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Growing up with hemophilia
Health related quality of life and psychosocial functioning
Limperg, P.F.
Publication date
2017
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Limperg, P. F. (2017). Growing up with hemophilia: Health related quality of life and
psychosocial functioning.
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Chapter 11
Introduction
This thesis ‘Growing up with hemophilia: health related quality of life and psychosocial functioning’ focused on the development and evaluation of reliable and valid instruments (Part I; chapters 2, 3, 4 and 5), health related quality of life (HRQOL) and psychosocial outcomes (Part II; chapters 6, 7, 8 and 9) and psychosocial care (Part III; chapter 10).
This fi nal chapter of this thesis summarizes the main fi ndings; it considers the limitations and challenges of the studies. Furthermore, clinical implications and future perspectives are discussed and fi nally, conclusions and key messages are highlighted. An overview of the main results of the studies are presented in Table 1.
Main fi ndings
Part I: development and evaluation of instruments
The fi rst study in this thesis, Chapter 2, addresses various important challenges when measuring HRQOL in children, such as generic versus disease-specifi c questionnaires, age-specifi c questionnaires with a narrow versus a wide age range, self-report versus proxy-report, and paper-pencil versus online questionnaires. Although not comprehensive, this overview provides the most relevant topics to keep in mind when considering the implementation of HRQOL measures in daily clinical practice or starting a research program measuring HRQOL in children.
The aim of Chapter 3, a systematic review, was to obtain a comprehensive overview of the measurement properties of HRQOL questionnaires in hemophilia across geographic and age boundaries, by systematically assessing the methodological quality of studies. In total, 22 articles were assessed, including 8 questionnaires. The fi ndings suggest that from the three questionnaires for children, the CHO-KLAT questionnaire is the most optimal disease-specifi c questionnaire to use at this moment. For adults, out of fi ve questionnaires, the Haemophilia Well-Being Index and the HAEMO-QoL-A are the most optimal instruments. No new disease-specifi c HRQOL questionnaires in hemophilia are required. However, additional research using the existing
207 Chapt er Aim Sample Measur es/cont ent Main findings/conclusions 2
To demonstrate the impor
tance o
f measuring
HRQOL in pediatrics and its challenges.
HRQOL measur
es
pr
ovide the unique
oppor
tunity to have
insight into a number of differ
ent domains o f the child’ s functioning. This chapter pr ovides a global over view o f the philosophy o f and tools used in HRQOL r esear ch in childr en. Impor tant challenges r egar
ding the use o
f HRQOL instruments ar e r epor ted: generic ver
sus disease-specific questionnair
es,
age-specific questionnair
es with a narr
ow
ver
sus a wide age range, self
-r epor t ver sus pr oxy-r epor t, and paper -pencil ver sus online questionnair es. 1) T
aking HRQOL into account in clinical practice is o
f utmost impor
tance, but comes with
challenges.
2) P
aying attention to HRQOL makes it possible to monitor a child over time and pr
ovide inter ventions wher e appr opriate. 3
To assess the methodological quality of studies on the psychometric pr
oper
ties
of HRQOL instruments developed in patients with hemophilia, using the COSMIN checklist.
The initial sear
ch yielded 1597 ar ticles, o f which 22 ar ticles wer e included
and assessed: full-text original r
esear
ch ar
ticles
(e.g. not an abstract or review), published in English, and focused on the development or evaluation o
f measur ement pr oper ties o f a HRQOL questionnair e. The questionnair e had to be self - or par ent pr oxy-repor
ted, and specifically
developed or evaluated in individuals with hemophilia (≥50% o
f the
sample with hemophilia A/B).
Thr
ee pediatric questionnair
es:
- CHO-KL
AT
- Haemo-QoL - Unnamed measur
e ('T
oddler questionnair
e')
Five adult questionnair
es: - Hemo filia-QoL - Haemophilia W ell-Being Index - HAEMO-QoL-A - Haem-A-QoL - SF-36 1) The CHO-KL
AT was the pediatric measur
e that showed the str
ongest measur
ement
pr
oper
ties in high quality studies.
2) The Haemophilia W
ell-Being Index and HAEMO-QoL-A per
for
med best among the
adult measur
es.
3) Ther
e is no need for new disease- specific HRQOL questionnair
es for hemophilia.
4) Additional r
esear
ch is necessar
y to document the measur
ement pr
oper
ties o
f the
curr
ently available questionnair
es, specifically focusing on the structural validity
, measur ement err or and r esponsiveness. 4 To assess the r eliability and validity o f the HCPT (boar d game), aiming
to assess coping and per
ception in boys with
hemophilia.
- N=32 boys with hemophilia (8-12 year
s).
- Socio-demographic questionnair
e
- The Hemophilia Coping and P
er
ception
Test (HCPT) - Coping with a Disease (C
ODI) - Questionnair e Op Koer s for Childr en (QOK-c) - State-T rait Anxiety Inventor y for Childr en (ST AI-C) - Evaluation questionnair e
1) The HCPT coping scale assesses the mor
e practical competencies o
f coping, such as
self
-management, rather than the psychological construct o
f coping.
2) The HCPT can be used by nur
ses or psychologists as a tool to get insight into the
knowledge, self
-management and per
ception o
f boys with hemophilia and to pr
ovide
tailor
ed psycho-education.
3) Boys and par
ents had a positive attitude towar
ds the HCPT
.
Table 1.
Main fi
ndings o
f this thesis: development and evaluation o
5 To validate and collect nor
mative data for
a generic HRQOL instrument for young adults. - N=649 young adults from the general population (18-30 year
s). - Socio-demographic questionnair e - P edsQL_Y A Generic Cor e Scale Y oung Adult ver sion (P edsQL_Y A)
1) The Dutch ver
sion o
f the P
edsQL_Y
A Generic Cor
e Scales demonstrates overall
adequate psychometric pr
oper
ties.
2) With the obtained nor
m data, the P
edsQL_Y
A can be utilized as a tool to evaluate
HRQOL in young adults.
