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Prevalence of Pyruvate Kinase Deficiency

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Prevalence of Pyruvate Kinase Deficiency P3513 Prevalence of Red Cell Pyruvate Kinase Deficiency: A Systematic Literature Review Mike Storm1, Matthew H Secrest2*, Courtney Carrington2, Deb Casso2, Keely Gilroy1, Leanne Pladson1, Audra N Boscoe1 1Agios Pharmaceuticals Inc., Cambridge, MA, USA; 2IQVIA Epidemiology & Drug Safety, Seattle, WA and Cambridge, MA, USA; *Affiliation at the time research was conducted BACKGROUND METHODS (continued) RESULTS (continued) RESULTS (continued) • Pyruvate Kinase (PK) deficiency is a rare congenital hemolytic anemia Exclusion Criteria The remaining 34 studies were grouped based on methods and study Among these 4 studies, an important distinction was made between studies characterized by diminished activity of the PK enzyme in red blood population (Table 1). reporting diagnosed prevalence (n=3) and overall disease prevalence cells (RBC).1 • Non-human studies; (diagnosed and undiagnosed PK deficiency; n=1). Table 1. Distribution of extracted studies by type of study (n=34) • Low PK enzyme activity can lead to lifelong chronic hemolysis with • Publications that were not the primary report of the data • Two studies estimated diagnosed PK deficiency prevalence as 3.2 per associated symptoms and complications such as anemia, jaundice, (e.g., literature reviews); Type of study Number million4 and 8.5 per million5 by identifying diagnosed PK deficiency cases of studies gallstones, splenectomy and associated thrombosis, iron overload, and • Studies of PK deficiency prevalence/incidence conducted within a source from source populations of known size. liver cirrhosis.2 Population-based prevalence 2 population of patients with symptoms of PK deficiency such as anemia • We estimated the prevalence of diagnosed PK deficiency in a general • PK deficiency is caused by compound heterozygosity or homozygosity for or jaundice; Molecular PKLR screening in a general population 5 population to be 6.5 per million6 using data from another high-quality study 3 one or more of the >300 known mutations to the PKLR gene. • Studies that only reported PKLR MAFs among PK deficiency patients; and that screened newborns for bilirubin and tested jaundiced newborns for Molecular PKLR screening in areas with endemic malaria 4 PK deficiency. ‒ These PKLR mutations have differing impacts on PK function and likely • Studies reporting only MAFs for PKLR mutations unlikely to cause 2 Molecular PKLR screening in other unique population 2 contribute to the notable clinical heterogeneity in the disorder. loss/reduction of PK function as stated by the authors or inferred from • These 3 studies are likely underestimates of overall disease prevalence amino acid substitution prediction models. Non-molecular PK deficiency screening in a general population 9 because they only consider diagnosed cases, and, in one study, only • Reports of PK deficiency prevalence vary by orders of magnitude, likely due diagnosed cases presenting with jaundice. to a combination of factors: Quality Assessment Non-molecular PK deficiency screening in areas with endemic malaria 3 • In the final study,7 the authors sought to limit biases related to the Hardy- ‒ The extreme rarity of the disorder; • A tailor-made, qualitative quality assessment tool was created. Quality Non-molecular PK deficiency screening in areas with high consanguinity 6 Weinberg equilibrium assumption, which incorrectly assumes the considerations included study generalizability, validity of methods, potential penetrance of each mutation to be 100%. ‒ Similar phenotype to other RBC disorders leading to misdiagnosis; Non-molecular PK deficiency screening in other unique population 3 sources of bias, and limitations as reported by the authors. ‒ Heterogeneous clinical presentation; - To address this, the authors identified a mutation known to have high • The generalizability, quality, and consistency of all outcome statistics were Potential sources of bias in estimating PK deficiency prevalence were penetrance (c.1529G>A), referred to as the ‘index mutation.’ They then ‒ Ethnic and geographic variability; and considered collectively to evaluate the weight and associated uncertainty of identified in 30 of 34 eligible studies and included: assumed that the frequency of the index mutation relative to other PK deficiency-causing mutations is the same between the general ‒ Different methods used in published reports of prevalence. the evidence of PK deficiency prevalence. • A non-generalizable study population (e.g., malaria-endemic areas); population and PK deficiency cases, which led to a prevalence estimate Study Selection Process • Use of diagnostic assays of questionable accuracy; (diagnosed and undiagnosed) of 51 per million (standard error: 32.5 per million). Studies were reviewed by two independent reviewers using the OBJECTIVES • Consideration of mutations with incomplete penetrance; and following process: The objectives of this systematic literature review were: • Consideration of mutations with unclear clinical significance. • Titles and abstracts of all references were screened for eligibility; and • To estimate the prevalence of PK deficiency by critically appraising reported The remaining 4 studies were considered high-quality for purposes of CONCLUSIONS prevalence rates; and • Data extraction and quality assessment were performed on studies meeting estimating overall disease prevalence (Table 2). all eligibility criteria after full-text review. • The prevalence of diagnosed PK deficiency in a general Western population • To better understand factors contributing to the wide range of reported Table 2. Overview of selected studies estimating overall prevalence of is probably in the range of 3.2-8.5 per million. prevalence values. PK deficiency (n=4) • Overall disease prevalence (diagnosed and undiagnosed) may be as high PKLR Prevalence as 51 per million population. First author Study genes Reported estimates METHODS RESULTS • Future studies are needed to understand the clinical significance of various (year)citation type sequenced results (per million) Information Sources • Of 1390 references screened, 1296 were excluded after title/abstract mutant alleles. Such studies may inform more accurate, clinically relevant review and 60 were excluded after full text review (Figure 1). Diagnosed prevalence PK deficiency prevalence estimates, identify the degree of and reasons The following sources were queried using PK deficiency and PKLR Emtree Carey, Population- N/A Period prevalence: 3.2* for underdiagnosis, and elucidate PK deficiency heterogeneity and Medical Subject Heading (MeSH) terms and keywords combined with PJ (2000)4 based 3.2 per million between populations. epidemiology and gene frequency Emtree/MeSH terms and keywords: Figure 1. Flow diagram of studies meeting inclusion/exclusion criteria prevalence study Disclosures • Embase (1/1/1974 – 1/22/2019) and Medline (1/1/1946 – 1/22/2019); † Records identified de Medicis, Population- N/A Period prevalence: 8.5 • A single conference year (2018) of the Deutsche Gesellschaft für through Embase/Medline E (1992)5 based 1 per 117,206 This study was funded by Agios Pharmaceuticals. MS, KG, LP, ANB: Agios – Hämatologie und Medizinische Onkologie (DGHO) not indexed by (n=1386), conference prevalence employment and stockholder. CC, DC: IQVIA – employment. MHS: IQVIA – study Embase/Medline; and abstract review (n=1), or Records excluded during title/abstract screening employment at time of study. † hand selection (n=3) (n=1296) Christensen, Non-molecular N/A Incidence for full 33 (total study • Other relevant references encountered over the course of the systematic (Total n=1390) • Not based on human patients (n=54); R (2010)6 pyruvate study population, population: literature review. • Not correct report type (n=1); kinase including polygamous and References • Not the primary report of epidemiologic/genetic deficiency polygamist non-polygamous) 1. Prchal JT. Pyruvate kinase deficiency. UpToDate. 2018. Inclusion Criteria data (n=4); screening community: • Only reported among PK deficiency patients or 2. Grace RF, et al. Clinical spectrum of pyruvate kinase deficiency: data from the study in area 1/30,000 • Peer-reviewed publications (articles, letters, editorials, or comments) patients selected with respect to PK deficiency or Pyruvate Kinase Deficiency Natural History Study. Blood. 2018;131(20):2183-2192. with high and conference abstracts published (or in press) in English before disease status (n=98); and Incidence for 4,000† January 23, 2019; • Unambiguously not relevant (n=1139). consanguinity 3. Bianchi P, et al. Genotype-Phenotype Correlation and Molecular Heterogeneity in RESULTSRecords submitted to full- polygamist (polygamous text review Pyruvate Kinase Deficiency: Data from the PKD Natural History Study. Blood. 2017; community: 1/250 community) • Publications describing one of the following: (n=94) 130 (Supplement 1): 3479. † ‒ PK deficiency epidemiology defined as one or more of the following Records excluded during full text screening Implied incidence 6.5 (non- 4. Carey PJ, et al. Prevalence of pyruvate kinase deficiency in a northern European (n=60) among a source population selected without respect to PK deficiency for non- polygamous population in the north of England. Blood. 2000;96(12):4005-6. • Duplicate record (n=4); polygamous population) symptoms: 5. de Medicis E, et al. Hereditary nonspherocytic hemolytic anemia due to pyruvate • Only reported among PK deficiency patients or population: 1 per patients selected with respect to PK deficiency or kinase deficiency:
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