Linköping University Medical Dissertations No.

1295

Aspects of Health-Related
Quality of Life
Associations with psychosocial and biological factors,
and use as patient-reported outcome
in routine health care

Evalill Nilsson

Department of Social and Welfare Studies &

Division of Community Medicine, Department of Medical and Health Sciences
Linköping University, Sweden

Linköping 2012
Evalill Nilsson, 2012

Published articles have been reprinted with the permission of the copyright
holder.

Printed in Sweden by LiU-Tryck, Linköping, Sweden, 2012

ISBN 978-91-7519-958-0
ISSN 0345-0082
 To Ulf, Marcus & Oscar

Allting är svårt innan det är enkelt

 Contents

CONTENTS

ABSTRACT ............................................................................................................... 1

LIST OF PAPERS ..................................................................................................... 3

ABBREVIATIONS ................................................................................................... 5

INTRODUCTION .................................................................................................... 7
The concept of Health-Related Quality of Life ............................................. 7
Determinants of Health-Related Quality of Life ........................................ 12
Models of Health-Related Quality of Life ................................................ 13
Health-Related Quality of Life as a determinant of mortality ............... 15
Measures of Health-Related Quality of Life ............................................... 19
EQ-5D .......................................................................................................... 20
SF-36 ............................................................................................................ 22
Health-Related Quality of Life as patient-reported outcome in routine
health care ........................................................................................................ 24
Usefulness of measures of Health-Related Quality of Life..................... 25
Aims of the thesis ............................................................................................ 28

METHODS .............................................................................................................. 29
Papers I and II .................................................................................................. 29
Paper III ............................................................................................................ 32
Paper IV ............................................................................................................ 34

RESULTS ................................................................................................................. 36
Associations of Health-Related Quality of Life with psychosocial and
biological factors ............................................................................................. 36
Use of Health-Related Quality of Life as a patient-reported outcome in
routine health care........................................................................................... 39
Contents

DISCUSSION ......................................................................................................... 43
Associations of Health-Related Quality of Life with psychosocial and
biological factors ............................................................................................. 43
Use of Health-Related Quality of Life as patient-reported outcome in
routine health care........................................................................................... 46
Measurement of Health-Related Quality of Life as an innovation ........ 49
Methodological discussions .......................................................................... 51
Summary .......................................................................................................... 55
Conclusions ...................................................................................................... 56
Future directions ............................................................................................. 57

ACKNOWLEDGEMENTS.................................................................................... 58

REFERENCES ......................................................................................................... 59
 Abstract

ABSTRACT
Background Health-related quality of life (HRQoL) is increasingly recognised
as an important patient-reported outcome in health care research. However,
the use is still restricted and several questions remain about the value and
feasibility of using measures of HRQoL in routine health care. The general
aims of the thesis were therefore to increase the understanding of these issues
by studying 1) associations of HRQoL with psychological and biological
factors, 2) comorbidity adjustments of HRQoL measurement results, and 3) the
patient-perceived value and feasibility regarding the use of measures of
HRQoL as patient-reported outcome in routine health care.

Methods Three different data sets were used; baseline data (questionnaire,
anthropometric, and biological) from the ongoing Life conditions, Stress, and
Health Study (n=1007, papers I and II), data from a population survey from the
County Council of Östergötland in combination with data from two national
Swedish registries, the National Inpatient Register and the Causes of Death
Register (n=6086, paper III), and data (questionnaire) from the multicentre
Swedish Health Promoting Hospitals Network Health outcome assessment
project (n=463, paper IV). The HRQoL measures used were the SF-36 and the
EQ-5D. Statistical methods include variance, correlation and regression
analyses.

Results Psychological resources (Self-esteem, Sense of Coherence, and

Perceived Control) as well as psychological risk factors (depressive mood)
were found to relate independently to HRQoL (SF-36) in the expected
directions (positive relations for resources and negative relations for risk
factors), but with fewer sex differences than expected (Paper I). Low HRQoL
(SF-36) was found to relate to higher levels of inflammatory biological factors
(C-reactive protein, Interleukin-6, and MatrixMetalloProteinase-9), and,
especially regarding Interleukin-6, many association remained significant,
though attenuated, after adjustment for factors of known importance to
HRQoL (age, sex, disease, lifestyle and psychological factors) (Paper II). A
new comorbidity index, the Health-related Quality of Life Comorbidity Index
(HRQL-CI), explicitly developed for use in HRQoL outcomes studies, showed
higher explanatory power (higher R2 values) than the commonly used
Charlson Comorbidity Index (CCI) regarding impact of comorbidity on

