Evaluation of data processing pipelines on real-world electronic health records data for the purpose of measuring patient similarity.

BACKGROUND: The ever-growing size, breadth, and availability of patient data allows for a wide variety of clinical features to serve as inputs for phenotype discovery using cluster analysis. Data of mixed types in particular are not straightforward to combine into a single feature vector, and techniques used to address this can be biased towards certain data types in ways that are not immediately obvious or intended. In this context, the process of constructing clinically meaningful patient representations from complex datasets has not been systematically evaluated. AIMS: Our aim was to a) outline and b) implement an analytical framework to evaluate distinct methods of constructing patient representations from routine electronic health record data for the purpose of measuring patient similarity. We applied the analysis on a patient cohort diagnosed with chronic obstructive pulmonary disease. METHODS: Using data from the CALIBER data resource, we extracted clinically relevant features for a cohort of patients diagnosed with chronic obstructive pulmonary disease. We used four different data processing pipelines to construct lower dimensional patient representations from which we calculated patient similarity scores. We described the resulting representations, ranked the influence of each individual feature on patient similarity and evaluated the effect of different pipelines on clustering outcomes. Experts evaluated the resulting representations by rating the clinical relevance of similar patient suggestions with regard to a reference patient. RESULTS: Each of the four pipelines resulted in similarity scores primarily driven by a unique set of features. It was demonstrated that data transformations according to each pipeline prior to clustering can result in a variation of clustering results of over 40%. The most appropriate pipeline was selected on the basis of feature ranking and clinical expertise. There was moderate agreement between clinicians as measured by Cohen's kappa coefficient. CONCLUSIONS: Data transformation has downstream and unforeseen consequences in cluster analysis. Rather than viewing this process as a black box, we have shown ways to quantitatively and qualitatively evaluate and select the appropriate preprocessing pipeline.

Evolving Treatment Patterns and Outcomes of Neovascular Age-Related Macular Degeneration Over a Decade.

PURPOSE: Management of neovascular age-related macular degeneration (nAMD) has evolved over the last decade with several treatment regimens and medications. This study describes the treatment patterns and visual outcomes over 10 years in a large cohort of patients. DESIGN: Retrospective analysis of electronic health records from 27 National Health Service secondary care healthcare providers in the UK. PARTICIPANTS: Treatment-naïve patients receiving at least 3 intravitreal anti-vascular endothelial growth factor (VEGF) injections for nAMD in their first 6 months of follow-up were included. Patients with missing data for age or gender and those aged less than 55 years were excluded. METHODS: Eyes with at least 3 years of follow-up were grouped by years of treatment initiation, and 3-year outcomes were compared between the groups. Data were generated during routine clinical care between September 2008 and December 2018. MAIN OUTCOME MEASURES: Visual acuity (VA), number of injections, and number of visits. RESULTS: A total of 15 810 eyes of 13 705 patients receiving 195 104 injections were included. Visual acuity improved from baseline during the first year, but decreased thereafter, resulting in loss of visual gains. This trend remained consistent throughout the past decade. Although an increasing proportion of eyes remained in the driving standard, this was driven by better presenting VA over the decade. The number of injections decreased substantially between the first and subsequent years, from a mean of 6.25 in year 1 to 3 in year 2 and 2.5 in year 3, without improvement over the decade. In a multivariable regression analysis, final VA improved by 0.24 letters for each year since 2008, and younger age and baseline VA were significantly associated with VA at 3 years. CONCLUSIONS: Our findings show that despite improvement in functional VA over the years, primarily driven by improving baseline VA, patients continue to lose vision after the first year of treatment, with only marginal change over the past decade. The data suggest these results may be related to suboptimal treatment patterns, which have not improved over the years. Rethinking treatment strategies may be warranted, possibly on a national level or through the introduction of longer-acting therapies.

Real world evidence on 5661 patients treated for macular oedema secondary to branch retinal vein occlusion with intravitreal anti-vascular endothelial growth factor, intravitreal dexamethasone or macular laser.

