 162 627 men) in our study, with a median follow-up of 9·0 years (IQR 8·0-10·0). 38 639 (11·0%) of 351 874 participants had PRISm at baseline. After adjustment, PRISm was strongly associated with obesity (odds ratio OR 2·40 2·26-2·55, p<0·0001), current smoking (1·48 1·36-1·62, p<0·0001), and patient reported doctor-diagnosed asthma (1·76 1·66-1·88, p<0·0001). Other risk factors identified included female sex, being overweight, trunk fat mass, and trunk fat percentage. PRISm was strongly associated with symptoms and comorbidity including increased risk of breathlessness (adjusted OR 2·0 95% CI 1·91-2·14, p<0·0001) and cardiovascular disease (adjusted OR 1·71 1·64-1·83, p<0·0001 for heart attack). Longitudinal analysis showed that 241 (12·2%) of 1973 participants who had PRISm at baseline had transitioned to airflow obstruction consistent with COPD. PRISm was associated with increased all-cause mortality (adjusted hazard ratio 1·61 95% CI 1·53-1·69, p<0·0001) versus control participants.
PRISm was associated with breathlessness, multimorbidity, and increased risk of death, which does not seem to be explained by smoking, obesity, or existing lung disease. Although for many patients PRISm is transient, it is important to understand which individuals are at risk of progressive lung function abnormalities. Further research into the genetic, structural and functional pathophysiology of PRISm is warranted.
UK Medical Research Council and University of Bristol.
Observational studies suggest an association between reduced lung function and risk of coronary artery disease and ischaemic stroke, independent of shared cardiovascular risk factors such as ...cigarette smoking. We use the latest genetic epidemiological methods to determine whether impaired lung function is causally associated with an increased risk of cardiovascular disease.
Mendelian randomisation uses genetic variants as instrumental variables to investigate causation. Preliminary analysis used two-sample Mendelian randomisation with lung function single nucleotide polymorphisms. To avoid collider bias, the main analysis used single nucleotide polymorphisms for lung function identified from UKBiobank in a multivariable Mendelian randomisation model conditioning for height, body mass index and smoking.Multivariable Mendelian randomisation shows strong evidence that reduced forced vital capacity (FVC) causes increased risk of coronary artery disease (OR 1.32, 95% CI 1.19-1.46 per standard deviation). Reduced forced expiratory volume in 1 s (FEV
) is unlikely to cause increased risk of coronary artery disease, as evidence of its effect becomes weak after conditioning for height (OR 1.08, 95% CI 0.89-1.30). There is weak evidence that reduced lung function increases risk of ischaemic stroke.
There is strong evidence that reduced FVC is independently and causally associated with coronary artery disease. Although the mechanism remains unclear, FVC could be taken into consideration when assessing cardiovascular risk and considered a potential target for reducing cardiovascular events. FEV
and airflow obstruction do not appear to cause increased cardiovascular events; confounding and collider bias may explain previous findings of a causal association.
Observational studies show an association between reduced lung function and impaired cognition. Cognitive dysfunction influences important health outcomes and is a precursor to dementia, but ...treatments options are currently very limited. Attention has therefore focused on identifying modifiable risk factors to prevent cognitive decline and preserve cognition. Our objective was to determine if lung function or risk of COPD causes reduced cognitive function using Mendelian randomization (MR).
Single nucleotide polymorphisms from genome wide association studies of lung function and COPD were used as exposures. We examined their effect on general cognitive function in a sample of 132,452 individuals. We then performed multivariable MR (MVMR), examining the effect of lung function before and after conditioning for covariates.
We found only weak evidence that reduced lung function (Beta - 0.002 (SE 0.02), p-value 0.86) or increased liability to COPD (- 0.008 (0.008), p-value 0.35) causes lower cognitive function. MVMR found both reduced FEV
and FVC do cause lower cognitive function, but that after conditioning for height (- 0.03 (0.03), p-value 0.29 and - 0.01 (0.03) p-value 0.62, for FEV1 and FVC respectively) and educational attainment (- 0.03 (0.03) p-value 0.33 and - 0.01 (0.02), p-value 0.35) the evidence became weak.
We did not find evidence that reduced lung function or COPD causes reduced cognitive function. Previous observational studies are probably affected by residual confounding. Research efforts should focus on shared risk factors for reduced lung function and cognition, rather than lung function alone as a modifiable risk factor.
