Data saves lives: optimising routinely collected clinical data for rare disease research

Necessity driven organisational change in the post-pandemic landscape has seen health care providers adopting innovations to manage and process health data. These include the use of ‘real-world’ datasets of routinely collected clinical information, enabling data-driven delivery. Rare disease risks being ‘left-behind’ unless our clinical and research communities engage with the challenges and opportunities afforded by the burgeoning field of health data informatics. We address the challenges to the meaningful use and reuse of rare disease data, and, through a series of recommendations around workforce education, harmonisation of taxonomy, and ensuring an inclusive health data environment, we highlight the role that those who manage rare disease must play in addressing them

Population screening for glaucoma in UK : current recommendations and future directions

Funding Information: APK is funded by a UKRI Future Leaders Fellowship and an Alcon Research Institute Young Investigator Award.Effective population screening for glaucoma would enable earlier diagnosis and prevention of irreversible vision loss. The UK National Screening Committee (NSC) recently published a review that examined the viability, effectiveness and appropriateness of a population-based screening programme for primary open-angle glaucoma (POAG). In our article, we summarise the results of the review and discuss some future directions that may enable effective population screening for glaucoma in the future. Two key questions were addressed by the UK NSC review; is there a valid, accurate screening test for POAG, and does evidence exist that screening reduces morbidity from POAG compared with standard care. Six new studies were identified since the previous 2015 review. The review concluded that screening for glaucoma in adults is not recommended because there is no clear evidence for a sufficiently accurate screening test or for better outcomes with screening compared to current care. The next UK NSC review is due to be conducted in 2023. One challenge for POAG screening is that the relatively low disease prevalence results in too many false-positive referrals, even with an accurate test. In the future, targeted screening of a population subset with a higher prevalence of glaucoma may be effective. Recent developments in POAG polygenic risk prediction and deep learning image analysis offer potential avenues to identifying glaucoma-enriched sub-populations. Until such time, opportunistic case finding through General Ophthalmic Services remains the primary route for identification of glaucoma in the UK and greater public awareness of the service would be of benefit.Publisher PDFPeer reviewe

Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study

PURPOSE: To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK.METHODS:U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40-69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview.RESULTS: Fifty four percent of participants aged 40-69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40-44 years increasing to 46% at 65-69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White).CONCLUSIONS: Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study

Temporal trends in frequency, type and severity of myopia and associations with key environmental risk factors in the UK: Findings from the UK Biobank Study

This study investigated temporal trends in the epidemiology of primary myopia and associations with key environmental risk factors in a UK population. Data were collected at recruitment (non-cycloplegic autorefraction, year of birth, sex, ethnicity, highest educational attainment, reason and age of first wearing glasses and history of eye disease) from 107,442 UK Biobank study participants aged 40 to 69 years, born between 1939 and 1970. Myopia was defined as mean spherical equivalent (MSE) ≤-1 dioptre (D). Temporal changes in myopia frequency by birth cohort (5-year bands using date of birth) and associations with environmental factors were analysed, distinguishing both type (childhood-onset, <18 years versus adult-onset) and severity (three categories: low -1.00 to -2.99D, moderate -3.00 to -5.99D or high ≥-6.00D). Overall myopia frequency increased from 20.0% in the oldest cohort (births 1939-1944) to 29.2% in the youngest (1965-1970), reflecting a relatively higher increase in frequency of adult-onset and low myopia. Childhood-onset myopia peaked in participants born in 1950-54, adult-onset myopia peaked in the cohort born a decade later. The distribution of MSE only shifted for childhood-onset myopia (median: -3.8 [IQR -2.4, -5.4] to -4.4 [IQR -3.0, -6.2]). The magnitude of the association between higher educational attainment (proxy for educational intensity) and myopia overall increased over time (adjusted Odds Ratio (OR) 2.7 [2.5, 2.9] in the oldest versus 4.2 [3.3, 5.2] in the youngest cohort), being substantially greater for childhood-onset myopia (OR 3.3 [2.8, 4.0] to 8.0 [4.2, 13]). Without delineating childhood-onset from adult-onset myopia, important temporal trends would have been obscured. The differential impact of educational experience/intensity on both childhood-onset and high myopia, amplified over time, suggests a cohort effect in gene-environment interaction with potential for increasing myopia frequency if increasing childhood educational intensity is unchecked. However, historical plateauing of myopia frequency does suggest some potential for effective intervention

