General study design
The PROactive cohort study has a continuous longitudinal design and includes children with a chronic condition in a broad age range. Inclusion can take place between 2 and 18 years of age, depending on the moment of diagnosis. Besides children with a chronic condition, children with unexplained medical symptoms are included in the PROactive cohort study.
Combination research assessments and clinical care assessments within a life cycle perspective
The PROactive cohort study forms an integral part of clinical care. Assessments are directly accessible for health care providers (viewer in EHR) and alerts are noted in the EHR if an individual scores beyond pre-specified thresholds.[19,20] This allows the physician to discuss the results of the questionnaires with the parents and children during an outpatient visit. Fatigue, daily life participation, and psychosocial well-being are assessed using patient-reported outcome measures (PROMs). Previous studies show that discussing PROMs in clinical care can improve the communication between patient and healthcare provider, lead to higher satisfaction with the received care, make problems easier to discuss for patients, and improve clinical outcomes.[21–24] Discussion of PROMs gives health care providers insight into aspects of the child’s health and functioning beyond the traditional clinical paradigm.[20,25] It gives children and parents an incentive to participate in the PROactive cohort study. Therefore, the PROactive cohort study does not use waves. Instead, children are included when they visit the outpatient clinic and are followed up annually, preferably linked to another outpatient visit. This interval was chosen, weighing the burden with the possibility to screen for problems and intervene in time. Currently, children are followed until 18 years of age, although follow-up into adulthood is in development.
STUDY POPULATION
Setting
In the PROactive cohort study, participating children complete questionnaires prior to their outpatient visit at the Wilhelmina Children’s Hospital (WKZ), the Netherlands. Children with various chronic conditions are included, with different starting points in data collection determined by the debut of their disease: cystic fibrosis (CF; December 2016), autoimmune diseases (such as juvenile idiopathic arthritis (JIA) or systemic autoimmune diseases (March 2017), chronic kidney disease (CKD; June 2019), primary immunodeficiency’s (PID; March 2017), inflammatory bowel disease (IBD; March 2019), auto inflammatory conditions (March 2017), congenital heart disease (CHD; July 2019) and children with unexplained symptoms (MUS; March 2017). Neonatology (follow-up of ex-premature) will collaborate at the beginning of 2022.
From 2017 - 2020, children in the first year after treatment for childhood cancer were also assessed as part of this cohort study. At the moment, baseline inclusion in the PROactive cohort study for this patient group has stopped, but follow-up data is still collected in children enrolled in the study until 5 years after diagnosis in the Princess Máxima Center for paediatric oncology, Utrecht, the Netherlands (collaborating partner).
In- and exclusion criteria
Children with a chronic condition are eligible to take part in the PROactive cohort study, if: 1) they are between 2-18 years of age, 2) they are diagnosed with one of the afore mentioned chronic conditions, and 3) they are at least one year post-diagnosis. Children with unexplained symptoms are included if 1) if they are between 2-18 years of age, and 2) if they present themselves with MUS with pain or fatigue as the main complaint at the Wilhelmina Children’s Hospital (WKZ). Children with MUS gives us the opportunity to study our outcomes in children with and without found pathophysiological changes. Exclusion criteria for chronic conditions and MUS symptoms are: 1) not being able to understand or read the Dutch language, 2) not being able to fill out online questionnaires, 3) in case of child-reported questionnaires, cognitive impairment below the level of functioning of an eight-year-old child.
The choice to include children one year post-diagnosis was made for two reasons. First, the diagnostic phase and initial treatment phase are often hectic for parents and children and participation in research, with reflection on psychosocial factors, may be perceived as too burdensome in this phase. Secondly, it may be easier to identify transdiagnostic modifiable or treatable factors when children are in a relatively stable phase of their disease, especially factors that are associated with fatigue.
The lower limit of inclusion from the age of 2 years was determined by the range of the chosen validated questionnaires used.
Informed consent
This study was classified by the Institutional Review Board as exempt from the Medical Research Involving Human Subjects Act (16-707/C). A digital informed consent was provided by both the child (> 11 years) and his/her parent(s) and comprised the use of data from the questionnaires for research and to extract data from the child’s medical records
RECRUITMENT AND FOLLOW-UP PROCEDURES
Recruitment
The physician's outpatient clinics are screened to check which children are eligible for baseline assessment. When a child meets the inclusion criteria, the family is invited to fill out questionnaires after obtaining informed consent. For younger children (< 8 years), one of the parents completes the assessment. For older children (8-18 years), both the child and one of the parents are asked to complete the assessment.
For the baseline assessment, families are contacted by e-mail three weeks before a regularly scheduled outpatient visit (Figure 3). Families are contacted twice per e-mail and once per telephone. In case of no response, this cycle is repeated at their next outpatient clinic visit. After the family completes the assessments, the raw results scores (with traffic light colours), the scores in a chart with threshold and a written summary become visible in the EHR. This makes the questionnaires easily interpretable.