BACKGROUND: Although the effects of resistant starch (RS) on postprandial glycemia and insulinemia have been extensively studied, little is known about the impact of RS on fat metabolism. This study ...examines the relationship between the RS content of a meal and postprandial/post-absorbative fat oxidation. RESULTS: 12 subjects consumed meals containing 0%, 2.7%, 5.4%, and 10.7% RS (as a percentage of total carbohydrate). Blood samples were taken and analyzed for glucose, insulin, triacylglycerol (TAG) and free fatty acid (FFA) concentrations. Respiratory quotient was measured hourly. The 0%, 5.4%, and 10.7% meals contained 50 muCi 1-14C-triolein with breath samples collected hourly following the meal, and gluteal fat biopsies obtained at 0 and 24 h. RS, regardless of dose, had no effect on fasting or postprandial insulin, glucose, FFA or TAG concentration, nor on meal fat storage. However, data from indirect calorimetry and oxidation of 1-14C-triolein to 14CO2 showed that addition of 5.4% RS to the diet significantly increased fat oxidation. In fact, postprandial oxidation of 1-14C-triolein was 23% greater with the 5.4% RS meal than the 0% meal (p = 0.0062). CONCLUSIONS: These data indicate that replacement of 5.4% of total dietary carbohydrate with RS significantly increased post-prandial lipid oxidation and therefore could decrease fat accumulation in the long-term.
Introduction: Traditional observational epidemiology has described an association between reduced lung function and lung disease with extra-pulmonary diseases. However, this method cannot establish ...causality and is affected by bias from residual confounding and reverse causation. If the observed association is causal, then treatments to maintain or improve lung function could reduce the huge burden of extra-pulmonary co-morbidity. My objective was to utilise novel genetic epidemiological techniques to determine if reduced lung function or lung disease has a causal effect on extra-pulmonary disease. I used both traditional and genetic epidemiology to research an understudied pathological lung function state, Preserved Ratio Impaired Spirometry (PRISm), and its extra-pulmonary associations. The COVID pandemic created a need to examine asthma and mental health during lockdown. Methods: Two Sample Mendelian Randomisation (MR) techniques were used to determine if reduced lung function and COPD have a causal effect on Alzheimer's Disease, cardiovascular disease, and cognitive function. I used the UK Biobank to examine the risk factors, associations, and mortality of PRISm and then performed a Genome-Wide Association Study of PRISm. Traditional epidemiology was used to examine the effect of asthma on mental health outcomes during COVID-19 lockdown in the Avon Longitudinal Parents and Child Cohort. Results: MR studies showed no strong evidence for an effect of reduced lung function/lung disease on cognitive function or the risk of Alzheimer's disease. However, there was strong evidence that reduced Forced Vital Capacity (FVC), but not Forced Expiratory Volume in one second (FEV1), causes an increased risk of coronary artery disease. PRISm is common, and despite being a relatively transient state is associated with co-morbidities and an increase in mortality compared to those with normal spirometry. Genetic studies show that there may be shared genetic risk factors for PRISm and its co-morbidities. Mental health outcomes in those with asthma worsened during the lockdown to lower levels than the general population. Discussion: There is a strong association between lung function, lung disease and extra-pulmonary disease, with genetic epidemiology providing evidence that this relationship is causal, and there may be shared genetic risk factors. This thesis demonstrates the value of triangulating different epidemiological methods and highlights future areas of research that may lead to lung function becoming a screening tool and/or modifiable risk factor for extra-pulmonary diseases.
Preserved ratio impaired spirometry (PRISm) is defined as a forced expiratory volume in 1 s (FEV
) <80% predicted and FEV
/forced vital capacity ≥0.70. PRISm is associated with respiratory symptoms ...and comorbidities. Our objective was to discover novel genetic signals for PRISm and see if they provide insight into the pathogenesis of PRISm and associated comorbidities.
We undertook a genome-wide association study (GWAS) of PRISm in UK Biobank participants (Stage 1), and selected single nucleotide polymorphisms (SNPs) reaching genome-wide significance for replication in 13 cohorts (Stage 2). A combined meta-analysis of Stage 1 and Stage 2 was done to determine top SNPs. We used cross-trait linkage disequilibrium score regression to estimate genome-wide genetic correlation between PRISm and pulmonary and extrapulmonary traits. Phenome-wide association studies of top SNPs were performed.
