Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 ...mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.
Background Characteristics of inhaled corticosteroids (ICSs) differ, but data comparing the real-life effectiveness of various ICSs for asthma are lacking. Objective We sought to compare real-life ...asthma outcomes and costs of extrafine hydrofluoroalkane (HFA)–beclomethasone and fluticasone administered through a pressurized metered-dose inhaler. Methods This retrospective matched cohort study examined database markers of asthma control from a large US longitudinal health care claims database over 1 baseline and 1 outcome year for 10,312 patients with asthma aged 12 to 80 years receiving their first ICS as HFA-beclomethasone or fluticasone and matched on baseline demographic characteristics and asthma severity. Results Patients started on HFA-beclomethasone had significantly higher odds (adjusted odds ratio, 1.19; 95% CI; 1.08-1.31) of achieving overall control (risk and impairment), which was defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection and less than 2 puffs per day of short-acting β-agonist; they also experienced a lower rate of respiratory-related hospitalizations or referrals (adjusted rate ratio, 0.82; 95% CI, 0.73-0.93) than patients started on fluticasone. Other database outcome measures were similar in the 2 cohorts. Prescribed HFA-beclomethasone doses were lower ( P < .001) than fluticasone doses (median, 320 μg/d interquartile range, 160-320 μg/d vs 440 μg/d interquartile range, 176-440 μg/d). Adjusted respiratory-related health care costs were significantly lower for HFA-beclomethasone than fluticasone (mean, $1869 95% CI, $1727-$2032 vs $2259 95% CI, $2111-$2404), representing a mean annual savings of $390 (95% CI, $165-$620) per patient prescribed HFA-beclomethasone rather than fluticasone. Conclusions Asthma treatment outcomes were similar or better with HFA-beclomethasone prescribed at significantly lower doses and with lower costs than fluticasone.
As more inhaled corticosteroid (ICS) devices become available, there may be pressure for health-care providers to switch patients with asthma to cheaper inhaler devices. Our objective was to evaluate ...impact on asthma control of inhaler device switching without an accompanying consultation in general practice.
This 2-year retrospective matched cohort study used the UK General Practice Research Database to identify practices where ICS devices were changed without a consultation for > or =5 patients within 3 months. Patients 6-65 years of age from these practices whose ICS device was switched were individually matched with patients using the same ICS device who were not switched. Asthma control over 12 months after the switch was assessed using a composite measure including short-acting beta-agonist and oral corticosteroid use, hospitalizations, and subsequent changes to therapy.
A total of 824 patients from 55 practices had a device switch and could be matched. Over half (53%) of device switches were from dry powder to metered-dose inhalers. Fewer patients in switched than matched cohort experienced successful treatment based on the composite measure (20% vs. 34%) and more experienced unsuccessful treatment (51% vs. 38%). After adjusting for possible baseline confounding factors, the odds ratio for treatment success in the switched cohort compared with controls was 0.29 (95% confidence interval CI, 0.19 to 0.44; p < 0.001) and for unsuccessful treatment was 1.92 (95% CI, 1.47 to 2.56; p < 0.001).
Switching ICS devices without a consultation was associated with worsened asthma control and is therefore inadvisable.