1
Abstract

HRQoL (SF-36 and EQ-5D). However, regarding mortality the CCI

discriminated better between those who died within a year from answering
the HRQoL questionnaires, died within ten years, or who were still alive after
ten years. This result is in line with the CCI’s original purpose as a mortality
predictor. Using morbidity data from mandatory, highly valid national health
data bases was found to be useful in a large study of this kind, where using
data from medical records might be impractical. (Paper III). Using measures
of HRQoL as patient-reported outcome measures in routine health care was
regarded as valuable by the majority of the patients in the Health outcome
assessment project. A new concept was introduced, respondent satisfaction,
and the respondent satisfaction summary score was in most cases equal, i.e.
SF-36 and EQ-5D were found to be quite similar regarding the cognitive
response process (understanding and responding to the items in the EQ-5D and
the SF-36) and patient-perceived content validity (if EQ-5D and SF-36 gave
patients the ability to describe their health in a comprehensive way) (Paper
IV).

Conclusions The four papers investigated different aspects of HRQoL that are
important for the implementation of the use of measures of HRQoL within the
health care system. In conclusion, 1) the use of measures of HRQoL to identify
patients with low HRQoL for further health promoting interventions might be
supported on a psychological (psychological resources are related to better
HRQoL) and biological basis (low HRQoL being an important sign of
increased biological vulnerability), 2) a comorbidity index specifically aimed
to adjust for comorbidity in patient HRQoL outcomes studies was found to be
valid in a normal population (that might serve as a reference population in
future studies), and 3) patients perceived the use of measures of HRQoL to be
valuable and feasible in routine health care, and questionnaire length and ease
of response were not found to be crucial arguments in the choice between SF-
36 and EQ-5D. Hence, in their own way, they all and together, contribute to
removing obstacles in the implementation process of using patient-reported
outcome measures in the health care system for quality improvement.

2
 List of Papers

LIST OF PAPERS
Paper I
Nilsson & Kristenson (2010). Psychological factors related to physical, social,
and mental dimensions of the SF-36: a population-based study of middle-aged
women and men. Patient Related Outcome Measures 1: 153-164

Paper II
Nilsson, Garvin, Ernerudh & Kristenson. Associations between SF-36 and
inflammatory biomarkers CRP, CXCL8, IL-1β, IL-6, IL-10, and MMP-9 in a
normal middle-aged Swedish population.

Paper III
Nilsson, Borgstedt Risberg, Orwelius, Unosson, Sjöberg & Kristenson. Impact
of comorbidity on health-related quality of life; a population-based study
using the Charlson Comorbidity Index and the new Health-Related Quality of
Life Comorbidity Index, with data from the Swedish National Inpatient
Register.

Paper IV
Nilsson, Wenemark, Bendtsen & Kristenson (2007). Respondent satisfaction
regarding SF-36 and EQ-5D, and patients’ perspectives concerning health
outcome assessment within routine health care. Quality of Life Research 16:1647-
54

3
List of papers

4
 Abbreviations

ABBREVIATIONS
ANOVA Analysis of Variance
BMI Body Mass Index
BP Bodily Pain
CCI Charlson Comorbidity Index
CES-D Center for Epidemiologic Studies Depression scale
CRP C-reactive protein
EQ-5D EuroQol - 5 Dimensions
FIT Feedback Intervention Theory
GH General Health
IL Interleukin
HPA Hypothalamus-Pituitary-Adrenal
HPH Health Promoting Hospitals
HRQL-CI Health-Related Quality of Life - Comorbidity Index
HRQoL Health-Related Quality of Life
ICD International Classification of Diseases and causes of death
LSH Life conditions, Stress and Health
MCS Mental Component Scale
MH Mental Health
MMP-9 Matrixmetalloproteinase – 9
NHP Nottingham Health Profile
PCS Physical Component Scale
PF Physical Functioning
QoL Quality of life
RE Role functioning – Emotional
RP Role functioning – Physical
SF Social Functioning
SF-36 Short Form - 36
SIP Sickness Impact Profile
SOC Sense of Coherence
SRH Self Rated Health
TNF Tumour Necrosis Factor
VAS Visual Analogue Scale
VT Vitality
WHO World Health Organization

5
Abbreviations

6
 Introduction

INTRODUCTION

The concept of Health-Related Quality of Life

Health-related quality of life (HRQoL) is a term that is being increasingly used

in the medical scientific literature. A literature search using the search term
“health-related quality of life” yielded 18812 hits on the 1st January 2012 (Table
1). There is an increase both in the number of articles about studies using
HRQoL as patient-reported outcome (the patients’ view of their health and the
results of the care given) and in articles discussing the concept in different
ways, including guides about how to choose the proper HRQoL measure.

Although numerous studies claim to have measured HRQoL, their authors do

not always explain what it is the term connotes (stands for). Mostly the
authors let HRQoL denote (refer to) the measures used, or they just use the
term without offering much of an explanation, as if it were common
knowledge and not in need of further clarification.

