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Small-area studies offer a powerful epidemiological approach to study disease patterns at the population level and assess health risks posed by environmental pollutants. They involve a public health investigation on a geographical scale (e.g. neighbourhood) with overlay of health, environmental, demographic and potential confounder data. Recent methodological advances, including Bayesian approaches, combined with fast-growing computational capabilities, permit more informative analyses than previously possible, including the incorporation of data at different scales, from satellites to individual-level survey information. Better data availability has widened the scope and utility of small-area studies, but has also led to greater complexity, including choice of optimal study area size and extent, duration of study periods, range of covariates and confounders to be considered and dealing with uncertainty. The availability of data from large, well-phenotyped cohorts such as UK Biobank enables the use of mixed-level study designs and the triangulation of evidence on environmental risks from small-area and individual-level studies, therefore improving causal inference, including use of linked biomarker and -omics data. As a result, there are now improved opportunities to investigate the impacts of environmental risk factors on human health, particularly for the surveillance and prevention of non-communicable diseases. [ABSTRACT FROM AUTHOR]

Background The UK Biobank (UKB) is a national epidemiological study of the health of 500 000 people, aged 40–69 years, who completed health-related tests and a questionnaire and gave samples of blood and urine. Salivas collected from 120 000 of these subjects were transported at 4°C and were placed in ultra-low temperature archives at up to 24 h after collection. The present study assessed how changes in saliva composition under UKB conditions influence a range of potential biomarkers resulting from holding saliva at 4°C for 24 h.Methods Unstimulated whole-mouth saliva samples were collected from 23 volunteers aged 45–69 years. Salivas were split into aliquots some of which were immediately frozen at −80°C, whereas others were stored at 4°C for 24 h and then frozen at −80°C, mimicking the UKB protocol.Results Assessment of mRNA by real-time polymerase chain reaction revealed no difference between samples that were analysed after the UKB protocol and those that were immediately preserved. Immunochemical analysis showed some loss of β-Actin under UKB conditions, whereas other salivary proteins including cytokines and C-reactive protein appeared to be unaffected. Cortisol and showed no reduction by UKB conditions, but salivary nitrite was reduced by 30%. The oral microbiome, as revealed by sequencing 16S rRNA genes, showed variations between subjects, but paired samples within subjects were very similar.Conclusions Our results suggest that many salivary components remain little affected under UKB collection and handling protocols, suggesting that the resource of 120 000 samples held in storage will be useful for phenotyping subjects and revealing potential prognostic disease biomarkers. [ABSTRACT FROM PUBLISHER]

Background The incidence of malignant melanoma is increasing worldwide and patients are being diagnosed earlier with thinner primary lesions. Most patients with very thin melanoma (Breslow thickness < 0·76 mm) are cured by surgery but 2–18% relapse locally or with distant metastases. Objectives The objective of this study was to establish potential new prognostic markers in very thin melanoma. Methods We identified a group of subjects with relapsing very thin primary cutaneous melanoma and a matched control group who had not relapsed. We investigated the expression of p16, Helix pomatia agglutinin (HPA), CD95 and CD95 ligand (CD95L) by immunohistochemistry on paraffin-embedded tissue sections from the subject group, their subsequent metastases and the control group. Results Reduced p16 expression was significantly associated with relapse in very thin melanoma ( P = 0·0129). Loss of p16 expression was also found in 76% of metastases. There was no significant association between HPA, CD95 or CD95L expression and subsequent relapse. Conclusions This work is the first to show a significant loss of p16 in relapsing very thin melanoma. [ABSTRACT FROM AUTHOR]

