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A.D. Shapiro et al.
ligneous conjunctivitis).12 HISTORY will record the preva- lence of different mutations in the affected and heterozy- gote population and attempt to determine the relation- ship between mutation and clinical penetrance hetero- geneity; it will also examine polymorphisms that may influence fibrinolytic capacity (e.g., in fibrinogen Aα and plasminogen activator inhibitor 1).52 The enrollment of relatives of people with PLGD may enable a refinement of plasminogen activity levels observed in heterozygotes.
The registry will also incorporate environmental and host-specific factors that may modify plasminogen levels and/or disease symptoms. A study in healthy subjects found that smoking contributes to plasma plasminogen levels;51 it is not known whether this and other environ- mental factors affect plasminogen plasma levels in patients with PLGD. It is also not clear whether an environmental trigger is required for symptom development and/or dis- ease expression, or whether and, if so, how specific plas- minogen antibodies develop. HISTORY will address some of these unknown environmental/host factors.
Plasminogen deficiency biorepository
Research involving human genetic or genomic informa- tion analyzed in conjunction with personal or health data has become increasingly important for untangling genet- ic, lifestyle and environmental disease determinants. A biorepository containing DNA, plasma, and serum will be created; samples will be stored for up to 15 years. If planned analyses are not revealing, stored samples will be utilized to explore other biomarkers to elucidate a corre- lation/prediction of phenotypic heterogeneity (e.g., poly- morphisms in inflammatory markers, whole genome analyses).
Data analyses
To understand the impact of specific data on disease expression, all collected data will be analyzed. Clinical data on people with PLGD will be evaluated for categor- ical characterization (i.e., asymptomatic, intermittently symptomatic, and continuously symptomatic). The probands’ age in each category will be analyzed to evalu- ate age as a variable for symptom expression. Categories will be modeled and analyzed against a range of variables including gender, environmental factors, genetic studies, laboratory coagulation parameters including specific and exploratory global assays, and treatment administration. Subjects with clinical symptoms will be evaluated for the presence of individual affected sites versus multiple/sys- temic symptoms, and also analyzed based on prior listed
variables. A descriptive analysis of symptoms reported by physiological system will be performed and modeled against study variables (levels, genetics, global assays, and exploratory investigations) to determine whether any of them are predictive. Symptoms and data will be reviewed to determine whether severity categories can be estab- lished. Urine analysis will be performed, as unpublished data suggest that PLGD may be associated with microal- buminuria; its prevalence in the wider PLGD population is unknown. Data will be collected on subjects who receive nonspecific and/or specific treatments if available; they will be analyzed for therapeutic response, disease control, and recurrence or emergence on therapy.
Further details of the methods, procedures, and planned analyses are reported in the Online Supplementary Material.
Conclusions
There is currently no central repository to collect and analyze data from people with PLGD; clinicians rely on case reports and individual experience to diagnose and treat patients, resulting in treatment variability and less than optimal outcomes. The HISTORY study may play a substantial role in addressing these deficits by collecting clinical, genetic, and laboratory data which will be ana- lyzed to identify potential markers that can assist in dis- ease course prediction and understanding heterogeneity in phenotypic expression. This study may also enable the development of standardized assays, the identification of at-risk groups, and guidelines for non-specific and specific therapies.
To date, no other international team of dedicated experts has been assembled to investigate the natural his- tory of PLGD and fill knowledge gaps; HISTORY pro- vides the first comprehensive effort to address this ultra- rare disease. It is not possible for one center or country to singlehandedly complete this study; all interested parties are therefore strongly encouraged to view the study web- site (www.plgdeficiency.com), participate if they know of or care for anyone with PLGD or contact the authors direct- ly to discuss potential involvement in this registry. Full enrollment and patient diversity will benefit all those with this disorder.
Acknowledgments
The authors would like to thank Ian S. Mitchell, Ph.D. and Sonia Nasr, Ph.D. of GLOVAL LLC, Broomfield, CO, USA for their assistance in writing and editing this manuscript.
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