Main findings in p
ar
t II o
f this thesis: HR
QOL and psy
chosocial out comes Chapt er Aim Sample Measur es/cont ent Main findings/conclusions 6
To assess the generic and disease-specific HRQOL of childr
en with bleeding disor der s. - N=146 childr en with bleeding disor der s (0-18 year s) - Socio-demographic questionnair e - T APQOL (0-5 year s ; n=43) - P edsQL (6-18 year s; n=103) - Haemo-QoL (4-18 year s; n=48) 1) Boys 0-12 year s do not r epor
t lower HRQOL than healthy peer
s.
2) Boys 13-18 year
s r
epor
t higher total HRQOL and emotional functioning than healthy
peer
s.
3) Girls (13-18 year
s r
epor
t lower total HRQOL, school functioning and psychosocial
health than healthy peer
s.
4) Boys with sever
e hemophilia r
epor
t wor
se family functioning than boys with
non-sever e hemophilia. 7 To captur e the per spectives o f
adolescents and young adults
(Y A) with congenital bleeding disor der s on
their condition and identif
y which themes ar
e
relevant in their daily life, based on qualitative data.
- N=12 Y A with bleeding disor der s (16-30 year s) - Socio-demographic questionnair e - 3 Focus gr oups 1) Y
A with bleeding disor
der
s still experience obstacles in daily life.
2) Major themes wer
e: r
elationship with par
ents, capabilities in spor
ts, capabilities in
outings and traveling, self
-management, illness per
ception and acceptance, and
capabilities in education and employment.
3) The findings pr
ovide additional insights into Y
A’s experiences, especially r
egar
ding the
transition period to adulthood.
8
To assess the health related quality o
f life,
developmental milestones and self
-esteem in
Dutch young adults with bleeding disor
der s, compar ed to a gr oup of peer s. - N=95 Y A (18-30 year s)
with bleeding disor
der s - Socio-demographic questionnair e - P edsQL_Y A - Cour se o f Life Questionnair e (CoL Q) - Rosenber g Self
-Esteem Scale (RSES)
1) Y
A men with bleeding disor
der
s r
epor
t an impair
ed total HRQOL, physical functioning,
school/work functioning and lower self
-esteem in comparison to their healthy peer
s. 2) Y A women do not r epor t differ ences on any o
f the outcomes in comparison to their
peer
s.
3) Systematic monitoring o
f HRQOL in daily clinical practice is needed.
9
To describe the psychosocial impact o
f hemophilia on mother s. - N=30 mother s o f boys
with hemophilia (8-12 year
s)
- Socio-demographic questionnair
e
- Hospital Anxiety and Depr
ession Scale (HADS) - Distr ess Ther mometer for P ar ents (D T-P) - Haemo-QoL (8-12 year s) 1) Mother s o
f boys with hemophilia do not r
epor
t aberrant levels o
f anxiety and
depr
ession in comparison to mother
s o f healthy childr en. 2) 21% o f mother s r epor
ted clinical levels o
f distr
ess (on distr
ess ther
mometer).
3) This underlines the impor
tance o
f monitoring mater
nal psychosocial functioning and
distr
ess systematically in daily clinical practice.
Table 1.
Main fi
ndings o
f this thesis: development and evaluation o
f instruments.
(Continued)
209
Main findings in p
ar
t III o
f this thesis: psy
chosocial car e Chapt er Aim Sample Measur es/cont ent Main findings/conclusions 10 To pr ovide a description of psychosocial car e pr ovided by the multidisciplinar y team
of the Hemophilia Compr
ehensive Car e Centr e (HC CC) at the Emma Childr en’ s Hospital in Amster dam, the Netherlands. Psychosocial car e pr ovided by the multidisciplinar y team,
for all childr
en under
treatment at the HC
CC
and their par
ents.
Cor
e elements o
f the psychosocial car
e ar
e
monitoring and scr
eening o
f HRQOL (e.g.
in daily clinical practice via www
.hetklikt.
nu), psychoeducation (hemophilia camp, hemophilia school, disease specific activities, meetings for girls, par
ent meetings), practical
help (Emma at W
ork, an employment agency
for adolescents and young adults; Educational Facility and school visits), psychosocial inter
ventions (the On Track gr oup inter vention
and the Hemophilia Coping and P
er
ception
Test), and individual car
e (psychological
counselling and r
eferrals).
1) By pr
oviding this over
view o
f psychosocial suppor
t o
ffer
ed and by sharing this
knowledge, psychosocial car
e can become mor
e structur
ed and consistent between
HC
CCs ar
ound the world. P
otentially
, pr
ocesses and outcomes o
f car e can be impr oved. Table 1. Main fi ndings o
f this thesis: development and evaluation o
f instruments.
(Continued)
measures, or items of the existing measures, is necessary to support and document the lacking measurement properties of currently available questionnaires. The results of this systematic review are intended to be used in choosing the best questionnaires for future research purposes, development of guidelines, evidence-based care, policymaking and core outcome sets.
Chapter 4 describes the reliability, validity and evaluation of the Hemophilia Coping and Perception Test (HCPT), which is a board game that has been developed by the Hemophilia Comprehensive Care Center (HCCC) of the Emma Children’s Hospital/AMC in 2009/2010. The HCPT consists of two scales (coping and perception), and can be played with children under supervision of a nurse or psychologist to get insight into coping and perception. The coping scale showed satisfactory reliability and low construct validity. Based on the insights gained during this study, we hypothesize that the HCPT coping scale assesses the more practical competencies of coping, such as self-management, rather than the psychological construct of coping. The perception scale showed adequate validity and low reliability, which may be caused by the items tackling diverging aspects of this concept (e.g. anxiety, feeling different). Regarding the evaluation, boys appreciated talking about experiences and diffi culties regarding their
disease in a playful way. The HCPT is a tool to get insight into the knowledge, self-management and perception of boys with hemophilia and to provide tailored psycho-education.
With the increase of research on young adults with a chronic health condition, and for use in clinical practice, norm data for this age group have become indispensable. Chapter 5 provides Dutch norm data and psychometric properties of the Pediatric Quality of Life Inventory Young Adult Generic Core Scales (PedsQL_YA) in 649 Dutch young adults (both men and women) aged 18–30 years. The Dutch version of the PedsQL_YA demonstrates overall adequate psychometric properties. With the obtained norm data, the PedsQL_ YA can be utilized as a tool to evaluate HRQOL in young adults with chronic health conditions, such as hemophilia.