Background The 100,000 Genomes Project aims to improve cancer care for NHS patients in the UK through personalised medicine. Our target is to return WGS results to clinicians in a clinically meaningful timescale to facilitate diagnosis and treatment choices for patients, and in parallel to provide a research platform of genomic data linked to longitudinal clinical data. Methods We present here an overview of clinical utility for reported outcomes. To date, bioinformatics reports for WGS, with links to potentially relevant therapies and UK clinical trials, have been produced for more than 14,000 cancer patients in the UK Currently our bioinformatics analysis of WGS includes clinical interpretation of somatic small variants, somatic structural and copy number variants (SV/CNV), germline pertinent findings, mutational burden and signatures. To iteratively develop a high-quality bioinformatics pipeline and to monitor clinical utility of returned results, we are collecting feedback via the 100,000 Genomes Project Interpretation Portal from NHS Molecular Tumour Boards. These data suggest that WGS has the potential to affect patient management. Future applications will include the utilisation of pan-genomic markers to better stratify patients within the context of a clinical study. Results WGS has the ability to replace multiple standard of care tests as it has the potential to detect all types of variants (SV/CNV/SNV/indels) as well as emerging pan-genome biomarkers in a single test. In this study we use samples submitted as part of the 100,000 Genomes Project to investigate the feasibility of WGS as an alternative to conventional testing. Overall comparison of WGS with the results of NGS panels (96 patients, 156 clinically-relevant SNVs), high-depth exome sequencing (10 patients, 3150 SNVs, 140 indels), cytogenetic FISH tests (70 patients, 259 SVs, 100 CNVs), immunohistochemistry tests for Mismatch Repair Deficiency (265 patients) and HER2 status (154 patients) demonstrated Positive Percentage Agreement > 90% and False Positive Rate < 5%. Conclusions Further work is required to validate fully all aspects of the WGS analysis pipeline but these results indicate that WGS can reliably detect clinically relevant biomarkers in the genomes of cancer patients. Legal entity responsible for the study Genomics England. Funding Genomics England. Disclosure All authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Juvenile-onset SLE (JSLE) is a systemic autoimmune disease affecting young people before the age of 17 years. Despite recent progress in understanding the pathogenesis of JSLE, it remains unclear. The lack of reliable biomarkers makes the assessment of disease activity and organ involvement challenging. A family of pro-inflammatory molecules known as S100 proteins have recently emerged as potential biomarkers for monitoring disease activity in an adult-onset SLE and various (auto-) inflammatory conditions. We investigated the usefulness of S100A8/A9 and S100A12 serum and urine levels as biomarkers for renal involvement and/or disease activity in JSLE. Methods Serum and urine from JSLE patients (n = 60), matched healthy controls (n = 53) and patients with IgA vasculitis (disease controls, n = 9) were collected. S100A8/A9 and S100A12 concentrations in serum and urine samples were quantified using the Meso Scale Discovery Immunoassay [serum; median ng/mL (I.Q.R), urine; median ng/mmol creatinine (I.Q.R)]. Furthermore, S100 protein concentrations in serum and urine were compared between groups and between JSLE patients with active (BILAG scores A, B, C) and inactive (BILAG scores D, E) renal disease. Potential effects of age, sex and global disease activity (SLEDAI scores) on S100 protein concentrations were tested. Results S100A8/A9 levels were significantly increased in the serum of JSLE patients [1577.80ng/mL (2313.97)] when compared to healthy controls [732.53 ng/mL (1003.47); p < 0.001)] and patients with IgA vasculitis [531.23 ng/mL (824.50); p < 0.05)]. This, however, was not reflected in patients' urine samples. S100A12 concentrations were significantly increased in both the serum [41.12 ng/mL = (106.06); p < 0.05] and urine [90.12ng/mmol creatinine (348.44); p < 0.05] when compared to healthy controls [serum;17.75ng/mL(47.16), urine; 14.88ng/mmol creatinine (198.36)]. No differences were seen between S100A12 protein levels in serum or urine of JSLE patients when compared to patients with IgA vasculitis. No differences were observed between S100 protein concentrations in the serum or urine of patients with JSLE with active vs. inactive renal disease, between ages or sexes. Also, global disease activity (SLEDAI) did not correlate with serum or urine S100 protein concentrations. Conclusion JSLE patients exhibit increased concentrations of S100A8/A9 