Table 1. Number of scientific articles found in a literature search performed on the 1st
January 2012, using the search term “health-related quality of life” (title, abstract,
keyword).
Time period Number of hits
1979 and before 0
1980-1989 15 (the first in 1982)
1990-1999 1695
2000 and after 17102
whereof in 2010 2110
whereof in 2011 2511
In total on the 1st January 2012 18812

The term HRQoL is a combination of two other terms, namely Health and
Quality of Life (QoL). Numerous definitions of both these terms have been
presented over the years. Therefore, health is a vague term, and/or a term with
various meanings, i.e. it has several connotations. It is also a general term since

7
Introduction

it lacks a reference, i.e. has no denotation [1]. However, two main views on
health can be clearly distinguished, the biomedical and the humanistic. The
biomedical view can today be said to be dominated by Christopher Boorse’s
biostatistical definition [1]. In short, according to this definition health
connotes body and mind functioning according to, for human beings, typical,
statistically normal patterns, i.e. having no biomedical dysfunction. The most
prominent of the humanistic views is the holistic view, where health often
connotes well-being or ability (under reasonable circumstances) to function
and achieve vital goals [1], irrespectively of having a biomedical dysfunction
or not.

The internationally most well-known and influential definition of health is the

WHO (World Health Organization) definition 1 from 1948 which states that
health is “a state of complete physical, mental and social well-being, and not merely
absence of disease or infirmity”. To include not only physical but also mental and
social aspects provides a holistic view of health that was considered quite
radical at the time, not at least because these aspects were regarded as going
beyond the responsibility of the health care system.

One demand that can be made on a definition is that it should be able to

operationalise, i.e. be able to measure [2]. To measure health according to the
WHO definition, traditional medical survival and disease specific data were
not sufficient. The emphasis of the definition of health on well-being led
researchers to the QoL research area, where measures were already available.
In ordinary (Swedish) dictionaries the concept of HRQoL is not
acknowledged; nor, in many cases, is the concept of health. However, QoL is
defined as non-material, positive contents of life [3]. While health is
considered an ancient concept, the term QoL was coined in the early twentieth
century, as a political term [4]. Soon a need for accurate measures of QoL
emerged, which led to the development of several QoL questionnaires. In the
1990s, WHO decided to develop an international measure of QoL, the
WHOQOL-100, and some years later also the shortened WHOQOL-BREF [5].
During this work, the preceding process of concept clarification resulted in the
WHO definition of QoL as “an individual's perception of their position in life in the
context of the culture and value systems in which they live and in relation to their
goals, expectations, standards and concerns. It is a broad ranging concept affected in a

1Preamble to the Constitution of the World Health Organization as adopted by the International Health
Conference, New York, 19 June - 22 July 1946; signed on 22 July 1946 by the representatives of 61 States (Official
Records of the World Health Organization, no. 2, p. 100) and entered into force on 7 April 1948. The definition has
not been amended since 1948.

8
 Introduction

complex way by the person's physical health, psychological state, personal beliefs,
social relationships and their relationship to salient features of their environment”.

Brülde and Tengland have discussed the connection between health and QoL,
and argue for differentiating between the concepts. Even if both concepts are
related to well-being, and both are often improved when well-being is
improved, there may still be improvements that are not health-related, e.g. in
the areas of love and work. Furthermore, even if the most important
associations between health and QoL are causal and a better health will often
lead to better QoL, the opposite might not hold true [1]. In his book “Teorier om
livskvalitet” (Theories on quality of life) Brülde further discusses how QoL, just
like health, has several connotations [6]. Patients themselves, in their role as
respondents to different measures of health status, QoL, and HRQoL, have
been reported to consider health status and QoL to be distinct constructs,
including more mental health aspects in the latter than in the former [7].

How did we move from the two terms Health and Quality of life to the
compound term Health-related quality of life? Many researchers, in the 1980s as
well as today, have reported about the confusion about the use of the terms [4,
8]. According to Guyatt et al, the term HRQoL was introduced to solve the
problem that QoL denotes a variety of medical as well as non-medical things.
The term HRQoL was intended to narrow the focus to the effects of health,
illness and treatment on QoL [9]. As a renowned researcher in the field, John E
Ware, puts it [8, 10]: “To distinguish the new multidimensional conceptualisation of
health from the old (i.e. health in terms of death and disease), the term quality of life
was adopted. It became fashionable to lump all measures that defines health beyond
traditional indicators of biological functioning into a single category of quality of life
measures. However, quality of life as traditionally defined is a much broader concept
than health. Quality of life encompasses standard of living, quality of housing and
neighbourhood, job satisfaction, health, and other factors. The goal of the health care
system is to maximize the health component of quality of life, i.e. health status, also
referred to as health-related quality of life.”
Therefore, according to Ware, the terms HRQoL and health (when defined
as physical, mental and social well-being and functioning) can be regarded as
synonyms.

