The birth prevalence of congenital hyperinsulinism: a narrative review of the epidemiology of a rare disease.

Background Congenital hyperinsulinism (HI) is a rare pediatric disease and the most common cause of severe, persistent hypoglycemia in childhood. It is characterized by the dysregulation of insulin secretion from the pancreas and can lead to irreversible brain damage with lifelong neurodisability. Summary The global birth prevalence of HI is currently unknown. An evidence-based estimate of HI birth prevalence is essential to improve diagnosis and patient management, to drive clinical research and the development of new treatments, and to inform public policy. In order to estimate the birth prevalence of persistent HI, a targeted literature review of studies that report HI epidemiological data was undertaken, and the strengths and limitations of each study were analyzed. Overall, eight global studies were identified that reported independently determined HI epidemiological data. Key messages The best estimate for the birth prevalence of persistent HI in European-ancestry populations is 3.5 per 100,000 births. Local consanguinity patterns appear to have a considerable impact on the birth prevalence of persistent HI in each country, precluding the application of this figure to all global populations. More epidemiological studies with robust methodology are needed to enable a reliable approximation of the incidence and prevalence of HI in global populations.

Strengths and limitations of new artificial intelligence tool for rare disease epidemiology.

The recent paper by Kariampuzha et al. describes an exciting application of artificial intelligence to rare disease epidemiology. The authors' AI model appears to offer a major leap over Orphanet, the resource which is often a "first stop" for basic epidemiological data on rare diseases. To ensure appropriate use of this exciting tool, it is important to consider its strengths and weaknesses in context. The tool currently incorporates only PubMed abstracts, so key information located in the full text of articles is absent. Such missing information may include incidence and prevalence values, as well as important elements of study design and context. Additionally, results from the public version of the tool differ from those described in the original article, including obsolete values for prevalence and the use of non-prevalence studies in place of those listed in the article. At present, it would be appropriate to utilize the AI tool much like Orphanet: a helpful "first stop" which should be manually checked for completeness and accuracy. Users should understand the benefits of this exciting technology, and that it is not yet a panacea for the challenges of analyzing rare disease epidemiology.

An analysis of Pompe newborn screening data: a new prevalence at birth, insight and discussion.

This study includes over 11.6M newborns screened (NBS) for Pompe Disease (PD) from 29 distinct universal screening programs across 8 countries and 4 continents. The birth prevalence of PD is 1:18,711, with no evidence of difference across populations of European, Latin American, or Asian ancestry, though differences may exist for PD subtypes. This study also compares these results, based on direct detection of disease and analyzed using a binomial method along with power analysis, with other methods for estimating the 'frequency' of rare genetic diseases (such as utilizing Hardy-Weinberg equilibrium on allele frequency and confidence interval analysis). This comparison demonstrates the implications of sample size and frames a discussion on its influence on the reliability of results when extrapolating to a population beyond the study dataset. Objectives: Primary: Establish a new figure for prevalence at birth for Pompe disease by collecting and analyzing the largest relevant dataset to date and using that result to project population prevalence at birth in a novel way. Secondary: Compare these results to previous analyses to offer a framework for evaluating 'frequency' data that can be applied to other rare, genetic diseases, along with methods to assess quality of estimates.

Healthcare resource utilization, total costs, and comorbidities among patients with myotonic dystrophy using U.S. insurance claims data from 2012 to 2019.

BACKGROUND: Myotonic dystrophy (DM) is a rare, inherited disorder with multi-systemic effects that impact the skeletal muscles, eyes, heart, skin and gastrointestinal, endocrine, respiratory, and central nervous systems. DM is divided into two subtypes: DM1 can present from early childhood through adulthood and also has a congenital form (cDM) while DM2 typically manifests during mid-adulthood. Both forms are progressive with no approved treatments, and unmet need for disease-modifying therapies remains high. This study interrogated health insurance claims data to explore the clinical experience, healthcare resource utilization (HCRU), and all-cause costs for DM. RESULTS: A total of 8541 patients with DM and 242 patients with cDM and their matched controls were selected from a database of over 200 million claimants. HCRU and all-cause costs, including pharmacy, outpatient, and inpatient services, were analyzed across four years in 12-month follow-up periods. Mean all-cause costs per DM patient were high in each of the four periods (range $14,640-$16,704) and showed a steady increase from 13 to 23 months on, while the control group mean costs declined from $9671 in the first 12 months after the index event, to approach the US population average ($5193) over time. For cDM, the highest mean costs were in the first 12-months ($66,496 vs. $2818 for controls), and remained high (above $17,944) across all subsequent periods, while control mean costs approached $0. For DM and cDM, HCRU was higher compared to controls across all study periods and all-cause healthcare costs were mostly driven by inpatient and outpatient encounters. Analysis of all diagnosis codes over the study period (comorbidities) demonstrated an elevated comorbidity profile consistent with the clinical profile of DM. CONCLUSIONS: This study is among the first to utilize claims data to increase understanding of the clinical experience and health economic outcomes associated with DM. The markedly elevated HCRU patterns and comorbidity profile presented here add to the broad body of scientific and clinical knowledge on DM. These insights can inform clinical care and support the development of disease modifying and/or symptom-targeting therapies that address the multi-systemic, progressive nature of DM.

