Simon Haworth

Ten years on: is dental general anaesthesia in childhood a risk factor for caries and anxiety?

Objectives To identify whether dental general anaesthesia (DGA) status is informative in assessing risk of caries or dental anxiety by (a) describing long-term oral health and dental anxiety for people who underwent DGA in childhood and (b) testing whether DGA status in childhood is associated with incident future dental caries or anxiety independently of preconceived risk factors.Design Analysis of prospectively obtained data.Setting An established population based cohort in the UK, the Avon Longitudinal Study of Parents and Children.Participants and methods In total 1,695 participants with dental data in childhood and adolescence were included in analysis. DGA status by age 7 and oral health measures at age 17 were identified from questionnaire data.Main outcome measures Filled or extracted permanent teeth at age 17, Corah Dental Anxiety Scale.Results One hundred and twenty-eight (7.6%) participants underwent DGA in childhood. Individuals who underwent DGA had higher measures of filled or extracted permanent teeth in adolescence (0.36 more affected teeth in fully-adjusted model [95% confidence interval: 0.27, 0.55; P <0.001]).Conclusions DGA in childhood predicts burden of treated caries in adolescence, independently of other risk factors. DGA status may be a clinically useful adjunct in identifying young people at high risk of further disease.

Common genetic variants and health outcomes appear geographically structured in the UK Biobank sample: Old concerns returning and their implications.

The inclusion of genetic data in large studies has enabled the discovery of genetic contributions to complex traits and their application in applied analyses including those using genetic risk scores (GRS) for the prediction of phenotypic variance. If genotypes show structure by location and coincident structure exists for the trait of interest, analyses can be biased. Having illustrated structure in an apparently homogeneous collection, we aimed to a) test for geographical stratification of genotypes in UK Biobank and b) assess whether stratification might induce bias in genetic association analysis. We found that single genetic variants are associated with birth location within UK Biobank and that geographic structure in genetic data could not be accounted for using routine adjustment for study centre and principal components (PCs) derived from genotype data. We found that GRS for complex traits do appear geographically structured and analysis using GRS can yield biased associations. We discuss the likely origins of these observations and potential implications for analysis within large-scale population based genetic studies.

Gene discovery for oral ulceration: a UK Biobank Study

Abstract Background Oral ulceration is a common, painful condition of uncertain aetiology. Ulcers are characterised by immune-mediated mucosal destruction, inflammation, and a proliferative healing phase. Oral ulceration is heritable but the genetic basis remains poorly characterised. We aimed to identify genetic risk factors for oral ulcers, and find evidence for a common genetic basis or causal association between oral ulceration and autoimmune traits. Methods A genome-wide association study was performed within the UK Biobank and replicated within the Avon Longitudinal Study of Parents and Children (ALSPAC). Outcome in UK Biobank, based on questionnaire data at recruitment (participants aged 40–73 years), was oral ulceration in the previous year. Outcome in ALSPAC, based on questionnaire data from a focus clinic (16–19 years), was ever having oral ulceration. Bidirectional causal effects were estimated with two-sample mendelian randomisation. Findings After exclusions and quality control measures, the genome-wide association study included 119 959 individuals and 9 341 558 genetic variants. The genomic inflation factor (λ) was 1·047. Replication included 2024 individuals. For ulcers, evidence for association was seen in or near IL12A1 (rs17753641, odds ratio 0·969 [95% CI 0·966–0·973], p=2·2E −62 in discovery; 0·72 [0·56–0·92], p=0·01 replication), IL10 (rs3024490, 1·015 [1·012–1·018], p=1·1E − 25 in discovery; 1·42 [1·18–1·70], p=0·0001 replication), CCR3 (rs6441955, p=2·4E −17 in discovery; unreplicated). Other variants were nominated in the discovery phase but not replicated in ALSPAC, including variants near HLA-DRB5 (rs11623911, p=1·1E − 13 ), PPP5C (rs8106592, p=4·2E −10 ) and IKZF1 (rs9649738, p=2·2E −08 ). When genotypes were used as a proxy for oral ulceration to investigate the impact of oral ulceration on autoimmune outcomes, evidence showed that oral ulceration reduced risk of Crohns disease (p=0·0037). In a genome-wide analysis no genetic correlation between ulcers and autoimmune traits was seen. Interpretation Variation in loci thought to regulate inflammatory function alters risk of oral ulceration. Oral ulceration appears to be a distinct inflammatory trait rather than a manifestation of other autoimmune diseases. The apparent protective effect of oral ulceration against Crohns disease is unexpected; this might be a biological effect—for example, divergence in inflammatory type could prevent both conditions from copresenting—or an artifactual finding. Funding UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish Government, and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation, and Diabetes UK. The Avon Longitudinal Study of Parents and Children receives core support from the Medical Research Council, Wellcome Trust (grant ref 102215/2/13/2), and University of Bristol.