The Heritability of Dry Eye Disease in a Female Twin Cohort

PURPOSE. We estimated the relative importance of genes and environment in dry eye disease (DED) using a classic twin study. METHODS. A large sample of 3930 female monozygotic and dizygotic twins from the UK Adult Twin Registry (TwinsUK) was questioned about the presence of a DED diagnosis and about DED symptoms in the preceding 3 months. In addition, a subset of 606 twins was examined for several dry eye signs. Genetic and environmental effects were estimated using maximum likelihood structural equation modeling. RESULTS. All DED outcome variables showed higher correlation in monozygotic twin pairs than in dizygotic twin pairs, suggesting genes have a contributory role in DED. The DED symptoms showed a heritability of 29% (95% confidence interval [CI], 18%-40%). A clinician's diagnosis of DED with concurrent use of artificial tears showed a heritability of 41% (95% CI, 26%-56%). Estimates of the heritability of DED signs were 25% (95% CI, 7%-42%) for interblink interval, 58% (95% CI, 43%-70%) for Schirmer value, 40% (95% CI, 25%-53%) for tear osmolarity, and 78% (95% CI, 59%-90%) for the presence of blepharitis. The unique environment explained the remainder of the variance. We found no significant heritability for tear breakup time. CONCLUSIONS. Genetic factors contribute moderately to the diagnosis, symptoms, and the signs of DED. Compared to other ocular phenotypes, the lower heritability might reflect some of the difficulties in objective phenotyping of DED in a population-based sample. However, future genetic studies are now justified and may help in unraveling the pathophysiology of DED

The potential of current polygenic risk scores to predict high myopia and myopic macular degeneration in multi-ethnic Singapore adults

Purpose: To evaluate the trans-ancestry portability of current myopia polygenic risk scores (PRS) to predict high myopia (HM) and myopic macular degeneration (MMD) in an Asian population. Design: Population-based study. Subjects: A total of 5,894 (2,141 Chinese, 1,913 Indians, and 1,840 Malays) adults from the Singapore Epidemiology of Eye Diseases (SEED) study were included in the analysis. The mean age was 57.0 (standard deviation, SD = 9.31) years. A total of 361 adults had HM (spherical equivalent, SE -0.5D). Methods: The PRS, derived from 687,289 HapMap3 SNPs from the largest genome-wide association study of myopia in Europeans to date (n = 260,974), was assessed on its ability to predict HM and MMD versus controls. Main outcome measures: The primary outcomes were the area under the receiver operating characteristic curve (AUROC) to predict HM and MMD. Results: The PRS had an AUROC of 0.73 (95% CI: 0.70, 0.75) for HM and 0.66 (95% CI: 0.63, 0.70) for MMD versus no myopia controls. The inclusion of the PRS with other predictors (age, sex, educational attainment (EA), and ancestry; age-by-ancestry; sex-by-ancestry and EA-by-ancestry interactions; and 20 genotypic principal components) increased the AUROC to 0.84 (95% CI: 0.82, 0.86) for HM and 0.79 (95% CI: 0.76, 0.82) for MMD. Individuals with a PRS in the top 5% had 4.66 (95% CI: 3.34, 6.42) times higher risk for HM and 3.43 (95% CI: 2.27, 5.05) times higher risk for MMD compared to the remaining 95% of individuals. Conclusion: The PRS is a good predictor for HM and will facilitate the identification of high-risk children to prevent myopia progression to HM. In addition, the PRS also predicts MMD and will help to identify high-risk myopic adults who require closer monitoring for myopia-related complications.info:eu-repo/semantics/publishedVersio

Cone-driven strong flash electroretinograms in healthy adults: Prevalence of negative waveforms