Prevalence of fibrodysplasia ossificans progressiva (FOP) in the United States: estimate from three treatment centers and a patient organization.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), an ultra-rare, progressive, and permanently disabling disorder of extraskeletal ossification, is characterized by episodic and painful flare-ups and irreversible heterotopic ossification in muscles, tendons, and ligaments. Prevalence estimates have been hindered by the rarity of FOP and the heterogeneity of disease presentation. This study aimed to provide a baseline prevalence of FOP in the United States, based on contact with one of 3 leading treatment centers for FOP (University of Pennsylvania, Mayo Clinic, or University of California San Francisco), the International Fibrodysplasia Ossificans Progressiva Association (IFOPA) membership list, or the IFOPA FOP Registry through July 22, 2020. RESULTS: Patient records were reviewed, collected, and deduplicated using first and last name initials, sex, state, and year of birth. A Kaplan-Meier survival curve was applied to each individual patient to estimate the probability that he or she was still alive, and a probability-weighted net prevalence estimate was calculated. After deduplication, 373 unique patients were identified in the United States, 294 of whom who were not listed as deceased in any list. The average time since last contact for 284 patients was 1.5 years. Based on the application of the survival probability, it is estimated that 279 of these patients were alive on the prevalence date (22 July 2020). An adjusted prevalence of 0.88 per million US residents was calculated using either an average survival rate estimate of 98.4% or a conservative survival rate estimate of 92.3% (based on the Kaplan-Meier survival curve from a previous study) and the US Census 2020 estimate of 329,992,681 on prevalence day. CONCLUSIONS: This study suggests that the prevalence of FOP is higher than the often-cited value of 0.5 per million. Even so, because inclusion in this study was contingent upon treatment by the authors, IFOPA membership with confirmed clinical diagnosis, and the FOP Registry, the prevalence of FOP in the US may be higher than that identified here. Thus, it is imperative that efforts be made to identify and provide expert care for patients with this ultra-rare, significantly debilitating disease.

Prevalence, characteristics, and costs of diagnosed homocystinuria, elevated homocysteine, and phenylketonuria in the United States: a retrospective claims-based comparison.

BACKGROUND: Classical homocystinuria (HCU), an inborn error of homocysteine metabolism, has previously been estimated to affect approximately 1 in 100,000-200,000 people in the United States (US). HCU is poorly detected by newborn screening, resulting in underestimates of its prevalence. This study compared characteristics, healthcare use and costs, and projected prevalence between patients with diagnosed HCU, elevated total homocysteine (tHcy), and diagnosed phenylketonuria (PKU). METHODS: Patients in the MarketScan® Research Databases were identified with strictly-defined HCU (> 2 diagnoses, including 1 ICD-10), broadly-defined HCU (> 1 ICD-10), elevated tHcy (> 20 µmol/L) without an HCU diagnosis, or > 1 ICD-9/ICD-10 PKU diagnosis during 1/1/2010-12/31/2016 (first qualifying claim = index). Demographics and healthcare utilization and costs per patient per month (PPPM) were compared between all cohorts, frequencies of comorbidities and medications were compared between HCU and elevated tHcy patients, and healthcare provider types were assessed among HCU patients. The prevalence of patients meeting each cohort definition was projected to the United States (US) population. RESULTS: Patients with strictly-defined (N = 2450) and broadly-defined (N = 6613) HCU, and with elevated tHcy (N = 2017), were significantly older than PKU patients (N = 5120) (57 vs. 56 vs. 53 vs. 18 years; p < 0.05). Vitamin D deficiency, hyperlipidemia, folic acid/B vitamins, and lipid-lowering medications, among others, were more common among diagnosed HCU patients vs. those with elevated tHcy (all p < 0.05). Rates of healthcare utilization were generally higher among HCU and elevated tHcy patients, compared to PKU, though total healthcare costs were similar between groups. Most HCU patients (~ 38%) received their index diagnosis from a primary care physician; very few (~ 1%) had any claim from a geneticist during their enrollment. The age-adjusted national prevalence of HCU was projected at 31,162 (95% CI: 30,411 - 31,913; ~ 1 in 10,000 of the US population) using the broad definition. CONCLUSIONS: The actual prevalence of HCU may be > 10 times prior estimates, at 1 in 10,000 in the US, and this study suggests that HCU is not being diagnosed until later in life. Improvements to newborn screening, detection in young children, and physician education regarding HCU among patients may be necessary to alleviate the burden of this genetic disease.

Estimated prevalence of moderate to severely elevated total homocysteine levels in the United States: A missed opportunity for diagnosis of homocystinuria?