Part II: HRQOL and psychosocial outcomes
In the second part of the thesis, HRQOL and psychosocial outcomes of patients (in different age groups) and of mothers are described. In Chapter 6, the generic and disease-specifi c HRQOL of patients (0-18 years) under treatment at the HCCC was assessed. In total, 146 children participated and results show that boys and girls with bleeding disorders (0-12 years) do not experience lower HRQOL than their peers. Contrary to our assumption, boys of 13-18 years report higher HRQOL than their chronically ill and healthy peers on total HRQOL and emotional functioning. On the other hand, girls (13-18 years) experience lower HRQOL than their healthy peers on total HRQOL, school functioning and psychosocial health. Boys with severe hemophilia report lower HRQOL than their peers with non-severe hemophilia on family functioning. The results suggest that the overall HRQOL of boys with hemophilia is comparable to peers. However, it is important to systematically monitor HRQOL, of girls especially, because possible infl uencing psychosocial factors can change over time.
Chapter 7 captures the perspectives of adolescents and young adults (YA; 16-30 years) with bleeding disorders on their condition and identifi es which themes are relevant in their daily life, based on qualitative data from
211
focus groups. In total, 3 focus groups were conducted, including 12 YA. Despite growing up in a developed country with adequate treatment, YA with bleeding disorders still experience obstacles in daily life. Several major themes were identifi ed: relationship with parents, capabilities in sports, capabilities in outings and traveling, self-management, illness perception and -acceptance, and capabilities in education and employment. Moreover, two paradoxes were identifi ed; with having the responsibility over their treatment, YA may feel that the consequences, such as joint damage or pain, are in their own hands. This responsibility creates a complex situation; when adherent to treatment, life can be lived to the fullest and YA feel ‘normal’. On the other hand, patients often do deviate and are not adherent, and confrontation with the consequences is immediate. The second paradox identifi ed was that YA are often being told to be grateful for living in a country and era where treatment is available, unlike many developing countries and previous generations, while they are still suffering from pain, arthropathy and limitations. This may result in feeling like they ought not to complain. These fi ndings provide additional insights into YA’s experiences, especially regarding the transition period to adulthood.
Chapter 8 builds on the fi ndings of Chapter 7, by administering several validated questionnaires to 95 YA (18-30 years) with bleeding disorders, related to the themes identifi ed. This study assesses HRQOL, developmental milestones and self-esteem in Dutch YA with bleeding disorders compared to a group of (healthy) peers. The results show impaired total HRQOL, physical functioning and school/work functioning young adult men with bleeding disorders. Signifi cant lower self-esteem was found in YA men with bleeding disorders in comparison to peers. YA men with bleeding disorder achieved signifi cantly more psychosexual developmental milestones than peers, but show a delay in ‘paid jobs, during middle and/or high school’. For YA women with bleeding disorders, no differences were found on any of the outcomes in comparison to their peers. These fi ndings emphasize the need for systematic monitoring of HRQOL, especially with regard to school/work functioning, in daily clinical practice.
Next, Chapter 9 addresses the psychosocial impact of hemophilia on mothers. Mothers of 32 boys with hemophilia (ages 8-12 years) do not report aberrant levels of anxiety and depression in comparison to mothers of healthy children. However, still 21% of mothers report clinical distress, which underlines the importance of also monitoring maternal psychosocial functioning and distress systematically.
Part III: psychosocial care
In Chapter 10, a description of the psychosocial care provided by the multidisciplinary team of the HCCC at the Emma Children’s Hospital in Amsterdam, the Netherlands, is given. The focus of the psychosocial care provided by the multidisciplinary team is on preventing psychosocial problems and medical related stress, and supporting and equipping the child with hemophilia and its parents with as many skills as possible to lead an independent life with a high HRQOL. Core elements of the psychosocial care are therefore monitoring and screening of HRQOL (e.g. in daily clinical practice via KLIK), psycho-education (hemophilia camp, hemophilia school, disease specifi c activities, meetings for girls, parent meetings), practical help (Emma at Work, an employment agency for adolescents and young adults; Educational Facility and school visits), psychosocial interventions (the On Track group intervention and the Hemophilia Coping and Perception Test), and individual care (psychological counselling and referrals). By providing this overview of psychosocial support offered and by sharing this knowledge, psychosocial care can become more structured and consistent between HCCCs around the world. Potentially, processes and outcomes of care can be improved.
Limitations
The studies described in this thesis have some overall limitations to take into account.
Adequate measurement properties
In pediatrics, the abundance of different instruments, user fees and limited
213
use in international research and clinical settings, makes it diffi cult to obtain enough empirical data about specifi c instruments’ measurement properties [1]. As a result, performing (methodological) research with such instruments is extremely complicated.
A guideline to assess the methodological quality of instruments, is the standardized COSMIN checklist, which we used in chapter 3. However, it has some limitations, such as high standards that often cannot be met in research in rare diseases such as hemophilia, or not being able to distinguish between low reporting and low methodological quality of studies. However, COSMIN has been developed in an international Delphi study and has widely been used internationally. It can be considered a strong starting point for a methodological assessment of outcomes [2, 3]; we are not aware of a more standardized applicable system for the rating of the quality of measurement properties.
Most measures available for patients with hemophilia have shown to have good group-level measurement properties (chapters 3 and 5). However, most are not suffi ciently strong to be able to make individual clinical decisions and most information on interpretability is lacking. When looking at the concrete steps to develop usable instruments, some of those steps have been missed in hindsight. For example, responsiveness was not addressed in our study in Chapter 5. Therefore, we have no information on how well the PedsQ_YA is able to detect change over time in HRQOL of YA in the Netherlands.
