A nationwide study of 331 rare diseases among 58 million individuals: prevalence, demographics, and COVID-19 outcomes
Authors: Thygesen Johan H , Zhang Huayu , Issa Hanane , Wu Jinge , Hama Tuankasfee , Phiho Gomes Ana Caterina , Groza Tudor , Khalid Sara , Lumbers Tom , Hocaoglu Mevhibe , Khunti Kamlesh , Priedon Rouven , Banerjee Amitava , Pontikos Nikolas , Tomlinson Chris , Torralbo Ana , Taylor Paul , Sudlow Cathie , Denaxas Spiros , Hemingway Harry , Wu Honghan 
Published: October 2023

Background

The Global Burden of Disease study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with single study design exists for hundreds of rare diseases. Consequently, many rare conditions lack population-level evidence including prevalence and clinical vulnerability. This has led to the absence of evidence-based care for rare diseases, prominently in the COVID-19 pandemic.

Method

This study used electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning healthcare settings for people alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet, we quality assured and filtered down to analyse 331 conditions with ICD-10 or SNOMED-CT mappings clinically validated in our dataset. We report 1) population prevalence, clinical and demographic details of rare diseases, and 2) investigate differences in mortality with SARs-CoV-2.

Findings

Among 58,162,316 individuals, we identified 894,396 with at least one rare disease. Prevalence data in Orphanet originates from various sources with varying degrees of precision. Here we present reproducible age and gender-adjusted estimates for all 331 rare diseases, including first estimates for 186 (56.2%) without any reported prevalence estimate in Orphanet. We identified 49 rare diseases significantly more frequent in females and 62 in males. Similarly we identified 47 rare diseases more frequent in Asian as compared to White ethnicity and 22 with higher Black to white ratios as compared to similar ratios in population controls. 37 rare diseases were overrepresented in the white population as compared to both Black and Asian ethnicities. In total, 7,965 of 894,396 (0.9%) of rare-disease patients died from COVID-19, as compared to 141,287 of 58,162,316 (0.2%) in the full study population. Eight rare diseases had significantly increased risks for COVID-19-related mortality in fully vaccinated individuals, with bullous pemphigoid (8.07[3.01-21.62]) being worst affected.

Interpretation

Our study highlights that National-scale EHRs provide a unique resource to estimate detailed prevalence, clinical and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision-making for these often neglected patient populations.

Funding

British Heart Foundation Data Science Centre, led by Health Data Research UK.

Research in context

Evidence before the study

We have previously published the largest study looking at COVID-19 across rare diseases, but with a sample size of 158 COVID-19 infected rare disease patients and 125 unaffected relatives, from Genomics England, the power of that study was limited. We searched PubMed from database inception to Apr 21, 2023, for publications using the search terms “COVID-19” or “SARS-CoV-2” and “rare disease” or “ORPHANET”, without language restrictions. There are many studies examining the severity of COVID-19 in rare disease patients. However, to date, most studies have focused on a single or a few rare diseases associated with severity of COVID-19, and not taken a comprehensive rare disease wide approach. So far no studies have examined the impact of vaccination on mortality in rare disease patients. Moreover, the sample size used to examine rare diseases is limited in most studies. The largest study we identified included 168,680 individuals but only focused on autoimmune rheumatic disease.

Added value of this study

In this study we use national scale EHR data from England to report age and gender adjusted point prevalence for 331 rare diseases, with clinically-validated ICD-10 and/or SNOMED-CT code lists. Among these, 186 (56.2%) diseases did not have existing point prevalence data available in Orphanet. To our knowledge, this is the first time that rare diseases have been examined on a national scale, encompassing a population of over 58 million people. The large sample size provides sufficient statistical power to detect and describe enough carriers of even very rare conditions <1 case per million. Our analysis of COVID-related mortality has demonstrated the clinical relevance of national data for rare diseases. Specifically, we identified eight rare conditions that are associated with a significantly increased risk of mortality from COVID-19, even among fully vaccinated individuals.

Implication of all the available evidence

These findings provide robust reproducible prevalence, gender, and ethnicity estimates for disease that may often have been under prioritised, and where such information in most cases was not previously available. Our COVID-19 mortality findings highlight the need for targeted policy and support addressing the high level of vulnerability of these patients to COVID-19.