and S100A12 proteins in the serum, independent of clinical disease activity. Furthermore, increased urine concentrations of S100A12 in JSLE patients are independent of current renal involvement or activity. Based on the small molecular weight of S100 proteins, this may suggest renal loss of elevated serum S100A12 (21 kDa) through the kidneys rather than being the result of kidney inflammation or damage. Thus, S100 proteins may help to distinguish JSLE patients from healthy controls and patients with the differential diagnosis IgA vasculitis, supporting previous reports in adult-onset SLE. Longitudinal assessment of S100 proteins for an individual patient and/or in combination with other biomarkers may be helpful in assessing disease activity in JSLE patients. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background An estimated 10-20% of all patients with systemic lupus erythematosus (SLE) develop clinical disease before the age of 18 years and are therefore classified as juvenile-onset SLE (JSLE). JSLE patients have a higher prevalence of lupus nephritis (LN) compared to adult-onset SLE and decreased long-term survival compared to JSLE patients without LN. We aimed to identify clinical and laboratory predictors of LN in JSLE patients by comparing the baseline characteristics of JSLE patients with and without LN. Methods This is a single-centre retrospective study that included JSLE patients reviewed in our young adult and adolescent clinics after transitioning from paediatric services. All data was analysed descriptively. Mann-Whitney U or Chi-square test were performed to compare the characteristics between patients with and without LN. In addition, we performed uni- and multivariate analysis to investigate potential predictor biomarkers for LN. Results We identified 134 JSLE patients, 45 (34%) of which had LN. 112 (83.6%) of the patients were female and the median age was 22 years (interquartile range [IQR] 20- 24). The median disease duration was longer in the patients with LN (10 years [IQR 8- 14]) in comparison with the patients without LN (8 years [IQR 6- 13]), p = 0.012. As expected, the highest dsDNAlevels ever were observed in patients with LN (p = 0.022). The overall clinical manifestations and complications did not differ between JSLE patients with or without LN, except for the prevalence of low bone mineral density. 16 (35.5%) patients with LN had low bone density and only 11 (12.4%) patients without LN (p = 0.008). Factors associated with low bone mineral density in a univariate logistic regression analysis were: the use of mycophenolate mofetil (p = 0.021) and the presence of LN (p = 0.007), while LN also associated with low bone density (p = 0.008) in a multivariate analysis. Skin involvement was the most common clinical manifestation in both JSLE patient groups. Treatment was more aggressive in patients with LN, including the use of cyclophosphamide, mycophenolate and rituximab, but there was no difference regarding the length of the steroid treatment. The majority of patients (67%) had one flare of nephritis. For the remaining patients, the number of flares ranged from 2 (13%) to 12 (2.2%). The class of nephritis was reported in 34 out of 45 patients, and focal lupus nephritis (class III) was the most common type (44%) reported. There were no statistically significant differences in the baseline characteristics or treatments among the different classes of LN. Conclusion Low bone mineral density in patients with JSLE is well described. However, this is the first study highlighting the association of low bone density with LN independent of total duration of steroid treatment or other clinical manifestations. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Poster presentation Tuesday 8 October Background Sjögren's syndrome, a chronic multisystem autoimmune disease is characterised by inflammation of the exocrine glands, principally the salivary and lacrimal glands resulting in xerostomia and xerophthalmia. It can also present with more extensive exocrinopathy as well as extra-glandular, systemic features. Defined as primary SS (pSS) when there is no association with other autoimmune disease, reported incidence and prevalence rates vary. Juvenile-onset pSS is believed to be rare; however it is likely that it is under-recognised and therefore under-diagnosed. To date there have been no studies reporting accurate incidence or prevalence of paediatric pSS (PpSS). Diagnosing pSS can be challenging. Many of the cardinal symptoms are non-specific and no gold standard biomarker of disease exists. Between 1965–2002 eleven diagnostic