Sample size and representativeness of patients
Small sample sizes often led to poor or fair rating for the quality of the study in the systematic review (chapter 3). Unfortunately this is often the reality with disease-specifi c questionnaires in rare diseases, making the development of instruments with adequate measurement properties diffi cult. In the case of chapter 4, the cause of a small sample in the HCPT study was due to the narrow age range of the HCPT (8-12 years old) and the response rate being rather low. Even though nearly 700 participants from the general Dutch population were included in the PedsQL_YA study (chapter 5), sample sizes were still
relatively small for some subgroup analyses. More importantly, the assessment of the health condition status was based on self-report rather than on physician-report, which is an important limitation in collecting normative data. Also, it is possible that more severely ill young adults did not participate because they were not able to sit behind the computer and complete questionnaires due to the severity of their health condition or not wanting to burden themselves with participation. Therefore, it is possible that our sample contains a slightly different type of chronic condition than encountered in clinical practice, which is a common issue when collecting norm data. Another concern with regard to representativeness of our samples, is that most participants were born in the Netherlands, were mostly highly educated and ethnic minorities were underrepresented. Moreover, we did not have information regarding non-respondents and their medical information, and therefore examining selection-bias was not possible in chapters 7, 8 and 9.
A reference group for the Distress Thermometer for Parents (DT-P) was not available in chapter 9. Thus, we could not compare our DT-P results to the general population. However, recently, normative data has been collected for the DT-P, and it would therefore be interesting to study a larger sample of both mothers and fathers, and compare their levels of distress to the general population [4].
Clinical implications and future perspectives Burden on patients and adequate measurement properties
When asking patients to report on their functioning, the burden should be as little as possible. To satisfy previously noted limitations (e.g. small sample sizes, inadequate measurement properties), patients would ideally only have to complete one single set of questionnaires, while this information is used for multiple purposes: research as well as clinical care. A method to decrease the burden for patients is with the use of computer adaptive testing (CAT). With CAT, items from an item bank (a set of questions that all measure the same construct) can be administered more effi ciently compared to short questionnaires with fi xed items [5]. The patient-reported outcomes measurements information system
215
(PROMIS) is an initiative developed in the USA, aiming to develop self-reported item banks using CAT and item response theory (IRT) that are applicable across a wide variety of chronic disorders. By using PROMIS item banks in the future, patients or parents may only need to answer 4–8 items per item bank, because with CAT only relevant questions are presented. This new system has shown to have higher validity, reliability, and better responsiveness than the existing PROMs [6-9]. It is expected that PROMIS will be implemented worldwide and will rapidly replace existing PROMs [5, 10-12]. PROMIS measures have already been used in several pediatric populations, such as sickle cell disease and asthma [13-15]. As emphasized by Recht et al. (2016), there is a need for personalization patient-reported outcomes in hemophilia. This could be an enormous improvement in psychometric assessment of HRQOL in hemophilia [15]. With the most appropriate items of existing questionnaires put together in a CAT, the most optimal HRQOL instrument can be developed for patients with hemophilia. Therefore, our next project is to develop a hemophilia-specifi c item bank, to facilitate the use in different international studies and to decrease the burden for patients.
Another option to minimize respondent burden and improve information on measurement properties, is by using core outcome sets of instruments across studies [16]. Core sets represent the minimum that should be measured and reported in all clinical trials of a specifi c condition [17]. It is expected that when core outcomes are always collected and reported, the results of trials can be compared, contrasted and combined [17]. For example, the systematic review performed in chapter 3, can provide a basis for what HRQOL questionnaires to choose in a core outcome set for hemophilia. It is obviously benefi cial to use corresponding strategies for HRQOL assessment in rare diseases such as hemophilia.
(Inter)national collaboration
With the previously mentioned issues of small sample sizes and lack of information on measurement properties (e.g. cross-cultural validity) in mind, expanding collaboration across centers and borders could overcome some
of these issues. Concrete steps in the development of internationally usable instruments involve item development, translation, psychometric testing (e.g., examination of reliability, validity, and responsiveness), and collection of norm data (obtaining reference data for the questionnaire from large (non)clinical populations). Guidelines on how to conduct these steps have been published [18, 19]. As stated in 2005 already, there is a need of (inter)national collaboration in clinical research on hemophilia [20]. Very few of the research questions can be tackled by studies done in single, albeit large, hemophilia centers. Suffi cient sample size is essential for research in a rare disease such hemophilia and this goal can only be achieved through collaborative multicenter studies. Moreover, it is necessary to maintain a high interest and expertise in the fi eld of hemophilia, with advances in treatment happening so quickly [20]. An excellent example of national collaboration is the ‘Hemophilia in the Netherlands’ (HiN) study; since 1972, a series of 5 national surveys have been performed [21, 22], and the sixth edition is planned for 2017.
New developments in hemophilia
Some very interesting advances in hemophilia treatment that are currently going on, behold the long acting factor replacement products. Several studies have shown that recombinant factor VIII and factor IX have prolonged half-life, and also demonstrated safety, bleeding control and prevention in patients with hemophilia A and B [23-25]. This means that, instead of infusing two or three times a week, patients now have the possibility to infuse once every two weeks. It is expected that this will infl uence HRQOL positively [23], since the treatment burden for patients will be lower. But on the other hand, new issues will arise such as staying adherent to (infrequent) treatment, insecurity related to remaining factor levels present in the blood or self-management issues regarding the decision on what day to infuse. Such issues can also infl uence HRQOL, which means a new area of discovery in hemophilia research and -care will be revealed. In any case, all HCCCs should pay close attention to patients shifting to new treatment products, systematic monitoring of HRQOL and adequate guidance in this process is warranted. With the use of the KLIK
217
system at the HCCC in Amsterdam, we will have the possibility to follow the HRQOL and psychosocial functioning of children and young adults shifting to new treatment products over time and compare their HRQOL to before the new products were used.