BACKGROUND/AIMS: Clinical trials suggest anti-vascular endothelial growth factor is more effective than intravitreal dexamethasone as treatment for macular oedema secondary to branch retinal vein occlusion. This study asks if 'real world' data from a larger and more diverse population, followed for a longer period, also support this conclusion. METHODS: Data collected to support routine care at 27 NHS (National Health Service) Trusts between February 2002 and September 2017 contained 5661 treatment-naive patients with a single mode of treatment for macular oedema secondary to branch retinal vein occlusion and no history of cataract surgery either during or recently preceding the treatment. Number of treatment visits and change in visual acuity from baseline was plotted for three treatment groups (anti-vascular endothelial growth factor (anti-VEGF), intravitreal dexamethasone, macular laser) for up to 3 years. RESULTS: Mean baseline visual acuity was 57.1/53.1/62.3 letters in the anti-VEGF/dexamethasone/macular laser groups, respectively. This changed to 66.72 (+9.6)/57.6 (+4.5)/63.2 (+0.9) at 12 months. Adequate numbers allowed analysis at 18 months for all groups (66.6 (+9.5)/56.1 (+3.0)/60.8 (-1.5)) and for anti-VEGF at 36 months (68.0, +10.9) Mean number of treatments were 5.1/1.5/1.2 at 12 months, 5.9/1.7/1.2 at 18 months for all three groups and 10.3 at 36 months for anti-VEGF. CONCLUSIONS: Visual acuity improvements were higher and more sustained with anti-VEGF. Higher treatment burden occurred with anti-VEGF but this reduced over 36 months. Patients with better vision at baseline than those in the clinical trials maintained high levels of vision with both anti-VEGF and dexamethasone.

Multicentre study of 4626 patients assesses the effectiveness, safety and burden of two categories of treatments for central retinal vein occlusion: intravitreal anti-vascular endothelial growth factor injections and intravitreal Ozurdex injections.

BACKGROUND/AIMS: To assess the effectiveness, burden and safety of two categories of treatment for central retinal vein occlusion (CRVO): intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) and dexamethasone (Ozurdex). METHODS: A retrospective analysis of Medisoft electronic medical record (EMR) data from 27 National Health Service sites in the UK identified 4626 treatment-naive patients with a single mode of treatment for macular oedema secondary to CRVO. Statistics describing the overall CRVO patient cohort and individual patient subpopulations stratified by treatment type were generated. Mean age at baseline, gender, ethnicity, social deprivation and visual acuity (VA) follow-up was reported. Absolute and change in VA using ETDRS are used to describe treatment effectiveness, the number of injections and visits used to describe treatment burden and endophthalmitis rates as a marker of treatment safety. RESULTS: Mean VA was 47.9 and 45.3 EDTRS letters in the anti-VEGF and Ozurdex groups, respectively. This changed to 57.9/53.7 at 12 months, 58.3/46.9 at 18 months and 59.4/51.0 at 36 months. Mean number of injections were 5.6/1.6 at 12 months, 6.0/1.7 at 18 months and 7.0/1.8 at 36 months. Endophthalmitis rates were 0.003% (n=4) for the anti-VEGF group and 0.09% (n=1) for the Ozurdex group. CONCLUSIONS: VA improvements were greater and more sustained with anti-VEGF treatment. Lower starting acuity resulted in bigger gains in both groups, while higher starting acuity resulted in higher VA at 36 months. Although treatment burden was greater with anti-VEGF, Ozurdex was associated with higher rates of endophthalmitis.

Identifying clinically important COPD sub-types using data-driven approaches in primary care population based electronic health records.

BACKGROUND: COPD is a highly heterogeneous disease composed of different phenotypes with different aetiological and prognostic profiles and current classification systems do not fully capture this heterogeneity. In this study we sought to discover, describe and validate COPD subtypes using cluster analysis on data derived from electronic health records. METHODS: We applied two unsupervised learning algorithms (k-means and hierarchical clustering) in 30,961 current and former smokers diagnosed with COPD, using linked national structured electronic health records in England available through the CALIBER resource. We used 15 clinical features, including risk factors and comorbidities and performed dimensionality reduction using multiple correspondence analysis. We compared the association between cluster membership and COPD exacerbations and respiratory and cardiovascular death with 10,736 deaths recorded over 146,466 person-years of follow-up. We also implemented and tested a process to assign unseen patients into clusters using a decision tree classifier. RESULTS: We identified and characterized five COPD patient clusters with distinct patient characteristics with respect to demographics, comorbidities, risk of death and exacerbations. The four subgroups were associated with 1) anxiety/depression; 2) severe airflow obstruction and frailty; 3) cardiovascular disease and diabetes and 4) obesity/atopy. A fifth cluster was associated with low prevalence of most comorbid conditions. CONCLUSIONS: COPD patients can be sub-classified into groups with differing risk factors, comorbidities, and prognosis, based on data included in their primary care records. The identified clusters confirm findings of previous clustering studies and draw attention to anxiety and depression as important drivers of the disease in young, female patients.

United Kingdom Diabetic Retinopathy Electronic Medical Record (UK DR EMR) Users Group: report 4, real-world data on the impact of deprivation on the presentation of diabetic eye disease at hospital services.