Quality improvement in documentation for patients with suspected facial fractures: use of a structured record keeping tool

Objective Patients with injuries to the midface frequently sustain ophthalmic injuries and fractures to the facial bones. Despite this, basic ophthalmic examination and assessment of important clinical signs are often missing from the records of patients attending the emergency department (ED). We implemented a structured record keeping tool to improve documentation for patients presenting to the ED with midface injuries. Methods At our institution, a structured record keeping tool was introduced to document important clinical features of maxillofacial injuries. This assessment tool included 17 key clinical diagnostic signs and symptoms including a six-part basic ophthalmic examination. We audited 369 patients attending the ED with suspected midface bony injuries using this tool. Results A statistically significant improvement in the documentation of all six ophthalmic parameters was seen. The documentation rate of visual acuity increased by 41.1% (SE 2.8; p<0.001); diplopia by 45% (2.9; p<0.001); double vision by 51% (2.9; p<0.001); lateral subconjunctival haemorrhage with no posterior limit by 83% (2.6; p<0.001) and enopthalmous by 86% (2.4; p<0.001). Documenting whether pupils were equal and react to light increased by 14% (1.4; p<0.001). In addition, 10 out of 11 non-ophthalmic parameters showed significant improvement. The mean global record keeping score increased from 45.3% (95% CI 42.7% to 47.7%) to 99.1% (95% CI 98.2% to 100%; p<0.001). Conclusions This work demonstrates that a structured record keeping tool is a simple and effective method of significantly improving clinical documentation for patients with facial injuries presenting to the ED.

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume

Cranial growth and development affects the closely related traits of head circumference (HC) and intracranial volume (ICV). Here we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV+HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood.

Age 23 years + oral health questionnaire in Avon Longitudinal Study of Parents and Children.

Oral health data in large longitudinal cohort studies is rarely collected at multiple time-points. This type of data is important for assessing oral health trajectories and their determinants. This data resource includes self-report questionnaire data on up to 4,222 young adults at approximately 23 years of age from the Avon Longitudinal Study of Parents and Children (ALSPAC). The resource includes questions on dental attendance, tooth restorations and extractions, third molars (wisdom teeth) and mouth ulcers. This round of data collection follows on from similar questionnaires at ages 7, 10 and 17 years. The ALSPAC study provides an opportunity to combine this oral health data with extensive phenotype, genetic, epigenetic and metabolomic data from the participants, their mothers and fathers.

