This was a qualitative, cross-sectional, noninterventional, concept elicitation (CE) study. A preliminary concept list was developed from a targeted literature review (TLR), patient blog posts, and clinician interviews to identify “concepts” (signs and/or symptoms, and impacts) affecting patients with AATD-LD, which were aggregated and prioritized based on the degree of support across the three sources ahead of the patient CE interviews. During the interviews, patients shared their disease background, demographics and relevant clinical information, described their experience of the signs and/or symptoms and impacts of AATD-LD, and provided the timing of their symptom onset, their fibrosis stage, and indications of disease progression. A conceptual model was developed based on concepts from the aggregated sources and from the patient CE interviews. An overview of the study design is shown in Fig. 1.

An overview of the study design. AATD-LD alpha-1 antitrypsin deficiency-associated liver disease, CE concept elicitation

A TLR was conducted that focused broadly on signs and/or symptoms, and impacts reported by patients with a wide range of chronic liver diseases, including hepatitis C, hepatitis B, metabolic dysfunction-associated steatotic liver disease, metabolic dysfunction-associated steatohepatitis, and AATD. The TLR identified fatigue, nausea, vomiting, and abdominal pain as the most commonly reported symptoms of chronic liver disease, and identified a range of emotional, social, and physical impacts. No specific AATD-LD-related signs and/or symptoms were identified.

Following the TLR, a search of blog posts from patients with AATD-LD was conducted using general search engines (Google and Bing), AATD resource/patient support websites, and websites for AATD patient advocacy groups (Alpha-1 Foundation, Alpha-1 UK Support Group, and Alpha-1 Global). In total, 11 posts from 11 unique patients with AATD-LD were identified (see Online Resource 1, Supplementary Table S1).

To enrich data gathered from the TLR and patient blog posts, interviews were conducted with five clinicians (two gastroenterologists, two pulmonologists, and one hepatologist) who had experience in managing/treating a combined total of 212 patients with AATD-LD (see Online Resource 1, Supplementary Table S2). The clinicians discussed approaches to diagnosis and staging, disease management and progression, clinical presentation, and their perspectives of patients’ experience with AATD-LD.

Insights from each phase of research—the TLR, patient blog posts, and clinician interviews—were taken into consideration when developing a preliminary concept list to discuss with patients during the CE interviews (see Online Resource 1, Supplementary Tables S3 and S4). Signs and/or symptoms identified from at least two of the three sources, or from one of the sources and also reported as appearing earlier than fibrosis stage F4, were included in the preliminary concept list. Impacts identified from two or more sources were also included in the preliminary concept list. Within the preliminary concept list, signs and/or symptoms identified from three sources, those reported as appearing earlier than fibrosis stage F4, and one symptom (muscle weakness) that had particularly strong support in the patient blog search, were classified as “highest priority” for further probing in the CE interviews. Impacts identified from three sources were classified as “highest priority” for further probing.

Patients who met the defined eligibility criteria (see Online Resource 1, Supplementary Table S5) were recruited for the CE interviews by Global Perspectives, a recruitment and patient engagement agency, and from an academic medical center in the Midwest of the USA interested in recommending their patients for participation in the study. Global Perspectives identified potential patients via an existing database of individuals who expressed interest in participating in the study and had previously shared their AATD diagnosis. In addition to identification of individuals via the database, Global Perspectives engaged in outreach efforts with patient advocacy groups, social media groups, and Alpha-1 Foundation clinical resource centers. The participating academic medical center shared an informational flyer with eligible patients; the flyer included a link to access and complete the online consent form and screener. Eligible individuals were contacted to participate in the scheduled telephone interview.

A physician-confirmed diagnosis form including fibrosis stage and genotype information was collected for all patients, and fibrosis stage and genotype were determined based on this confirmation (see Online Resource 1, Supplementary Material S6). Eligible patients were English-speaking, US adults (aged 18 years or older) diagnosed with AATD-LD with or without lung involvement, a Pi*ZZ, Pi*SZ, or Pi*MZ genotype, METAVIR fibrosis stage F2–F4, and without liver cancer. Originally, the study was planned to recruit only patients who had AATD-LD with a Pi*ZZ genotype. However, owing to patient recruitment challenges, the eligibility criteria were broadened to include patients with Pi*SZ or Pi*MZ genotypes, given that these patients also experience liver disease.