AIM: To assess the impact of deprivation on diabetic retinopathy presentation and related treatment interventions, as observed within the UK hospital eye service. METHODS: This is a multicentre, national diabetic retinopathy database study with anonymised data extraction across 22 centres from an electronic medical record system. The following were the inclusion criteria: all patients with diabetes and a recorded, structured diabetic retinopathy grade. The minimum data set included, for baseline, age and Index of Multiple Deprivation, based on residential postcode; and for all time points, visual acuity, ETDRS grading of retinopathy and maculopathy, and interventions (laser, intravitreal therapies and surgery). The main  outcome measures were (1) visual acuity and binocular visual state, and (2) presence of sight-threatening complications and need for early treatment. RESULTS: 79 775 patients met the inclusion criteria. Deprivation was associated with later presentation in patients with diabetic eye disease: the OR of being sight-impaired at entry into the hospital eye service (defined as 6/18 to better than 3/60 in the better seeing eye) was 1.29 (95% CI 1.20 to 1.39) for the most deprived decile vs 0.77 (95% CI 0.70 to 0.86) for the least deprived decile; the OR for being severely sight-impaired (3/60 or worse in the better seeing eye) was 1.17 (95% CI 0.90 to 1.55) for the most deprived decile vs 0.88 (95% CI 0.61 to 1.27) for the least deprived decile (reference=fifth decile in all cases). There is also variation in sight-threatening complications at presentation and treatment undertaken: the least deprived deciles had lower chance of having a tractional retinal detachment (OR=0.48 and 0.58 for deciles 9 and 10, 95% CI 0.24 to 0.90 and 0.29 to 1.09, respectively); in terms of accessing treatment, the rate of having a vitrectomy was lowest in the most deprived cohort (OR=0.34, 95% CI 0.19 to 0.58). CONCLUSIONS: This large real-world study suggests that first presentation at a hospital eye clinic with visual loss or sight-threatening diabetic eye disease is associated with deprivation. These initial hospital visits represent the first opportunities to receive treatment and to formally engage with support services. Such patients are more likely to be sight-impaired or severely sight-impaired at presentation, and may need additional resources to engage with the hospital eye services over complex treatment schedules.

Oligosaccharide model of the vascular endothelial glycocalyx in physiological flow.

Experiments have consistently revealed the pivotal role of the endothelial glycocalyx layer in vasoregulation and the layer's contribution to mechanotransduction pathways. However, the exact mechanism by which the glycocalyx mediates fluid shear stress remains elusive. This study employs atomic-scale molecular simulations with the aim of investigating the conformational and orientation properties of highly flexible oligosaccharide components of the glycocalyx and their suitability as transduction molecules under hydrodynamic loading. Fluid flow was shown to have nearly no effect on the conformation populations explored by the oligosaccharide, in comparison with static (diffusion) conditions. However, the glycan exhibited a significant orientation change, when compared to simple diffusion, aligning itself with the flow direction. It is the tethered end of the glycan, an asparagine amino acid, which experienced conformational changes as a result of this flow-induced bias. Our results suggest that shear flow through the layer can have an impact on the conformational properties of saccharide-decorated transmembrane proteins, thus acting as a mechanosensor.

Methods for enhancing the reproducibility of biomedical research findings using electronic health records.

BACKGROUND: The ability of external investigators to reproduce published scientific findings is critical for the evaluation and validation of biomedical research by the wider community. However, a substantial proportion of health research using electronic health records (EHR), data collected and generated during clinical care, is potentially not reproducible mainly due to the fact that the implementation details of most data preprocessing, cleaning, phenotyping and analysis approaches are not systematically made available or shared. With the complexity, volume and variety of electronic health record data sources made available for research steadily increasing, it is critical to ensure that scientific findings from EHR data are reproducible and replicable by researchers. Reporting guidelines, such as RECORD and STROBE, have set a solid foundation by recommending a series of items for researchers to include in their research outputs. Researchers however often lack the technical tools and methodological approaches to actuate such recommendations in an efficient and sustainable manner. RESULTS: In this paper, we review and propose a series of methods and tools utilized in adjunct scientific disciplines that can be used to enhance the reproducibility of research using electronic health records and enable researchers to report analytical approaches in a transparent manner. Specifically, we discuss the adoption of scientific software engineering principles and best-practices such as test-driven development, source code revision control systems, literate programming and the standardization and re-use of common data management and analytical approaches. CONCLUSION: The adoption of such approaches will enable scientists to systematically document and share EHR analytical workflows and increase the reproducibility of biomedical research using such complex data sources.