Self-reported bovine milk intake is associated with oral microbiota composition

Bovine milk intake has been associated with various disease outcomes, with modulation of the gastro-intestinal microbiome being suggested as one potential mechanism. The aim of the present study was to explore the oral microbiota in relation to variation in self-reported milk intake. Saliva and tooth biofilm microbiota was characterized by 16S rDNA sequencing, PCR and cultivation in 154 Swedish adolescents, and information on diet and other lifestyle markers were obtained from a questionnaire, and dental caries from clinical examination. A replication cohort of 31,571 adults with similar information on diet intake, other lifestyle markers and caries was also studied. Multivariate partial least squares (PLS) modelling separated adolescents with low milk intake (lowest tertile with <0.4 servings/day) apart from those with high intake of milk (≥3.7 servings/day) based on saliva and tooth biofilm, respectively. Taxa in several genera contributed to this separation, and milk intake was inversely associated with the caries causing Streptococcus mutans in saliva and tooth biofilm samples by sequencing, PCR and cultivation. Despite the difference in S. mutans colonization, caries prevalence did not differ between milk consumption groups in the adolescents or the adults in the replication cohort, which may reflect that a significant positive association between intake of milk and sweet products was present in both the study and replication group. It was concluded that high milk intake correlates with different oral microbiota and it is hypothesized that milk may confer similar effects in the gut. The study also illustrated that reduction of one single disease associated bacterial species, such as S. mutans by milk intake, may modulate but not prevent development of complex diseases, such as caries, due to adverse effects from other causal factors, such as sugar intake in the present study.

Consortium-based genome-wide meta-analysis for childhood dental caries traits

Abstract Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5–18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Tooth loss is a complex measure of oral disease: Determinants and methodological considerations

Abstract Objectives Counts of missing teeth or measures of incident tooth loss are gaining attention as a simple way to measure dental status in large population studies. We explore the meaning of these metrics and how missing teeth might influence other measures of dental status. Methods An observational study was performed in 2 contrasting adult populations. In total, 62 522 adult participants were available with clinically assessed caries and periodontal indices from the Swedish arm of the Gene‐Lifestyle Interactions and Dental Endpoints Study (GLIDE) and the Korea National Health and Nutrition Examination Survey (KNHANES) in the Republic of Korea. Longitudinal measures of tooth loss were available for 28 244 participants in GLIDE with median follow‐up of 10.6 years. Results In longitudinal analysis, hazard for tooth loss was associated with baseline dental status (previous tooth loss, periodontal status and caries status) and socio‐demographic variables (age, smoking status and highest educational level). Analysis of cross‐sectional data suggested that indices of caries exposure were not independent of periodontal status. The strength and direction of association varied between groups, even for measures specifically intended to avoid measuring tooth loss. Individuals with impaired periodontal health (community periodontal index [CPI] 3 or higher in any sextant) had higher standardized decayed and filled surfaces (DFS; number of DFS divided by total number of tooth surfaces) in GLIDE (incidence risk ratio [IRR] 1.05 [95% CI: 1.04, 1.07], but lower standardized DFS in KNHANES (IRR: 0.95 [0.92, 0.98]) than individuals with better periodontal health (CPI <3 in all sextants). Conclusions Incident tooth loss is a complex measure of dental disease, with multiple determinants. The relative importance of dental caries and periodontal disease as drivers of tooth loss differs between age groups. Measures of dental caries exposure are associated with periodontal status in the studied populations, and these associations can be population‐specific. Consideration of the study‐specific properties of these metrics may be required for valid inference in large population studies.

A clinical decision rule to predict zygomatico-maxillary fractures

Patients presenting with periorbital trauma require clinical assessment to exclude zygomatico-maxillary fractures. A single-centre pilot investigation was undertaken at a general hospital in the United Kingdom. The sample was composed of 229 adult patients attending our emergency department with periorbital injuries. Findings from 17 signs or symptoms of facial injury were recorded on a validated tool. The relationship between clinical presentation and displaced zygomatico-maxillary fracture was assessed using diagnostic test parameters and tests for correlation. A decision-making rule was derived. The presence of a) palpable bony step, b) bony asymmetry, c) lateral sub-conjunctival haemorrhage with no posterior limit, d) anaesthesia or paraesthesia to lip/cheek or side of nose and e) palpable emphysema were all specific features of radiographically displaced zygomatico-maxillary fracture (specificity all >75.0 %, p value for correlation all <0.001). A decision-making rule based on the presence of any one of features (a),(c),(d) or (e) identified all patients with displaced zygomatico-maxillary fractures in this sample (sensitivity 100% (95% CI 93.4%-100.0%), specificity 72.6% (95% CI 65.3%-79.0%). Implementation of this clinical decision-making rule would identify all patients with displaced fractures at the triage stage whilst reducing radiographic exposures by 55% in this sample.