Biomarker data visualisation for decision making in clinical trials.

OBJECTIVE: To understand how visualization of biomarker data is used for decision making in clinical trials, and identify problems with and suggest improvements to this process. METHODS: We carried out semi-structured interviews with 18 professionals involved in various aspects of developing or using visualizations of biomarker data for decision making in clinical trials. We used an inductive thematic analysis to identify implicit and explicit ideas within the data captured from the interviews. RESULTS: We identified 6 primary themes, including: how visualizations were used in clinical trials; the importance of having a clear understanding of the underlying data; the purpose or use of the visualization, and the properties of the visualizations themselves. The results show that participants' 'trust' in the visualization depends on access to the underlying data, and that there is currently no standard or straightforward way to support this access. CONCLUSIONS: Incorporating information about data provenance into biomarker-related visualizations used for decision making in clinical trials may increase users' trust, and therefore facilitate the decision making process.

Prediction of primary non-response to methotrexate therapy using demographic, clinical and psychosocial variables: results from the UK Rheumatoid Arthritis Medication Study (RAMS).

BACKGROUND: Methotrexate (MTX) remains the disease-modifying anti-rheumatic drug of first choice in rheumatoid arthritis (RA) but response varies. Predicting non-response to MTX could enable earlier access to alternative or additional medications and control of disease progression. We aimed to identify baseline predictors of non-response to MTX and combine these into a prediction algorithm. METHODS: This study included patients recruited to the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre prospective observational study of patients with RA or undifferentiated polyarthritis, commencing MTX for the first time. Non-response to MTX at 6 months was defined as "no response" using the European League Against Rheumatism (EULAR) response criteria, discontinuation of MTX due to inefficacy or starting biologic therapy. The association of baseline demographic, clinical and psychosocial predictors with non-response was assessed using logistic regression. Predictive performance was assessed using the area under the receiver operating characteristic curve (AUC) and calibration plots. RESULTS: Of 1050 patients, 449 (43%) were classified as non-responders. Independent multivariable predictors of MTX non-response (OR (95% CI)) were rheumatoid factor (RF) negativity (0.62 (0.45, 0.86) for RF positivity versus negativity), higher Health Assessment Questionnaire score (1.64 (1.25, 2.15)), higher tender joint count (1.06 (1.02, 1.10)), lower Disease Activity score in 28 joints (0.29 (0.23, 0.39)) and higher Hospital Anxiety and Depression Scale anxiety score (1.07 (1.03, 1.12)). The optimism-corrected AUC was 0.74. CONCLUSIONS: This is the first model for MTX non-response to be developed in a large contemporary study of patients commencing MTX in which demographic, clinical and psychosocial predictors were considered. Patient anxiety was a predictor of non-response and could be addressed at treatment commencement.

Epistasis between FLG and IL4R Genes on the Risk of Allergic Sensitization: Results from Two Population-Based Birth Cohort Studies.

Immune-specific genes as well as genes responsible for the formation and integrity of the epidermal barrier have been implicated in the pathogeneses of allergic sensitization. This study sought to determine whether an epistatic effect (gene-gene interaction) between genetic variants within interleukin 4 receptor (IL4R) and filaggrin (FLG) genes predispose to the development of allergic sensitization. Data from two birth cohort studies were analyzed, namely the Isle of Wight (IOW; n = 1,456) and the Manchester Asthma and Allergy Study (MAAS; n = 1,058). In the IOW study, one interaction term (IL4R rs3024676 × FLG variants) showed statistical significance (interaction term: P = 0.003). To illustrate the observed epistasis, stratified analyses were performed, which showed that FLG variants were associated with allergic sensitization only among IL4R rs3024676 homozygotes (OR, 1.97; 95% CI, 1.27-3.05; P = 0.003). In contrast, FLG variants effect was masked among IL4R rs3024676 heterozygotes (OR, 0.53; 95% CI, 0.22-1.32; P = 0.175). Similar results were demonstrated in the MAAS study. Epistasis between immune (IL4R) and skin (FLG) regulatory genes exist in the pathogenesis of allergic sensitization. Hence, genetic susceptibility towards defective epidermal barrier and deviated immune responses could work together in the development of allergic sensitization.

In vitro modeling of COPD inflammation and limitation of p38 inhibitor - SB203580.