criteria sets were developed, none of which have gained universal acceptance or been validated for use in a paediatric population. Until recently, the most widely used criteria were those developed by the American-European Consensus Group. It remains well-recognised that international consensus on classification is important for standardisation, particularly in relation to research and monitoring treatment outcomes. With this in mind, the 2016 ACR/EULAR criteria were developed. However, there still remains a paucity of validated classification criteria for diagnosis of juvenile-onset pSS. Paediatric-focused criteria are required as features of pSS in children differ from those observed in adults. Children experience less dryness and more frequently experience systemic symptoms and parotid enlargement. Hence, simply applying adult criteria to a paediatric population may lead to mis- and/or under-diagnosis. The overarching aim of this study is to identify epidemiological, clinical and laboratory characteristics of PpSS in a multi-centre cohort of patients. Using this data our goal is to develop universally accepted classification criteria validated for use in a paediatric population. Going forward, this would enable standardisation of PpSS classification allowing for robust studies into disease pathogenesis, management and prognosis. Methods Inclusion criterion for entry into the UK/Ireland PpSS cohort study and repository is diagnosis of pSS before 18 years. A data collection pack will be sent to authors willing to participate. Information collected will include demographic, clinical and laboratory/histological data at diagnosis and subsequent follow-up appointments. Biological samples including blood, tears, saliva, urine, and glandular and extra-glandular (e.g. renal) tissue will be collected prospectively if available. Outcome measures related to disease activity and damage, as well as patient reported outcomes will also be collected at set time-points. Results No results to report. Conclusion The UK/Ireland PpSS cohort study and repository will capture data on a significant cohort of children with pSS providing a powerful resource to help improve our understanding of this rare disease. Prospective data collection will allow a fuller analysis of poor prognostic features, impact of therapy, damage accrual and variable outcome of PpSS. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: High-throughput profiling of circulating metabolites may improve cardiovascular risk prediction over established risk factors., Methods and Results: We applied quantitative nuclear magnetic resonance metabolomics to identify the biomarkers for incident cardiovascular disease during long-term follow-up. Biomarker discovery was conducted in the National Finnish FINRISK study (n=7256; 800 events). Replication and incremental risk prediction was assessed in the Southall and Brent Revisited (SABRE) study (n=2622; 573 events) and British Women's Health and Heart Study (n=3563; 368 events). In targeted analyses of 68 lipids and metabolites, 33 measures were associated with incident cardiovascular events at P<0.0007 after adjusting for age, sex, blood pressure, smoking, diabetes mellitus, and medication. When further adjusting for routine lipids, 4 metabolites were associated with future cardiovascular events in meta-analyses: higher serum phenylalanine (hazard ratio per standard deviation, 1.18; 95% confidence interval, 1.12-1.24; P=4×10(-10)) and monounsaturated fatty acid levels (1.17; 1.11-1.24; P=1×10(-8)) were associated with increased cardiovascular risk, while higher omega-6 fatty acids (0.89; 0.84-0.94; P=6×10(-5)) and docosahexaenoic acid levels (0.90; 0.86-0.95; P=5×10(-5)) were associated with lower risk. A risk score incorporating these 4 biomarkers was derived in FINRISK. Risk prediction estimates were more accurate in the 2 validation cohorts (relative integrated discrimination improvement, 8.8% and 4.3%), albeit discrimination was not enhanced. Risk classification was particularly improved for persons in the 5% to 10% risk range (net reclassification, 27.1% and 15.5%). Biomarker associations were further corroborated with mass spectrometry in FINRISK (n=671) and the Framingham Offspring Study (n=2289)., Conclusions: Metabolite profiling in large prospective cohorts identified phenylalanine, monounsaturated fatty acids, and polyunsaturated fatty acids as biomarkers for cardiovascular risk. This study substantiates the value of high-throughput metabolomics for biomarker discovery and improved risk assessment., (© 2015 American Heart Association, Inc.)