Purpose Both rod and cone-driven signals contribute to the electroretinogram (ERG) elicited by a standard strong flash in the dark. Negative ERGs usually reflect inner retinal dysfunction. However, in diseases where rod photoreceptor function is selectively lost, a negative waveform might represent the response of the dark-adapted cone system. To investigate the dark-adapted cone-driven waveform in healthy individuals, we delivered flashes on a dim blue background, designed to saturate the rods, but minimally adapt the cones. Methods ERGs were recorded, using conductive fibre electrodes, in adults from the TwinsUK cohort. Responses to 13 cd m−2 s white xenon flashes (similar to the standard DA 10 flash), delivered on a blue background, were analysed. Photopic and scotopic strengths of the background were 1.3 and 30 cd m−2, respectively; through a dilated pupil, this is expected to largely saturate the rods, but adapt the cones much less than the standard ISCEV background. Results Mean (SD) participant age was 62.5 (11.3) years (93% female). ERGs from 203 right and 204 left eyes were included, with mean (SD) b/a ratios of 1.22 (0.28) and 1.18 (0.28), respectively (medians, 1.19 and 1.17). Proportions with negative waveforms were 23 and 26%, respectively. Right and left eye b/a ratios were strongly correlated (correlation coefficient 0.74, p &lt; 0.0001). We found no significant correlation of b/a ratio with age. Conclusions Over 20% of eyes showed b/a ratios less than 1, consistent with the notion that dark-adapted cone-driven responses to standard bright flashes can have negative waveforms. The majority had ratios greater than 1. Thus, whilst selective loss of rod function can yield a negative waveform (with reduced a-wave) in some, our findings also suggest that loss of rod function can occur without necessarily yielding a negative ERG. One potential limitation is possible mild cone system adaptation by the background

An Analysis of the Effect of ABCA4 p.Asn1868Ile Genotypes on Retinal Structure in 26,558 Participants in the UK Biobank

PURPOSE: To determine whether the ABCA4 retinopathy-associated variant p.Asn1868Ile (c.5603A>T) is associated with retinal structure or subclinical disease among the general population. METHODS: UK Biobank participants of European ancestry with available spectral-domain optical coherence tomography (OCT) passing quality control metrics and exome sequencing data were included. Regression analyses using both linear and recessive models tested for the association between the p.Asn1868Ile variant and total retinal thickness, clinically relevant segmented layer thicknesses, and visual acuity. Further regression analyses were performed with automated quality control metrics to determine if the p.Asn1868Ile variant is associated with poor quality or abnormal scans. RESULTS: Retinal layer segmentation and sequencing data for the p.Asn1868Ile variant were available for 26,558 participants, following exclusions. We identified no significant association between the p.Asn1868Ile variant and retinal thickness, any of the segmented layers, or visual acuity. There was also no significant difference for homozygous p.Asn1868Ile when tested under the assumption of a recessive model. No association was identified for any of the quality control metrics, and a χ2 test showed that participants with the p.Asn1868Ile variant were not more likely to be excluded during quality control due to poor quality scans (P = 0.56). CONCLUSIONS: The p.Asn1868Ile variant does not appear to affect the retinal structure or have pathogenic or subclinical effects on its own within the general population. The variant is likely to require other specific cis- or trans-acting modifying factors to cause ABCA4 retinopathy

A commonly occurring genetic variant within the NPLOC4-TSPAN10-PDE6G gene cluster is associated with the risk of strabismus.

Strabismus refers to an abnormal alignment of the eyes leading to the loss of central binocular vision. Concomitant strabismus occurs when the angle of deviation is constant in all positions of gaze and often manifests in early childhood when it is considered to be a neurodevelopmental disorder of the visual system. As such, it is inherited as a complex genetic trait, affecting 2-4% of the population. A genome-wide association study (GWAS) for self-reported strabismus (1345 cases and 65,349 controls from UK Biobank) revealed a single genome-wide significant locus on chromosome 17q25. Approximately 20 variants across the NPLOC4-TSPAN10-PDE6G gene cluster and in almost perfect linkage disequilibrium (LD) were most strongly associated (lead variant: rs75078292, OR = 1.26, p = 2.24E-08). A recessive model provided a better fit to the data than an additive model. Association with strabismus was independent of refractive error, and the degree of association with strabismus was minimally attenuated after adjustment for amblyopia. The association with strabismus was replicated in an independent cohort of clinician-diagnosed children aged 7 years old (116 cases and 5084 controls; OR = 1.85, p = 0.009). The associated variants included 2 strong candidate causal variants predicted to have functional effects: rs6420484, which substitutes tyrosine for a conserved cysteine (C177Y) in the TSPAN10 gene, and a 4-bp deletion variant, rs397693108, predicted to cause a frameshift in TSPAN10. The population-attributable risk for the locus was approximately 8.4%, indicating an important role in conferring susceptibility to strabismus