Summary Background Beclometasone dipropionate is an inhaled corticosteroid (ICS) available in both extrafine and larger-particle hydrofluoroalkane formulations. Extrafine beclometasone has greater ...small airway distribution and inhalation technique tolerance than larger-particle beclometasone; therefore, its use may be associated with improved asthma outcomes at population levels. The study objective was to compare real-life effectiveness of extrafine and larger-particle beclometasone. Methods Retrospective matched cohort study including primary care patients with asthma (ages 12–60 and non-smokers 61–80 years) prescribed extrafine or larger-particle beclometasone by metered-dose inhaler. We studied patients receiving their first ICS (initiation population, n = 11,289) or switched from another ICS without dose change (switch population, n = 19,065). The extrafine and larger-particle beclometasone cohorts were matched in each population for demographic and database measures of asthma control during a baseline year; and endpoints assessed during 1 outcome year were adjusted for residual confounding factors. Results The odds of no loss of asthma control (no asthma-related hospital attendance, consultation for lower respiratory tract infection, or oral corticosteroids) were significantly higher in the extrafine beclometasone cohorts of both initiation population (adjusted odds ratio aOR 1.12; 95% CI 1.02–1.23) and switch population (aOR 1.10; 95% CI 1.01–1.19). The odds of better adherence to ICS therapy were also significantly higher in both extrafine beclometasone cohorts (initiation population, aOR 1.64; 95% CI 1.52–1.75 and switch population, aOR 1.35; 95% CI 1.27–1.43). Conclusions These findings are consistent with the hypothesis that delivery of beclometasone in extrafine particle size produces real-life asthma treatment benefits. Clinical trials no. NCT01400217.
Randomized controlled trials indicate that addition of a long-acting muscarinic antagonist (LAMA) such as tiotropium may improve asthma control and reduce exacerbation risk in patients with poorly ...controlled asthma, but broader clinical studies are needed to investigate the effectiveness of LAMA in real-life asthma care.
Medical records of adults with asthma (aged ≥18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 2001-2013. Patients diagnosed with chronic obstructive pulmonary disease were excluded, but no other clinical exclusions were applied. Two primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription with lower respiratory consultation). Secondary outcomes included lung function test results and short-acting β2 agonist usage. The Wilcoxon signed-rank test was used for variables measured on the interval scale, the marginal homogeneity test for categorized variables, and the paired t-test for lung function indices.
Of the 2,042 study patients, 83% were prescribed an inhaled corticosteroid and 68% a long-acting β2 agonist during the baseline year; 67% were prescribed both. Comparing baseline and outcome years, the percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001). There were no significant changes in lung function, and usage of short-acting β2 agonists (in salbutamol/albuterol equivalents) increased from a median (interquartile range) of 274 (110, 548) to 329 (110, 603) μg/day (P=0.01).
In this real-life asthma population, addition of LAMA therapy was associated with significant decreases in the incidence of exacerbations and antibiotic prescriptions for lower respiratory tract infections in the following year.
Correct use of inhaler devices is fundamental to effective asthma management but represents an important challenge for patients. The correct inhalation manoeuvre differs markedly for different ...inhaler types. The objective of this study was to compare outcomes for patients prescribed the same inhaler device versus mixed device types for asthma controller and reliever therapy.
This retrospective observational study identified patients with asthma (ages 4-80 years) in a large primary care database who were prescribed an inhaled corticosteroid (ICS) for the first time. We compared outcomes for patients prescribed the same breath-actuated inhaler (BAI) for ICS controller and salbutamol reliever versus mixed devices (BAI for controller and pressurised metered-dose inhaler pMDI for reliever). The 2-year study included 1 baseline year before the ICS prescription (to identify and correct for confounding factors) and 1 outcome year. Endpoints were asthma control (defined as no hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and severe exacerbations (hospitalisation or oral corticosteroids for asthma).
Patients prescribed the same device (n=3,428) were significantly more likely to achieve asthma control (adjusted odds ratio, 1.15; 95% confidence interval CI, 1.02-1.28) and recorded significantly lower severe exacerbation rates (adjusted rate ratio, 0.79; 95% CI, 0.68-0.93) than those prescribed mixed devices (n=5,452).
These findings suggest that, when possible, the same device should be prescribed for both ICS and reliever therapy when patients are initiating ICS.
Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered
. Here we used ...whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants
, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
The Human Phenotype Ontology in 2017 Köhler, Sebastian; Vasilevsky, Nicole A; Engelstad, Mark ...
Nucleic acids research,
01/2017, Letnik:
45, Številka:
D1
Journal Article
Recenzirano
Odprti dostop
Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three ...components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.