HRQOL and longitudinal data
As we have seen in this thesis, the HRQOL of boys growing up with hemophilia in the Netherlands is good. This may raise eyebrows and doubts with regard to the necessity of monitoring HRQOL and providing a broad range of psychosocial care for this population. However, as we described in the introduction of this thesis, several factors are of infl uence on HRQOL, such as psychosocial stressors (e.g. restrictions, treatment) and stress processing. Psychosocial stressors, but also child- and family factors, change continuously [26]. For this reason, although this population of boys with hemophilia fares well, it is important to keep monitoring HRQOL and psychosocial problems in clinical practice. Moreover, the fi nding that girls with bleeding disorders (13-18 years) report lower HRQOL supports this as well. It is hypothesized that girls are confronted with issues regarding their bleeding disorder as teenagers (e.g. when they start menstruating, which can lead to very heavy bleeding), while boys start to face consequences and issues when they are older (e.g. physical impairments). From another perspective, it is also possible that these boys are doing so well because of the psychosocial care they are receiving from the HCCC (e.g. psycho-education, peer support). For that reason, it will be interesting to follow this population over time.
Longitudinal data were not incorporated in this thesis. Longitudinal analysis provides insight into the causality of outcomes over time. With this information, children and adolescents can be identifi ed who are more likely to develop problems in daily life (e.g. low self-esteem), as well as having more insight into the causality of problems. A method to collect this longitudinal data is with the data collected in the KLIK portal, which has been described in chapters 6 and 10 [27, 28]. KLIK has become standard care in fi ve Dutch HCCCs; Amsterdam, Rotterdam, Leiden, Groningen and Nijmegen. In the future, while
increasing sample size, data from all these HCCCs should be analyzed in a collaborative study.
In addition, KLIK has recently been implemented (since January 2017) in the daily care for YA (18-30 years) with bleeding disorders in Amsterdam. This provides the opportunity to monitor children with bleeding disorders over time (from 0-30 years with the PedsQL questionnaire) while they grow up into YA. The studies in this thesis have incorporated two broad, but separate, groups of patients: children and young adults. This hinders the within-group comparison in children and YA at this point. In the future however, with the use of KLIK, we will be able to make statements about the course of HRQOL and psychosocial functioning over time in patients with bleeding disorders. Not only does this give insight in their functioning during the transitional phase, but the adult healthcare provider already has information on how the patient was functioning before transition. Moreover, this implementation also adds opportunities to our previously identifi ed needs for (inter)national collaboration; KLIK can be implemented for young adults in other HCCCs in the Netherlands as well.
Furthermore, as we have seen in chapter 3, the CHO-KLAT [29] has shown to be the most optimal measurement in children at this point. However, the Haemo-QoL questionnaire has been incorporated in KLIK since 2014. Consequently, it would be interesting to add the CHO-KLAT to the KLIK system, perhaps instead of the Haemo-QoL [30], and study the lacking measurement properties.
Work and education
YA with bleeding disorders struggle with the impact of their condition on daily life. This fi nding is disturbing when realizing the adequate HRQOL boys (0-18 years) with bleeding disorders reported during childhood (as shown in chapter 6). In contrast to their younger counterparts, YA show impaired HRQOL (as shown in chapter 8). For all children, transition into adulthood is challenging. But the transition for YA with bleeding disorders is more challenging than for healthy peers, perhaps even more than expected. Although this is in line with previous research in patients with chronic health conditions [31], this could be
219
a starting point for increased psychosocial care for young adults with bleeding disorders. Apparently, transition is associated with a decrease in HRQOL in YA with bleeding disorders, indicating the necessity of awareness of this issue in both pediatric and adult healthcare providers. From our results, we can deduce that autonomy development is a complex process. Chapter 7, for example, shows that YA struggle with many issues regarding gaining independence; relationship with parents, being able to travel, fi nding a suitable job. Chapter 8 adds to these fi ndings by demonstrating a lower HRQOL related to school/ work functioning in YA men, as well as lower rates of paid employment. The previously mentioned nationwide HiN study also demonstrated that patients with severe hemophilia participated less in full-time work in 2001 compared with the general population, despite having comparable educational levels [32]. Although it can be assumed that those numbers have improved over the years, a possible explanation for this difference may be that hemophilia patients more often follow fulltime education over a longer period of time. This seems likely, as a higher level of education is needed for ‘white collar’ jobs, which are often suitable jobs for hemophilia patients, since the risk of bleeding due to physical activities at work is low [32]. It will be interesting to compare these fi ndings in the sequel of the HiN study.
Transition in healthcare
Another factor that adds to the diffi culties during the transition phase is the large difference between pediatric and adult healthcare. The multidisciplinary care for children with bleeding disorders is extensive (as is demonstrated in chapter 10), and YA are expected to be independent and fully responsible for their own treatment when they are 18 years old. However, research has demonstrated that the mean age of YA for complete self-management and responsibility is not reached until the age of 22 [33]. With this information in mind, the gap between pediatric and adult healthcare is currently too large. Despite the availability of protocols for transition, more effort should be put into the improvement of healthcare during transition [34-36]. A fi rst step that just has been taken is the monitoring of HRQOL with KLIK during the transitional
phase. A step further could be to use the questionnaires incorporated in KLIK as reports of symptoms and health status from home before, or instead, of visiting the outpatient clinic. This way, KLIK can be used as a tool to decide whether a patient needs an outpatient visit, and care can become more patient-centered. Moreover, the increase of cross-over outpatients clinics (with both the pediatric and adult healthcare providers present) could be benefi cial. In the current situation, YA have one conjunct consultation before transition. It is advisable to start with such conjunct consultations earlier, during adolescence (around age 15) and continue until the age of 25 years. In this process, the role of the pediatric hematologist, in collaboration with parents and YA, should be diminished slowly, while the role of the adult hematologist and YA slowly increases. A pediatric nurse can also be involved to smoothen this process, being a familiar person for the YA with hemophilia. In addition, implementing a transition checklist for healthcare providers into daily clinical practice may be benefi cial. Initiatives such as the Transition Readiness Questionnaire (TRAQ [37]) and the Dutch ‘On Your Own Feet Transfer Experiences Scale’ [31] could be useful to incorporate in KLIK for this challenging population.
