Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report

Ashenhurst, James R.; Nhan, Hoang; Wu, Sheng Nan; Stoller, James K.; Agee, Michelle; Aslibekyan, Stella; Auton, Adam; Babalola, Elizabeth; Bell, Robert K.; Bielenberg, Jessica; Bryc, Katarzyna; Bullis, Emily; Cameron, Briana; Coker, Daniella; Partida, Gabriel Cuellar; Dhamija, Devika; Das, Sayantan; Elson, Sarah L.; Filshtein, Teresa; Fletez-Brant, Kipper; Fontanillas, Pierre; Freyman, Will; Gandhi, Pooja; Heilbron, Karl; Hicks, Barry; Hinds, David A.; Jewett, Ethan M.; Jiang, Yunxuan; Kleinman, Aaron; Kukar, Katelyn; Lane, Vanessa A.; Lin, Keng-Han; Lowe, Maya; Luff, Marie K.; McCreight, Jennifer C.; McIntyre, Matthew H.; McManus, Kimberly F.; Micheletti, Steven J.; Moreno, Meghan E.; Mountain, Joanna L.; Mozaffari, Sahar V.; Nandakumar, Priyanka; Noblin, Elizabeth S.; O’Connell, Jared; Petrakovitz, Aaron A.; Poznik, G. David; Schumacher, Morgan; Shastri, Anjali J.; Shelton, Janie F.; Shi, Jingchunzi; Shringarpure, Suyash; Tian, Chao; Tran, Vinh D.; Tung, Joyce Y.; Wang, Xin; Wang, Wei; Weldon, Catherine H.; Wilton, Peter R.

doi:10.1016/j.chest.2021.09.041

Cited by 15 publications

(9 citation statements)

References 28 publications

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“…Here, the time delay in AATD diagnosis identified is comparable to previous reports of delayed diagnosis of 5–8 years 41–43 . There are multiple hypotheses that may explain this delay.…”

Section: Discussionsupporting

confidence: 86%

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Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Wu,

Hagiwara,

Gnass

et al. 2023

Aliment Pharmacol Ther

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SummaryBackgroundAlpha‐1 antitrypsin deficiency (AATD) is caused by mutations in SERPINA1, which encodes alpha‐1 antitrypsin, a protease inhibitor (Pi). Individuals with AATD and the homozygous Pi*ZZ genotype have variable risk of progressive liver disease but the influence of comorbid lung disease is poorly understood.AimsTo characterise patients with AATD Pi*ZZ and liver disease (AATD‐LD‐Pi*ZZ) with or without lung disease and describe liver disease‐related clinical events longitudinally.MethodsThis was an observational cohort study of patients in the Mayo Clinic Healthcare System (January 2000–September 2021). Patients were identified using diagnosis codes and natural language processing. Fibrosis stage (F0–F4) was assessed using a hierarchical approach at baseline (90 days before or after the index date) and follow‐up. Clinical events associated with liver disease progression were assessed.ResultsAATD‐LD‐Pi*ZZ patients with lung disease had a longer median time from AATD diagnosis to liver disease diagnosis versus those without lung disease (2.2 vs. 0.2 years, respectively). Compared to those without lung disease, patients with lung disease had a longer time to liver disease‐related clinical events (8.5 years and not reached, respectively). AATD‐LD‐Pi*ZZ patients without lung disease were more likely to undergo liver transplantation compared with those with lung disease.ConclusionIn patients with AATD and lung disease, there is a delay in the diagnosis of comorbid liver disease. Our findings suggest that liver disease may progress more rapidly in patients without comorbid lung disease.

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Section: Discussionsupporting

confidence: 86%

“…14,15 Here, the time delay in AATD diagnosis identified is comparable to previous reports of delayed diagnosis of 5-8 years. [41][42][43] There are multiple hypotheses that may explain this delay. For instance, the presence of other risk factors for chronic liver disease may contribute to further diagnostic uncertainty.…”

Section: Discussionmentioning

confidence: 99%

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Wu,

Hagiwara,

Gnass

et al. 2023

Aliment Pharmacol Ther

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“…Similarly, time to diagnosis has also registered median values of over a year for some rare metabolic diseases: alpha-1 antitrypsin deficiency (22.3 years) [27] , Pompe disease (12.9 years) [28] , alpha-mannosidosis (72 months) [29] , adult hypophosphatasia (over 3.8 years) [30] , Farber’s disease (13.7 months) [31] , and mucopolysaccharidosis type III (39 months) [32] . This delay in the diagnosis of rare metabolic diseases is more common among those that do not form part of neonatal screening or do not exhibit altered levels of biochemical parameters in routine biological samples [33] .…”

Section: Discussionmentioning

confidence: 98%

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Benito-Lozano

López-Villalba

Arias-Merino

et al. 2022

Orphanet J Rare Dis

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Background According to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them. Methods Using data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960–2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression. Results Detailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2–7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07–1.45); in cases with symptom onset at age 30–44 years (OR 1.48; 95% CI 1.19–1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26–7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02–1.88). Conclusions This is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

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“…Recently, the possibility of self-sampling has been reported with the use of direct-to-consumer genetic testing for AATD. The results show that not only is it possible to make a correct diagnosis with auto-sampling, but also that it was associated with positive changes in behavior [12].…”

Section: Discussionmentioning

confidence: 82%

Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

et al. 2022

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Introduction Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. Methods This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge. Results The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. Conclusions Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.

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Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report

Cited by 15 publications

References 28 publications

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Liver disease progression in patients with alpha‐1 antitrypsin deficiency and protease inhibitor ZZ genotype with or without lung disease

Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry

Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis

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