Follow-up
Annual follow-up assessments are linked to an outpatient visit if applicable. Follow-up assessments are divided into core- and extended sets. The core assessment contains a smaller amount of questionnaires focused on the main outcome parameters of the cohort. At the developmentally important ages of 3, 6, 9, 12, 15 and 18 years, children and their parents fill out an extended set of questionnaires (Figure 2). These ages are aligned in a healthy Dutch cohort to allow comparison between chronically ill children and their healthy peers.[12] The current overview of questionnaires of each assessment is available on the PROactive cohort study’s DataverseNL page (https://doi.org/10.34894/FXUGHW).[26] For the annual follow-up assessments, families are contacted by e-mail three weeks before a regularly scheduled outpatient visit (figure 3). If no outpatient visit is scheduled they will be contacted 11 months after the baseline assessment. The second follow-up will take place 23-26 months after baseline assessment, the third follow-up will take place 35-38 months after baseline assessment and so on. Children with MUS usually no longer receive hospital care one year after their initial visit. If they are no longer in care, follow-up data is collected only for research purposes.
DATA COLLECTION
Choice of measurements
In this study, we only used validated concepts and (sub)scales that could be compared to outcomes of other studies with healthy children or children with other diseases. Child reported questionnaires are only about the child, parent questionnaires can be both about the child or about the parent themselves. All selected patient-reported biological, psychological, and social factors are related to the primary outcomes: fatigue, daily life participation, and psychosocial well-being. The selection of determinants may also include current topics, such as screen/social media use and the effect of the COVID-19 pandemic on children. All outcomes and determinants of the PROactive cohort study are described in table 1 and 2. Various measurements were aligned with Dutch health population cohorts. [12,14,18]
Data collection PROMs
All PROMs are offered via a web-based portal, KLIK (www.hetklikt.nu). [19,20] Children are allowed to use parental assistance if needed. The estimated time participants need to complete the by PROactive cohort study selected questionnaires is 15-20 minutes for the core set assessment, and 30-45 minutes for the baseline and extended assessment.
Data collection of demographic and clinical data
During outpatient visits several measurements are documented in the EHR. For the PROactive cohort study, we extract data regarding disease activity, disease duration, comorbidities and medication use. Twice a year, data extraction of pre-selected biological variables takes place. If there are several moments of clinical assessments, the data entry closest to filling out the PROMs is chosen.
DATA MANAGEMENT
The PROactive cohort study has a data management plan (DMP) and applies FAIR (Findable, Accessible, Interoperable, Reusable) principles to the data generated in the study [29]. The (re)use of data by internal and external partners to answer more research questions is encouraged. Given the data are sensitive, the data themselves cannot be published openly. However, the metadata are published with a DOI on DataverseNL and will therefore be findable for other researchers (https://doi.org/10.34894/FXUGHW).[26] This metadata includes a data management plan, a description of the data, a codebook, and a Data Access Protocol which outlines procedures and guidelines on how to request and reuse the data. All project materials and data are organized and documented to ensure efficient reuse. The PROactive cohort study attempts to share data in interoperable formats or provide recommendations on how to achieve interoperability. These requests are discussed with clinicians representing the specific disease groups. Depending the nature of the data request, we may either utilize data transfer agreements or the Digital Research Environment (DRE) to share data safely and securely, in line with European data protection and privacy regulations.
CURRENT STATUS
The PROactive cohort study was launched in December 2016. Over time, several disease groups within the Wilhelmina Children's Hospital in The Netherlands have joined. The study is still ongoing and has no expected end date. Inclusions and follow-up assessments are still being collected and the following description is a snapshot of the current status (March 2021). Also, adjustments in collaborating disease groups may change over time.
As of March 2021, N=1918 of the N=2770 invited patients completed the PROactive cohort study baseline and provided informed consent (69% response rate). The PROactive cohort study consist of 1306 child reported baseline assessments and 1761 parent reported baseline assessments. The mean overall age was 11.9 years (IQR: 8.4-15.9 year), 57% of the participants is female. There are seven paediatric disease groups represented in the PROactive cohort study (CF, autoimmune disease, CKD, PID, IBD, CHD, MUS). The overall follow-up percentages across disease groups varied between 54% and 83% (baseline). Figure 4 showes the response rates of the PROactive cohort study.
A cohort specific power calculation[30] was performed, and demonstrated sufficient power with the current inclusions (≥N= 73 advisable). This power calculation is based on 21%[5] expected incidence of fatigue in children with a chronic condition (cross-sectional study), the assumed relative risk of 4, confidence level of 0,95% and the desire power of 80. The data collection system (www.hetklikt.nu) does not allow accidental skipping questions because of this the PROactive cohort study has no missing values caused by accidental skipping questions. However, it has happened that participants returned questionnaires prematurely, or only the parent version or the child version was completed and not both. Missing data has not been taken into account in the above power calculation.
EMBEDDING
As previously described, the PROactive cohort study consists of a collaboration of different subspecialists in paediatric chronic conditions within the Wilhelmina Children's Hospital Utrecht, the Netherlands. The PROactive cohort study collaborates closely with the Princess Maxima Centre (https://www.prinsesmaximacentrum.nl/en) (paediatric oncology Utrecht, the Netherlands) and Dynamics of Youth[12] (Utrecht University, The Netherlands). There are collaborations with Dutch healthy population cohorts to make it possible to compare children growing up with a chronic condition and healthy children. This concerns the YOUth cohort (Utrecht)[12], HBSC[18] and Whistler Cohort[14]. Since the data collection is still ongoing and growing, the number of collaborating research groups, in- and outside the Netherlands, is expected to increase. The study has an open policy with regard to collaboration with other research groups.