Screening parents and families at risk
The results of chapter 9 underline the importance for healthcare providers to be aware of the fact that parents, mothers in this case, of boys with hemophilia are at risk for distress. In clinical practice, parents with high levels of distress should be identifi ed by the multidisciplinary team. In the Emma Children’s Hospital/AMC, the Distress Thermometer for Parents (DT-P) is used in clinical practice as a screening tool for parental distress. However, it is still diffi cult to identify which parents need or want psychosocial support in advance. The identifi cation of families at risk for psychosocial problems can be improved by screening early with the Psychosocial Assessment Tool (PAT). This is a screening instrument developed in the US, that assesses psychosocial risk in families [38]. In the PAT, psychosocial problems are assessed, as well as problems in beliefs regarding the illness, availability of social support, symptoms of traumatic stress, and other psychosocial stressors within the family [39]; domains that are
221
related to the risk- and protective factors described in the model by Wallander & Varni in the introduction of this thesis [26, 40]. The PAT has potential clinical utility in hemophilia practice and has been validated among multiple pediatric populations [39, 41, 42]. The PAT takes 10-15 minutes to complete, and could be included in the KLIK portal to be completed (once) before clinic visits to assess the risk for psychosocial problems, for example when patients are new to the HCCC. This screening could make the psychosocial support more targeted towards those families who need it the most, while preventing problems from deteriorating.
As mentioned earlier, the fi ndings in chapter 9 encourage more research on psychosocial functioning of mothers of boys with hemophilia. In hemophilia, mothers have a unique position. Due to the X-linked nature of the condition, mothers are often carriers of the hemophilia gene, which means they have a father or brother who has hemophilia as well. However, the difference between the generation of the father growing up with hemophilia and a son growing up with hemophilia is immense. It has been shown that a family history of hemophilia is related to increased stress in mothers of children with hemophilia [43]. Our clinical experience points in the same direction; mothers of children with hemophilia are often stressed, worried and anxious. This could be related to the degree of enmeshed cohesion shown by mothers [43]. In addition, it suggests that prior knowledge of hemophilia does not necessarily improve coping: it is not the same when a brother or father has hemophilia compared to a son. Although levels of distress and anxiety may also depend on the stage the parents have attained in their management of hemophilia and how well they are managing the condition, this has never been truly captured in research before [44, 45]. Relating these outcomes to the psychosocial functioning of children would be interesting.
Furthermore, questionnaires currently used for parents are possibly not capturing the true experience, including feelings of guilt and continuous anxiety for life-threatening bleeds. By adding a qualitative aspect to future research, other problems can come into focus, which do not result from questionnaires. We learned from conducting focus groups, as described in chapter 7, that
some problems are not exposed easily and perhaps cannot be captured in questionnaires [46]. An interview or focus group approach could add value to identify what mothers of boys with hemophilia experience, but also to get insight into what ways we can support them, tailored to their needs. For example, although more research is needed in parents of children with hemophilia to develop the appropriate treatments for parents, parent support groups could be benefi cial. The previously mentioned group course ‘On Track’ has just been developed online for parents of chronically ill children at the Emma Children’s Hospital/AMC, and its effectiveness is being studied at this point. In this online group course, problem solving therapy and stimulation of social support are an important base of the intervention.
In addition to an increased need for research in mothers, young girls who are carriers or who have lower factor levels in their blood deserve more attention. Within the range of hemophilia being a rare condition, being a girl with a bleeding disorder (or low levels of factor VIII/IX due to being a carrier) is even more rare. Nevertheless, problems are substantial, as is shown in chapter 6, where girls with bleeding disorders show lower HRQOL than their healthy peers. This should be kept in mind when developing new studies or interventions.
Cost-eff ectiveness
Psychosocial care is not standard everywhere, mostly due to lack of fi nancial resources. Although the role of psychosocial care providers (such as health psychologists and social workers) is increasingly recognized, guidelines as to what minimum of psychosocial care should be offered, do not exist unfortunately [47-50]. It is recommended that such guidelines are established. For the future, it would be interesting to address the cost-effectiveness of the psychosocial care. Interventions can have other desirable outcomes, related to costs. For example, interventions that promote adaptation to the illness and that promote adherence to treatment could potentially reduce hospital days, use of clotting factor, visits to the clinic and prevent problems from deteriorating [51]. Another cost-benefi cial example can be the use of online interventions
223
and networks, especially for adolescents. Modern communication technologies may offer health benefi ts through peer support and learning gained through online social networking [52].
Conclusions
In this thesis, three major elements in the research around growing up with hemophilia are presented: development and evaluation of instruments (Part I), HRQOL and psychosocial outcomes (Part II) and psychosocial care (Part III). This thesis is the fi rst to describe what it is like to grow up with hemophilia, in terms of HRQOL and psychosocial functioning, for both patients and their mothers. The development and evaluation of several HRQOL and psychosocial instruments (Part I) showed us that this process is diffi cult, although measuring HRQOL with adequate instruments is indispensable, and should be an integral part of care. Additional research using the existing measures is necessary to support and document the lacking measurement properties of currently available questionnaires. The instruments developed and evaluated gave us the opportunity to assess psychosocial outcomes (Part II), showing that HRQOL in young boys with hemophilia, in contrast to their females counterparts, is not impaired, until young adulthood is reached. YA men are struggling with physical impairments, gaining autonomy, transfer to adult healthcare and school/work functioning. All these aspects have a great impact on YA, and appropriate support should be offered during this transitional phase, to YA but also to parents; the gap between the extensive multidisciplinary care in childhood in terms of psychosocial support (part III) and YA healthcare is too big. Continuity of multidisciplinary healthcare for children, adolescents, YA and parents is necessary to ensure adequate health related quality of life and psychosocial functioning, and improve that of vulnerable groups (such as girls and YA men).
Key messages Part I
• Measuring HRQOL in pediatric patients is challenging.
• For children with hemophilia, the CHO-KLAT is the most optimal questionnaire at this point. For adults, the Haemophilia Well-Being Index and HAEMO-QoL-A are most optimal.
• The HCPT is a useful tool to assess knowledge, self-management and perception in boys with hemophilia (8-12 years).
• The PedsQL_YA reliably measures HRQOL in young adults (18-30 years) and with the obtained norm data, the PedsQL_YA can be utilized to evaluate HRQOL in young adults with chronic health conditions, such as hemophilia.
