Pathway analysis of genome-wide association study data in primary biliary cirrhosisa

Genome-wide association studies (GWAS) have successfully identified several genetic loci associated with inherited predisposition to primary biliary cirrhosis (PBC), the most common autoimmune disease of the liver. Pathway-based tests constitute a novel paradigm for GWAS analysis. By evaluating genetic variation across a biological pathway (gene set), these tests have the potential to determine the collective impact of variants with subtle effects that are individually too weak to be detected in traditional single variant GWAS analysis. To identify biological pathways associated with the risk of development of PBC, GWAS of PBC from Italy (449 cases and 940 controls) and Canada (530 cases and 398 controls) were independently analyzed. The linear combination test (LCT), a recently developed pathway-level statistical method was used for this analysis. For additional validation, pathways that were replicated at the P <0.05 level of significance in both GWAS on LCT analysis were also tested for association with PBC in each dataset using two complementary GWAS pathway approaches. The complementary approaches included a modification of the gene set enrichment analysis algorithm (i-GSEA4GWAS) and Fisher's exact test for pathway enrichment ratios. Twenty-five pathways were associated with PBC risk on LCT analysis in the Italian dataset at P<0.05, of which eight had an FDR<0.25. The top pathway in the Italian dataset was the TNF/stress related signaling pathway (p=7.38×10 -4, FDR=0.18). Twenty-six pathways were associated with PBC at the P<0.05 level using the LCT in the Canadian dataset with the regulation and function of ChREBP in liver pathway (p=5.68×10-4, FDR=0.285) emerging as the most significant pathway. Two pathways, phosphatidylinositol signaling system (Italian: p=0.016, FDR=0.436; Canadian: p=0.034, FDR=0.693) and hedgehog signaling (Italian: p=0.044, FDR=0.636; Canadian: p=0.041, FDR=0.693), were replicated at LCT P<0.05 in both datasets. Statistically significant association of both pathways with PBC genetic susceptibility was confirmed in the Italian dataset on i-GSEA4GWAS. Results for the phosphatidylinositol signaling system were also significant in both datasets on applying Fisher's exact test for pathway enrichment ratios. This study identified a combination of known and novel pathway-level associations with PBC risk. If functionally validated, the findings may yield fresh insights into the etiology of this complex autoimmune disease with possible preventive and therapeutic application.^

Multi-component assessment of chronic obstructive pulmonary disease : an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

Funding The International Primary Care Respiratory Group (IPCRG) provided funding for this research project as an UNLOCK group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Database access for the OPCRD was provided by the Respiratory Effectiveness Group (REG) and Research in Real Life; the OPCRD statistical analysis was funded by REG. The Bocholtz Study was funded by PICASSO for COPD, an initiative of Boehringer Ingelheim, Pfizer and the Caphri Research Institute, Maastricht University, The Netherlands.

Evaluation of total purchasing pilots in England and Scotland and implications for primary care groups in England: personal interviews and analysis of routine data

Objectives: To evaluate the reported achievements of the 52 first wave total purchasing pilot schemes in 1996-7 and the factors associated with these; and to consider the implications of these findings for the development of the proposed primary care groups.

Data feedback and behavioural change intervention to improve primary care prescribing safety (EFIPPS) : multicentre, three arm, cluster-randomised controlled trial

Funding and trial registration: Scottish Government Chief Scientist Office grant CZH/3/17. ClinicalTrials.gov registration NCT01602705.

RACIAL/ETHNIC VARIABILITY IN THE EFFECT OF RADIATION ON SECOND PRIMARY THYROID CANCER IN CHILDREN: ANALYSIS USING SURVEILLANCE EPIDEMIOLOGY AND END RESULTS DATA

Increases in pediatric thyroid cancer incidence could be partly due to previous clinical intervention. This retrospective cohort study used 1973-2012 data from the Surveillance Epidemiology and End Results program to assess the association between previous radiation therapy exposure in development of second primary thyroid cancer (SPTC) among 0-19-year-old children. Statistical analysis included the calculation of summary statistics and univariable and multivariable logistic regression analysis. Relative to no previous radiation therapy exposure, cases exposed to radiation had 2.46 times the odds of developing SPTC (95% CI: 1.39-4.34). After adjustment for sex and age at diagnosis, Hispanic children who received radiation therapy for a first primary malignancy had 3.51 times the odds of developing SPTC compared to Hispanic children who had not received radiation therapy, [AOR=3.51, 99% CI: 0.69-17.70, p=0.04]. These findings support the development of age-specific guidelines for the use of radiation based interventions among children with and without cancer.

Primary prevention of neural tube defects: data from the portuguese national registry of congenital anomalies (RENAC)

Background: In Portugal folic acid supplementation is recommended to start at least 2-3 months before conception for primary prevention of Neural Tube Defects. The aim of this study was to evaluate, within gestations with at least one congenital anomaly, possible association between maternal socio-demographic factors and the use of folic acid. Methods: Using data from the Portuguese national registry of congenital anomalies, for the 2004-2013 period, the association between folic acid use during pregnancy and maternal characteristics was studied using the chi-square test. Results: Considering all reported cases with congenital anomaly, the use of folic acid before conception was reported by 12.7% (n = 1233) of the women; 47.8% (n = 4623) started supplementation during the 1st trimester, 7% (n = 680) did not take folic acid and 32.5% (3143) of the records had no information on folic acid use. Women with professions that require higher academic differentiation started the use of supplements before pregnancy (p <0.001); women under 19 years old and with Arab ethnicity (p <0.001) did not take folic acid. Mothers with a previous pregnancy reported less use of folic acid (11.5% versus 14.7%) than mothers without a previous pregnancy (p <0.001). Conclusions: The results suggest some degree of association between maternal characteristics and use of folic acid. To increase the consumption of folic acid before pregnancy new measures are need to promote this primary prevention, among couples and health professionals. This study highlights some maternal characteristics and subgroups of mothers for who the measures should be reinforced.