Between August 1 and November 2, 2022, patients were interviewed one-to-one by a third-party research organization via telephone and, with the patients’ permission, the interviews were recorded. The interviews lasted approximately 60 min. The interviewers followed a central Institutional Review Board-approved discussion guide to inform the structure and flow of the conversations. The study involved up to three moderators who were trained in interviewing patients for CE and cognitive interviews. The Project Director provided oversight and direction to the study team and ensured that all research procedures were implemented as outlined in the protocol.

Patients were asked to share their background and demographic information, relevant clinical information including any comorbidities, the date of their AATD diagnosis and whether they had a diagnosis of liver disease only or both liver and lung disease diagnoses, receipt of AAT augmentation therapy, fibrosis stage and genotype, and the specialty of the clinician who made the diagnosis and/or was managing the condition. Patients then described the signs and/or symptoms, and impacts they experienced that were thought to be due to their AATD-LD. The interviewers probed on the highest priority concepts from the preliminary concept list to determine which of the concepts were relevant. Details such as severity, duration, frequency, triggers, and coping mechanisms were also discussed. Ratings were collected to determine the degree of bothersomeness or disturbance for signs and/or symptoms and impacts, respectively. Interviewers probed for the timing of disease onset and inquired about patients’ fibrosis stage (in addition to information obtained from their confirmation of diagnosis form) and disease progression.

Qualitative data from the patient CE interviews were analyzed using both deductive and inductive coding techniques. A deductive coding approach allowed researchers to apply findings from previous “waves” of interviews and continuously update the codebook, which was developed prior to the commencement of coding based on other sources, including the targeted literature review, patient blog post search, and clinician interviews. Inductive coding is a technique where codes are derived from the data as concepts and ideas naturally emerge. This combined approach facilitated analysis of concept frequencies and saturation, while also providing an opportunity to thematically analyze new concepts and themes as they emerged.

Each transcript was coded by one coder. An experienced coding lead provided oversight of the coding process and closely reviewed 20% of transcripts to identify any discrepancies and ensure consistency and accuracy of coding. After coding was completed, data were reviewed by the coding lead in collaboration with the coder to ensure that frequency counts, codes for saturation analysis, and overall qualitative coding were accurate. After data were cleaned and any inaccuracies were corrected by the coding lead in collaboration with the coder, coding outputs were generated in MAXQDA (VERBI GmbH, Berlin, Germany), a qualitative analysis software, for analysis and reporting.

Based on the aggregated sources (TLR, patient blog posts, and clinician interviews) and patient CE interviews, a conceptual model of AATD-LD was developed. Concepts were considered as “most salient” if reported by ≥ 50% of patients (n = 8) with a mean bothersomeness/disturbance rating of  ≥ 5, “highly salient” if reported by > 5 and < 8 patients with a mean bothersomeness/disturbance rating of  ≥ 5 on a scale of 0–10 (0 as not at all bothersome or disturbing; 10 as extremely bothersome or disturbing). Concepts were mapped to a saliency grid to visualize and characterize relative saliency in the context of all signs and/or symptoms and impacts reported.

To determine concept saturation relating to signs and/or symptoms, that is, confirmation that no new concepts were emerging, interviews were conducted in three waves involving five patients each. This sequencing allowed for minor modifications of the discussion guide and inclusion of new concepts. Transcripts were organized chronologically and then grouped according to waves. Codes were derived and compared across all three waves of interviews. Concept saturation was not evaluated for impacts because signs and/or symptoms were the primary focus of the study. Additionally, not every impact was discussed with every participant because some impacts did not arise until later in the interviews. Finally, the wide range and number of signs and/or symptoms reported by participants did not allow time for an extensive discussion of impacts.