Part II
• HRQOL of boys with hemophilia (0-18 years) is comparable to peers, girls with bleeding disorders (13-18) do report lower HRQOL than their peers. • Despite growing up in a developed country with adequate treatment, young
adults with bleeding disorders still experience obstacles in daily life. • Young adult men with bleeding disorders have a lower HRQOL and
self-esteem than their (healthy) peers and struggle with school/professional functioning. Young adults with bleeding disorders do not experience a delay in developmental milestones compared to their peers.
• One in fi ve mothers of boys with hemophilia (8-12 years) reports clinical distress.
Part III
• The current psychosocial care, with different degrees of intensity, is extensive for children with bleeding disorders and their parents at the Emma Children’s Hospital/AMC.
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References
1. Bullinger M, Globe D, Wasserman J, Young NL, Von Mackensen S. Challenges of Patient-Reported Outcome Assessment in Hemophilia Care: a State of the Art Review. Value in
Health 2009; 12: 808-20.
2. Terwee C, Mokkink L, Knol D, Ostelo RJG, Bouter L, de Vet HW. Rating the methodological quality in systematic reviews of studies on measurement properties: a scoring system for the COSMIN checklist. Quality of Life Research 2012; 21: 651-7.
3. Mokkink LB, Terwee CB, Patrick DL, Alonso J, Stratford PW, Knol DL, et al. The COSMIN checklist for assessing the methodological quality of studies on measurement properties of health status measurement instruments: an international Delphi study. Quality of Life
Research 2010; 19: 539-49.
4. van Oers HA, Schepers SA, Grootenhuis MA, Haverman L. Dutch normative data and psychometric properties for the Distress Thermometer for Parents. Qual Life Res 2016. 5. Reeve BB, Wyrwich KW, Wu AW, Velikova G, Terwee CB, Snyder CF, et al. ISOQOL
recommends minimum standards for reported outcome measures used in patient-centered outcomes and comparative effectiveness research. Quality of Life Research 2013; 22: 1889-905.
6. Irwin DE, Gross HE, Stucky BD, Thissen D, DeWitt EM, Lai JS, et al. Development of six PROMIS pediatrics proxy-report item banks. Health Qual Life Outcomes 2012; 10: 22. 7. Forrest CB, Bevans KB, Tucker C, Riley AW, Ravens-Sieberer U, Gardner W, et al. Commentary:
The Patient-Reported Outcome Measurement Information System (PROMIS®) for Children and Youth: Application to Pediatric Psychology. Journal of Pediatric Psychology 2012; 37: 614-21.
8. Irwin DE, Varni JW, Yeatts K, DeWalt DA. Cognitive interviewing methodology in the development of a pediatric item bank: a patient reported outcomes measurement information system (PROMIS) study. Health and Quality of Life Outcomes 2009; 7: 3. 9. Terwee CB, Roorda LD, de Vet HC, Dekker J, Westhovens R, van Leeuwen J, et al.
Dutch-Flemish translation of 17 item banks from the patient-reported outcomes measurement information system (PROMIS). Qual Life Res 2014; 23: 1733-41.
10. Haverman L, Grootenhuis MA, Raat H, van Rossum MAJ, van Dulmen-den Broeder E, Hoppenbrouwers K, et al. Dutch–Flemish translation of nine pediatric item banks from the Patient-Reported Outcomes Measurement Information System (PROMIS)(®). Quality of Life
Research 2016; 25: 761-5.
11. Riley WT, Pilkonis P, Cella D. Application of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) to Mental Health Research. The
journal of mental health policy and economics 2011; 14: 201-8.
12. Eisenstein EL, Diener LW, Nahm M, Weinfurt KP. Impact of the Patient-Reported Outcomes Management Information System (PROMIS) upon the design and operation of multi-center clinical trials: a qualitative research study. Journal of medical systems 2011; 35: 1521-30. 13. Dampier C, Jaeger B, Gross HE, Barry V, Edwards L, Lui Y, et al. Responsiveness of PROMIS(R)
Pediatric Measures to Hospitalizations for Sickle Pain and Subsequent Recovery. Pediatric
blood & cancer 2016; 63: 1038-45.
14. Howell CR, Thompson LA, Gross HE, Reeve BB, DeWalt DA, Huang IC. Responsiveness to Change in PROMIS((R)) Measures among Children with Asthma: A Report from the PROMIS((R)) Pediatric Asthma Study. Value Health 2016; 19: 192-201.
15. Recht M, Konkle BA, Jackson S, Neufeld EJ, Rockwood K, Pipe S. Recognizing the need for personalization of haemophilia patient-reported outcomes in the prophylaxis era.
Haemophilia 2016; 22: 825-32.
16. Bullinger M, Globe D, Wasserman J, Young NL, von Mackensen S. Challenges of patient-reported outcome assessment in hemophilia care-a state of the art review. Value in Health 2009; 12: 808-20.
17. Williamson P, Altman D, Blazeby J, Clarke M, Gargon E. Driving up the Quality and Relevance of Research Through the Use of Agreed Core Outcomes. Journal of Health Services Research
& Policy 2012; 17: 1-2.
18. Bullinger M, Anderson R, Cella D, Aaronson N. Developing and evaluating cross-cultural instruments from minimum requirements to optimal models. Quality of Life Research 1993; 2: 451-9.
19. Beaton DE, Bombardier C, Guillemin F, Ferraz MB. Guidelines for the process of cross-cultural adaptation of self-report measures. Spine 2000; 25.
20. Mannucci PM, Roberts HR. Uncertain times for research on hemophilia and allied disorders.
Journal of Thrombosis and Haemostasis 2005; 3: 423-.
21. Plug I, van der Bom JG, Peters M, Mauser-Bunschoten EP, de Goede-Bolder A, Heijnen L, et
al. Thirty years of hemophilia treatment in the Netherlands, 1972-2001, 2004.
22. Triemstra AH, Smit C, HM VDP, Briet E, Rosendaal FR. Two decades of haemophilia treatment in the Netherlands, 1972-92. Haemophilia 1995; 1: 165-71.
23. Wyrwich KW, Krishnan S, Auguste P, Poon JL, von Maltzahn R, Yu R, et al. Changes in health-related quality of life with treatment of longer-acting clotting factors: results in the A-LONG and B-LONG clinical studies. Haemophilia 2016; 22: 6.
24. Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood 2014; 123: 317-25.
25. Powell JS, Pasi KJ, Ragni MV, Ozelo MC, Valentino LA, Mahlangu JN, et al. Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. The New England journal of
medicine 2013; 369: 2313-23.
26. Wallander JL, Varni JW. Effects of pediatric chronic physical disorders on child and family adjustment. Journal of child psychology and psychiatry, and allied disciplines 1998; 39: 29-46.
27. Haverman L, Van Oers HA, Limperg PF, Hijmans CT, Schepers SA, Sint Nicolaas SM, et al. Implementation of Electronic Patient Reported Outcomes in Pediatric Daily Clinical Practice: The KLIK Experience. Clinical Practice in Pediatric Psychology 2014; 2: 50-67.
28. Haverman L, Engelen V, van Rossum MA, Heymans HS, Grootenhuis MA. Monitoring health-related quality of life in paediatric practice: development of an innovative web-based application. BMC Pediatr 2011; 11.
29. Young NL, Bradley CS, Blanchette V, Wakefi eld CD, Barnard D, Wu JK, et al. Development of a health-related quality of life measure for boys with haemophilia: the Canadian Haemophilia Outcomes--Kids Life Assessment Tool (CHO-KLAT). Haemophilia 2004; 10 Suppl 1: 34-43. 30. von Mackensen S, Bullinger M, Haemo-Qo LG. Development and testing of an instrument
to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-QoL).
Haemophilia 2004; 10 Suppl 1: 17-25.
31. van Staa A, Sattoe JN. Young Adults’ Experiences and Satisfaction With the Transfer of Care.
J Adolesc Health 2014.
32. Plug I, Peters M, Mauser-Bunschoten EP, de Goede-Bolder A, Heijnen L, Smit C, et al. Social participation of patients with hemophilia in the Netherlands. Blood 2008; 111: 1811-5. 33. Schrijvers L, Beijlevelt-Van der Zande M, Peters M, Lock J, Cnossen M, Schuurmans M,
et al. Achieving self-management of prophylactic treatment in adolescents: The case of
227
haemophilia. Patient Education and Counseling 2016; 99: 1179-83.
34. Bolton-Maggs PH. Transition of care from paediatric to adult services in haematology. Arch
Dis Child 2007; 92: 797-801.
35. Breakey VR, Blanchette VS, Bolton-Maggs PH. Towards comprehensive care in transition for young people with haemophilia. Haemophilia 2010; 16: 848-9.
36. Geerts E, van de Wiel H, Tamminga R. A pilot study on the effects of the transition of paediatric to adult health care in patients with haemophilia and in their parents: patient and parent worries, parental illness-related distress and health-related Quality of Life.
Haemophilia 2008; 14: 1007-13.
37. Wood DL, Sawicki GS, Miller MD, Smotherman C, Lukens-Bull K, Livingood WC, et al. The Transition Readiness Assessment Questionnaire (TRAQ): its factor structure, reliability, and validity. Academic pediatrics 2014; 14: 415-22.
38. Kazak AE. Pediatric Psychosocial Preventative Health Model (PPPHM): Research, practice, and collaboration in pediatric family systems medicine. Families, Systems, & Health 2006; 24: 381-95.
39. Kazak AE, Prusak A, McSherry M, Simms S, Beele D, Rourke M, et al. The Psychosocial Assessment Tool (PAT)©: Pilot data on a brief screening instrument for identifying high risk families in pediatric oncology. Families, Systems, & Health 2001; 19: 303-17.
40. Wallander JL, Varni JW. Adjustment in children with chronic physical disorders: programmatic research on a disability-stress-coping model. 1992.
41. Crosby LE, Joffe NE, Reynolds N, Peugh JL, Manegold E, Pai ALH. Psychometric Properties of the Psychosocial Assessment Tool-General in Adolescents and Young Adults With Sickle Cell Disease. Journal of Pediatric Psychology 2016; 41: 397-405.
42. Pai ALH, Patiño-Fernández AM, McSherry M, Beele D, Alderfer MA, Reilly AT, et al. The Psychosocial Assessment Tool (PAT2.0): Psychometric Properties of a Screener for Psychosocial Distress in Families of Children Newly Diagnosed with Cancer. Journal of
pediatric psychology 2008; 33: 50.
43. Torres-Ortuno A, Cuesta-Barriuso R, Nieto-Munuera J. Parents of children with haemophilia at an early age: assessment of perceived stress and family functioning. Haemophilia 2014; 20: 756-62.
44. Beeton K, Neal D, Watson T, Lee CA. Parents of children with haemophilia, a transforming experience. Haemophilia 2007; 13: 570-9.
45. Bullinger M, von Mackensen S, Fischer K, Khair K, Petersen C, Ravens-Sieberer U, et al. Pilot testing of the ‘Haemo-QoL’ quality of life questionnaire for haemophiliac children in six European countries. Haemophilia 2002; 8 Suppl 2: 47-54.
46. Limperg P, Peters M, Gibbons E, Coppens M, Valk C, Grootenhuis M, et al. Themes in daily life of adolescents and young adults with congenital bleeding disorders: a qualitative study.
Haemophilia 2016; 22: e330-e3.
47. Spilsbury M. Models for psychosocial services in the developed and developing world.
Haemophilia 2004; 10: 25-9.
48. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19: e1-e47.
49. Garcia-Dasi M, Torres-Ortuno A, Cid-Sabatel R, Barbero J. Practical aspects of psychological support to the patient with haemophilia from diagnosis in infancy through childhood and adolescence. Haemophilia 2016; 22: e349-58.
50. Cassis FRMY. Psychosocial Care for People with Hemophilia. Treatment of Hemophilia, 2007. 51. Kazak AE, Rourke MT, Alderfer MA, Pai A, Reilly AF, Meadows AT. Evidence-based Assessment,
Services Across Treatment. Journal of Pediatric Psychology 2007; 32: 1099-110.
52. Khair K, Holland M, Carrington S. Social networking for adolescents with severe haemophilia.
Haemophilia 2012; 18: e290-e6.