BACKGROUND: Systemic inflammation and steroid resistance are the hallmarks of COPD. We examined the impact of p38 inhibitor (SB203580) in in vitro assays of systemic inflammation using pulmonary cells and patients' sera. OBJECTIVE AND METHODS: Data from 66 COPD patients and 15 age-/sex-matched healthy controls were compared. Interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and CCL5 were measured in serum samples and culture media from peripheral blood mononuclear cells. The impact of sera on IL-10 and CCL5 expression in alveolar macrophage cell line (MH-S) was examined. The in vitro effects of SB203580 on lipopolysaccharide-induced inflammation were investigated. RESULTS: Peripheral blood mononuclear cells from Global initiative for chronic Obstructive Lung Disease (GOLD) D patients produced more CCL5 and TNF-α, and less IL-10 compared to GOLD A-C patients. SB203580 treatment suppressed CCL5 and TNF-α and stimulated IL-10 production; however, the effect of SB203580 on IL-10 was lower in the COPD group. Culture of MH-S cells with COPD serum showed a significant increase in CCL5 and a significant decrease in IL-10 compared to healthy serum. This effect was not suppressed with SB203580 treatment. CONCLUSION: COPD serum has a potent proinflammatory effect on pulmonary cells. Inhibition of p38 phoshorylation had a limited effect in restoring impaired lymphocyte function and suppressing inflammation induced by COPD serum, implying important p38-independent inflammatory mechanisms in COPD.

Age, sex and the association between skin test responses and IgE titres with asthma.

BACKGROUND: Skin prick tests (SPTs) and allergen-specific serum IgE (sIgE) measurements are the main diagnostic tools for confirming atopic sensitization. Results are usually reported as 'positive' or 'negative', using the same arbitrary cut-offs (SPT>3 mm, sIgE>0.35 kUA /l) across different ages and sexes. We investigated the influence of age and sex on the interpretation of allergy test in the context of childhood asthma. METHODS: In a population-based birth cohort (n = 1051), we ascertained the information on asthma/wheeze (validated questionnaires) and performed SPTs and sIgE measurement to inhalant allergens (dust mite, cat, dog) at follow-ups between ages three and 11 years. We investigated the association between quantitative sensitization (sum of SPT mean wheal diameters [MWD] and sIgE titres to the three allergens) and current wheeze and asthma across ages and sexes. RESULTS: We observed a significant association between the SPT MWD and sIgE titres and wheeze/asthma at most ages and for both sexes. However, the strength of this association was age- and sex-dependent. For SPTs, the strength of the association between MWD and asthma increased with increasing age; we observed the opposite pattern for sIgE titre. For any given SPT MWD/sIgE titre, boys were significantly more likely to express clinical symptoms, particularly in early life; this difference between males and females diminished with age and was no longer significant by age 11 years. CONCLUSIONS: Age and sex should be taken into account when interpreting the results of skin tests and sIgE measurement, and age- and sex-specific normative data are needed for these allergy tests.

Interaction between glutathione S-transferase variants, maternal smoking and childhood wheezing changes with age.

BACKGROUND: Maternal smoking increases the risk of respiratory symptoms in children. Glutathione S-transferases (GSTs) detoxify xenobiotics from tobacco smoke, and functional polymorphism in GST gene(s) could predispose children to the detrimental effects of maternal smoking. Our objective was to investigate interactions between GST variants and maternal smoking in relation to the development of wheezing during childhood and whether any such interaction changes with time. METHODS: In a population-based birth cohort, we assessed maternal smoking and current wheeze at five time points during the first 11 yr of life. DNA was genotyped for GSTP1, GSTM1 and GSTT1 (n = 807). Longitudinal analyses were performed using generalized estimating equations. RESULTS: During early childhood, children whose mothers smoked were more likely to wheeze, with the strongest association observed at age 3 yr (p = 0.006). In a longitudinal model, children with GSTP1 AA and AG genotypes had significantly higher risk of wheeze compared with GG homozygotes. We observed a significant interaction between GSTP1 and maternal smoking where the risk of infantile wheezing was significantly increased in AA homozygotes, but only if their mothers smoked (OR 2.59, [1.08-6.21], p(int) = 0.03). Furthermore, amongst AA carriers, there was a significant interaction between child's age and maternal smoking, with the effect of maternal smoking on the risk of wheeze significantly diminishing with age (p(int) = 0.05); no such findings were observed for GSTM1 and GSTT1. CONCLUSIONS: Children with AA genotype for GSTP1 are at increased risk of early-life wheezing if their mothers smoke, but the effect of maternal smoking on wheezing diminishes with time.