Classical homocystinuria (HCU) is a genetic disorder caused by mutations in the cystathionine beta synthase gene, which results in impaired metabolism of the sulfur-bearing amino acid homocysteine and its accumulation in blood and tissues. Classical HCU can be detected via newborn screening in the United States, but the test is widely acknowledged to miss many patients. While severely elevated homocysteine levels (>100 µmol /L) frequently lead to a classical HCU diagnosis, intermediate levels (>30 to 100 µmol /L), though linked to many of the known complications of HCU, are not always recognized as associated with HCU. We aimed to identify and describe potentially undiagnosed classical HCU patients using a nationally-representative database of administrative claims and laboratory results. We estimated the national prevalence of patients with homocysteine >30 µmol /L, and compared their demographic and clinical characteristics to those of patients with homocysteine levels ≤30 µmol/L. Among 57,580 patients with a homocysteine test result, 1.8% had a value >30 µmol /L. Patients with homocysteine >30 µmol /L were more frequently diagnosed with hypothyroidism (39.2% vs. 20.7%, p < .001) and renal disease (9.7% vs. 5.5%, p < .001), and were more likely to have a prescription for an anxiolytic/antidepressant (44.5% vs. 38.9%), opioid (58.4% vs. 53.1%), steroid (46.4% vs. 42.5%), or thyroid hormone (38.8% vs. 18.8%), compared to patients with homocysteine ≤30 µmol /L (all p < .05). Both groups were equally likely to have a diagnosis of homocystinuria or another disorder of sulfur-bearing amino acid metabolism (3.8% vs. 4.0%, p = .752). The age-adjusted national prevalence of homocysteine >30 µmol /L was estimated at 33,068 (95% CI: 1033 - 35,104). These findings suggest that thousands of people in the US may be living with intermediate to severely elevated homocysteine levels and may require further evaluation for the presence of classical HCU.

Prevalence of fibrodysplasia ossificans progressiva (FOP) in France: an estimate based on a record linkage of two national databases.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is a rare, severely disabling, and life-shortening genetic disorder that causes the formation of heterotopic bone within soft connective tissue. Previous studies found that the FOP prevalence was about one in every two million lives. The aim of this study is to estimate the FOP prevalence in France by probabilistic record-linkage of 2 national databases: 1) the PMSI (Programme de médicalisation des systèmes d'information), an administrative database that records all hospitalization activities in France and 2) CEMARA, a registry database developed by the French Centres of Reference for Rare Diseases. RESULTS: Using a capture-recapture methodology to adjust the crude number of patients identified in both data sources, 89 FOP patients were identified, which results in a prevalence of 1.36 per million inhabitants (CI95% = [1.10; 1.68]). FOP patients' mean age was 25 years, only 14.9% were above 40 years, and 53% of them were males. The first symptoms - beside toe malformations- occurred after birth for 97.3% of them. Mean age at identified symptoms was 7 years and above 18 years for only 6.9% of patients. Mean age at diagnosis was 10 years, and above 18 years for 14.9% of the patients. FOP patients were distributed across France. CONCLUSIONS: Despite the challenge of ascertaining patients with rare diseases, we report a much higher prevalence of FOP in France than in previous studies elsewhere. We suggest that efforts to identify patients and confirm the diagnosis of FOP should be reinforced and extended at both national and European level.

Newborn screening for hyperargininemia due to arginase 1 deficiency.

Hyperargininemia caused by Arginase 1 deficiency is a rare disorder of the urea cycle that can be diagnosed by elevation of arginine in newborn screening blood spots when analyzed by tandem mass spectrometry. Hyperargininemia is currently included as a secondary target on the U.S. Recommended Uniform Screening Panel, which directly influences state-based newborn screening. Because of the apparent low disease frequency and lack of case detection and treatment data, detailed attention has not been given to a model newborn screening algorithm including appropriate analytical cutoff values for disease indicators. In this paper we assess the frequency of hyperargininemia in the U.S. identified by newborn screening to date and document the current status and variability of hyperargininemia newborn screening across U.S. newborn screening programs. We also review other data that support improved screening efficacy by utilizing the arginine/ornithine ratio and other amino acid ratios as discriminators in the screening algorithm. Analysis of archived California screening data showed that an arginine cutoff of 50µM combined with an arginine/ornithine ratio of 1.4 would have resulted in a recall rate of 0.01%. Using an arginine cutoff of 60µM and an arginine/(phenylalanine x leucine) ratio of 1.4, reportedly used in one screening program, or the R4S Tool Runner, would have resulted in a recall rate of <0.005%. All 9 diagnosed patients would have been found for either protocol. Thus, use of appropriate ratios as part of the screening algorithm has the potential to increase both screening sensitivity and specificity. Improved newborn screening effectiveness should lead to better case detection and more rapid treatment to lower plasma arginine levels hence improving long term outcome of individuals with hyperargininemia.