A retrospective analysis of data from the PICTURE study was conducted, the design and methods of which have been reported previously [
18]. The PICTURE study was a cross-sectional burden of illness study of physician and caregiver-reported information for patients with PFIC type 1 or 2 in France, Germany, the United Kingdom and the United States from September 2020 through to March 2021. While the PICTURE study captured information related to the clinical, humanistic and economic burden of PFIC, this paper’s analysis focuses on the caregiver-reported humanistic burden of PFIC.
The PICTURE study design has two main sources of data: physicians and caregivers. Physicians provided clinical and resource use data of PFIC patients at the time of consultation, via an electronic Case Report Form (eCRF). Caregivers of PFIC patients, recruited by the physician as they attended a clinical appointment with the patient, completed online specific self-completion questionnaires about the impact of the disease on their lives.
The study was conducted under the guidance and expertise of an Expert Reference Group (ERG), consisting of a representative of academia as principal investigator (University of Chester), partnering charity and advocacy representatives (PFIC Network and Children’s Liver Disease Foundation), as well as experts in the field of liver diseases: Prof. Karen Murray, Prof. Jorn Schattenberg, Prof. Anil Dhawan and Jose Willemse.
The study protocol and materials were approved by the Research Ethics Sub-Committee of the Faculty of Health and Social Care at the University of Chester (no. RESC0820-1042). The study was conducted in accordance with all relevant ethical guidelines; all caregivers provided informed consent.
Participants
Participant outreach and recruitment was conducted via electronic media, using both a standard fieldwork approach and a hybrid approach. The standard fieldwork approach was conducted from September 2020 through to March 2021 and aimed to recruit representative samples of physicians treating PFIC in each country (including hepatologists, gastroenterologists, general practitioners, pediatricians, and medical geneticists). Eligible physicians had to have ≥ 2 years of practice experience and have treated ≥ 1 patient with PFIC in the last 12 months. Participating physicians recruited consecutive eligible patients/caregivers (maximum of 10) during routine clinical visits for any reason, including adult caregivers/guardians of patients (any age) with genetic diagnosis of PFIC (subtypes 1, 2 or 3) ≥ 12 months prior to study entry. Patients/caregivers were excluded for current or recent (≤ 12 months) clinical trial participation. Physicians completed electronic case report forms (eCRFs) with clinical and economic information based on the patient’s medical history. Caregivers completed online questionnaires regarding the impact of PFIC on their lives and productivity. Physicians performed all activities outside of professional practice parameters and received remuneration based on fair market value; caregivers also received remuneration for completion of questionnaires.
The hybrid recruitment approach was conducted through February and March 2021 to bolster caregiver participation, as their involvement was likely affected by the COVID-19 pandemic over 2020 fieldwork months. Partnerships with the PFIC Network (pfic.org) and the Children’s Liver Disease Foundation (CLDF; childliverdisease.org) facilitated direct outreach to families of patients with PFIC. Participants recruited through the hybrid approach completed the same online questionnaire on the impact of PFIC as in the fieldwork approach, with 5 additional questions related to clinical outcomes and resource use, to facilitate analyses of clinical and economic burden in the absence of eCRFs completed by the physicians.
Given that PFIC is a rare disease, measures were taken to solidify the investigators’ confidence that the study sample was based on patients identified with PFIC. An interim quality-control analysis of incoming data revealed that a high percentage of cases reported were adults, with no surgical history (no partial biliary diversion [PBD] or liver transplantation). This suggested that non-progressive cholestasis cases were included for participation in the study. Therefore, a clinical algorithm was developed and applied post-hoc, to select children and young adults most likely to exhibit PFIC. The requirements were patients < 5 years old at the time point of PFIC diagnosis and < 18 years old at the time of study entry. Exceptions were made for those aged 18–35 at study entry and ≤ 5 years old at diagnosis if they had a record of a PFIC-related surgery such as PBD or liver transplantation (Additional file
1: Fig. S1). Otherwise, older patients (diagnosed > 5 years of age and/or aged > 35 years at study entry) were not likely to have had PFIC or to have survived PFIC without a record of life-sparing surgery.
Variables and outcomes
Patient and caregiver characteristics were provided by the physicians and caregivers (fieldwork approach) or caregivers only (hybrid approach), including age, sex, country, PFIC subtype, caregiver type (i.e., mother, father), highest caregiver education level, marital status, and urbanicity (rural, village, town, city). Caregivers provided information about the impact of PFIC on HRQoL, work productivity, their professional career, sleep, and relationships. A supplemental question regarding the impact of the COVID-19 pandemic on PFIC caregiving was also included.
Caregiver-reported HRQoL was captured using the validated 7-dimension CarerQoL-7D and the caregiver HRQoL visual analog scale (CarerQoL-VAS; Institute for Medical Technology Assessment, The Netherlands;
www.imta.nl/carerqol/) [
19,
20]. The 7 dimensions of the CarerQoL-7D indicate 3-level responses (“no”, “some”, or “a lot of”) for 2 ‘positive’ dimensions regarding level of fulfilment carrying out care tasks and availability of support when needed to carry out care tasks, and 5 ‘negative’ dimensions related to relationship problems with the care receiver, problems with the caregiver’s own mental health, financial problems due to care tasks, and problems with the caregiver’s own physical health [
20]. A weighted average utility score based on UK utility weights [
21] (Additional file
1: Table S1) was calculated on a 0–100-point scale where 0 represents the “worst possible caregiving situation” and 100 represents the “perfect caregiving situation” (a lower weighted score indicated greater caregiver burden). For the CarerQoL-VAS, responders marked a continuous 0–10 scale indicating how they felt at the moment, from “completely unhappy” (0) to “completely happy” (10).
Work productivity was assessed using the Work Productivity and Activity Impairment questionnaire Adapted for Companion or Caregiving v2.0 (WPAI;
www.eprovide.mapi-trust.org). The WPAI captures the percentage of impairment in the past 7 days, in terms of work-related absenteeism (not being present at work), presenteeism (present at work, but with productivity limitations), work productivity loss (based on absenteeism and presenteeism), and impairment of regular activities due to health-related caregiver duties, where higher scores indicate greater impairment, or worse outcomes [
22]. Further productivity impact was assessed via employment status, impact on work in the past 3 months (missed workdays or productivity impact), stopping work due to caregiving (missed work years), and impact on career building (alternate career choice, prevention of career progression, prevention from working more hours).
Caregivers reported the impact of caregiving on their sleep (no, some, moderate, or severe difficulty sleeping, or hardly ever sleep) and relationships (no effect, affected relationship with partner, affected relationship with other family members, affected relationship with friends). Results were examined overall, by PFIC type (1 or 2), by history of surgery (with PBD/Liver transplant vs. without PBD/Liver transplant), and by history of specific procedures (PBD, Liver transplant, both, neither).
Caregivers also indicated their ability or lack thereof to access supplementary professional care. The impact of the COVID-19 pandemic was also assessed, in relation to the impact on resource use, caregiver mental health, and caregiver physical health.