22 signals reached significance in the joint meta-analysis, including four signals novel for lung function. A strong genome-wide genetic correlation (r
) between PRISm and spirometric COPD (r
=0.62, p<0.001) was observed, and genetic correlation with type 2 diabetes (r
=0.12, p=0.007). Phenome-wide association studies showed that 18 of 22 signals were associated with diabetic traits and seven with blood pressure traits.
This is the first GWAS to successfully identify SNPs associated with PRISm. Four of the signals, rs7652391 (nearest gene
), rs9431040 (
), rs62018863 (
) and rs185937162 (
), have not been described in association with lung function before, demonstrating the utility of using different lung function phenotypes in GWAS. Genetic factors associated with PRISm are strongly correlated with risk of both other lung diseases and extrapulmonary comorbidity.
With dietary intervention studies, it is important to ensure that subjects adhere to the test diet. Current methods to monitor adherence have substantial limitations. Therefore, a dose-response test ...curve was constructed to determine whether small differences in serum Li could be detected in response to ingestion of variable Li doses indicative of full or partial dietary compliance. During 3 separate weeks, subjects consumed a test meal that included a single food containing Li citrate daily for 4 d. Doses of 250, 213, or 175 μmol Li were used each week to approximate compliance levels of 100, 85, and 70%. On d 4, blood samples were taken before and 1, 2, 3, 5, 7, 9, and 24 h after ingesting the test meal. Compared with the 100% dose, serum Li was significantly lower at all times after the 70% dose and at most times after the 85% dose. Data were analyzed to determine a cutoff value so that if a subject's serum Li was below that value, they would be declared noncompliant. The probability that a subject was declared to be noncompliant when in fact they were compliant was set to 0.05 (specificity was set to 0.95) and the probability of noncompliance (sensitivity) was estimated. Test performance was best in the 3- to 9-h range, for which 90–95% of subjects “noncompliant” at the 70% dose were identified. Li can be used as a biomarker to determine dietary compliance. Measuring serum Li 3–9 h after the last dose provides the highest sensitivity and specificity for noncompliance at doses <70%.
Continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO) have been recommended for acute hypoxemic respiratory failure in patients with COVID-19. Uncertainty exists regarding the ...effectiveness and safety of these noninvasive respiratory strategies.
To determine whether either CPAP or HFNO, compared with conventional oxygen therapy, improves clinical outcomes in hospitalized patients with COVID-19-related acute hypoxemic respiratory failure.
A parallel group, adaptive, randomized clinical trial of 1273 hospitalized adults with COVID-19-related acute hypoxemic respiratory failure. The trial was conducted between April 6, 2020, and May 3, 2021, across 48 acute care hospitals in the UK and Jersey. Final follow-up occurred on June 20, 2021.
Adult patients were randomized to receive CPAP (n = 380), HFNO (n = 418), or conventional oxygen therapy (n = 475).
The primary outcome was a composite of tracheal intubation or mortality within 30 days.
The trial was stopped prematurely due to declining COVID-19 case numbers in the UK and the end of the funded recruitment period. Of the 1273 randomized patients (mean age, 57.4 95% CI, 56.7 to 58.1 years; 66% male; 65% White race), primary outcome data were available for 1260. Crossover between interventions occurred in 17.1% of participants (15.3% in the CPAP group, 11.5% in the HFNO group, and 23.6% in the conventional oxygen therapy group). The requirement for tracheal intubation or mortality within 30 days was significantly lower with CPAP (36.3%; 137 of 377 participants) vs conventional oxygen therapy (44.4%; 158 of 356 participants) (absolute difference, -8% 95% CI, -15% to -1%, P = .03), but was not significantly different with HFNO (44.3%; 184 of 415 participants) vs conventional oxygen therapy (45.1%; 166 of 368 participants) (absolute difference, -1% 95% CI, -8% to 6%, P = .83). Adverse events occurred in 34.2% (130/380) of participants in the CPAP group, 20.6% (86/418) in the HFNO group, and 13.9% (66/475) in the conventional oxygen therapy group.
Among patients with acute hypoxemic respiratory failure due to COVID-19, an initial strategy of CPAP significantly reduced the risk of tracheal intubation or mortality compared with conventional oxygen therapy, but there was no significant difference between an initial strategy of HFNO compared with conventional oxygen therapy. The study may have been underpowered for the comparison of HFNO vs conventional oxygen therapy, and early study termination and crossover among the groups should be considered when interpreting the findings.
isrctn.org Identifier: ISRCTN16912075.
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