Observational research is essential to evaluate the real-life effectiveness of asthma treatments and can now make use of outcomes derived from electronic medical records.
The aim of this study was to ...investigate the utility of several database outcome measures in asthma.
This study identified cohorts of patients with active asthma from a UK primary care database - Optimum Patient Care Research Database - approximately 10% of which was prospectively supplemented with questionnaire data. The "Questionnaire cohort" included patients aged 18-60 years with valid questionnaire data and 1 year of continuous primary care data. Separate "ICS initiation" and "ICS step-up" cohorts included patients aged 5-60 years initiated on inhaled corticosteroids (ICSs), who had 1 year of continuous primary care data before, and after, this index visit. Database measures of asthma symptom control and exacerbations were identified in the Optimum Patient Care Research Database and cross-tabulated with corresponding patient-reported (questionnaire) data. Responsiveness of the database outcomes was analyzed, using McNemar's and Wilcoxon's signed rank tests, and Poisson regression was used to estimate the association between database outcomes and future risk of database exacerbations, in the ICS initiation cohort.
The final study included 2,366 Questionnaire cohort patients and 51,404 ICS initiation patients. Agreement between patient-reported and database-recorded exacerbations was fair (kappa 0.35). Following the initiation of ICS, database risk domain asthma control (based on exacerbations) improved (proportion of patients with uncontrolled asthma decreased from 24.9% to 18.6%;
<0.001) and mean number of database exacerbations decreased from 0.09 to 0.08 per patient per year (
=0.001). However, another measure of asthma control which includes short-acting beta-agonist prescription as part of the definition did not show this improvement. Patients with prior exacerbations had a higher risk of future exacerbation (rate ratio 95% confidence interval, 3.23 3.03-3.57).
Asthma control and exacerbations derived from primary care databases were responsive, with the exception of short-acting beta-agonist prescriptions, and useful for risk prediction.
Because randomized controlled trials of established pediatric asthma therapies are expensive and difficult to perform, observational studies may fill gaps in the evidence base.
To compare the ...effectiveness of representative small-particle inhaled corticosteroid (ICS) with that of standard size–particle ICS for children initiating or stepping up ICS therapy for asthma (analysis 1) and to compare the effectiveness of ICS dose step-up using small-particle ICS with adding long-acting β2-agonist (LABA) to the ICS (analysis 2).
These historical matched cohort analyses drew on electronic medical records of children with asthma aged 5 to 11 years. Variables measured during 2 consecutive years (1 baseline year for confounder definition and 1 outcome year) included risk-domain asthma control (no hospital attendance for asthma, acute oral corticosteroids, or lower respiratory tract infection requiring antibiotics) and rate of severe exacerbations (asthma-related emergency, hospitalization, or oral corticosteroids).
In the initiation population (n = 797 in each cohort), children prescribed small-particle ICS versus standard size–particle ICS experienced greater odds of asthma control (adjusted odds ratio, 1.49; 95% CI, 1.10-2.02) and lower severe exacerbation rate (adjusted rate ratio, 0.56; 95% CI, 0.35-0.88). Step-up outcomes (n = 206 in each cohort) were also significantly better for small-particle ICS, with asthma control adjusted odds ratio of 2.22 (95% CI, 1.23-4.03) and exacerbations adjusted rate ratio of 0.49 (95% CI, 0.27-0.89). The number needed to treat with small-particle ICS to achieve 1 additional child with asthma control was 17 (95% CI, 9-107) for the initiation population and 5 (95% CI, 3-78) for the step-up population. Outcomes were not significantly different for stepped-up small-particle ICS dose versus ICS/LABA combination (n = 185 in each cohort).
Initiating or stepping up the ICS dose with small-particle ICS rather than with standard size–particle ICS is more effective and shows similar effectiveness to add-on LABA in childhood asthma.
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