How do researchers using measures of HRQoL in their research define the

term HRQoL? When the term was quite new researchers would presumably
have been very accurate in describing what they meant by it, so looking at the

9
Introduction

earliest articles from the 1980s might provide the answer. Five of the articles
contained brief mentions in the abstract about definitions and/or use of the
term HRQoL. Two examples:

• “Quality of life is a broad concept that incorporates all aspects of an

individual's existence. Health-related quality of life is a subset relating
only to the health domain of that existence.”[11]
• “HQOL is a multi-dimensional concept that includes the physical,
psychological, and social functioning associated with an illness or its
treatment.”[12]

This observation, together with the content of the other abstracts implies that
the concept was not regarded as altogether new. Moreover, in the full-text
articles an explanation was not always present. One example:

• “Over the last 15 years, medical and health services researchers have
developed new ways to assess health status quantitatively. These
measures are often called quality of life measures. Because they are used
exclusively to evaluate health status, the more descriptive health-related
quality of life is preferred.”[13]

As a contrast the latest articles found using the term “health-related quality of
life” were also collected. On the 1st January 2012, 29 articles had already been
registered for the year 2012. In only one of these abstracts was the meaning of
HRQoL mentioned. Moreover, in the full-text articles it often seems to be
taken for granted that the definition of HRQoL is common knowledge. A
striking feature is that measures of HRQoL are often mentioned by name
directly in abstracts, without stating that they measure HRQoL. Could the
definition of HRQoL in many cases perhaps have become an operational
definition (describing how to decide if the phenomenon exists instead of
stating the characteristics of the phenomenon), i.e. your HRQoL is low because
you score low on the measure of HRQoL, and vice versa? Perhaps HRQoL has
in many people’s eyes become synonymous with that which we measure with
the common measures of HRQoL used today?

The impact of disease (and treatments) on QoL seems to be imperative in

many definitions and descriptions of HRQoL, probably due to its origin in
patient-related studies. Does that imply that, in many cases, HRQoL is in fact
DRQoL, i.e. disease-related quality of life? Is seeing HRQoL as impact of

10
 Introduction

disease really compatible with seeing health and HRQoL as synonyms

(provided that you see health as more than the absence of disease)? However,
HRQoL is also used outside the context of disease, e.g. as a subjective measure
in population studies. Does this custom in fact imply two different
connotations of HRQoL? That is, as an impact of disease vs. as well-being and
functioning in general, independent of any disease?

The lack of consensus about a definition of the term HRQoL is sometimes

regarded as a problem. Though some call for a universal definition of HRQoL,
most researchers seem to use the term in their articles without reflecting upon
its meaning, and also sometimes use the terms health (or health status), QoL
and HRQoL interchangeably. It is probably as difficult to find a consensus
definition for HRQoL as it is for health (and quality of life), and maybe it
would not be necessary if everyone always clearly stated what they were
referring to, when using the term(s). In “Teorier om livskvalitet” Brülde calls
attention to the fact that within the health care system the term QoL is not
used in the traditional philosophical way, distinguishing between final (a goal,
e.g. happiness) and instrumental (a means to achieve your goal, e.g. money)
values. Instead the outcome perspective of the health care system has resulted
in “all” psychosocial factors indiscriminately being called QoL or HRQoL.
Consequently the concepts of QoL and health (defined holistically) tend to
become blurred. Furthermore, without being based on formal definitions and
well thought-out theories, final and instrumental values may without deeper
reflection become mixed into the same measure, which, Brülde claims, is often
the case today [6].

In the present thesis HRQoL is defined as physical, mental and social

wellbeing and functioning, in line with the comprehensive WHO definition of
health. HRQoL might then be seen as the patient-reported part of the WHO
definition, if absence of disease or infirmity is the profession-reported part,
based on medical diagnoses.

11
Introduction

Determinants of Health-Related Quality of Life

Determinants of HRQoL have been much studied, especially in patient-based

research. HRQoL is influenced by a number of sociodemographic,
psychosocial as well as lifestyle and biomedical factors. A related area of
interest is the observation that HRQoL itself may in turn be a determinant of
mortality.

Sociodemographic determinants
The impact of sociodemographic factors such as socioeconomic status,
ethnicity, marital status, sex, and age on HRQoL is now well established and
consequent [14]; low socioeconomic status, immigrant status, and
single/nonmarital status are all related to poorer HRQoL. However, one
problem is that many of these determinants are interrelated and may act as
proxies for each other; for example, ethnicity might be a proxy for
socioeconomic status. However, ethnicity has been shown to have an
(independent) association with HRQoL among persons of dissimilar ethnicity,
but sharing the same sociocultural context [15]. Furthermore, determinants
may have varied importance in different age periods [16], and it has been
shown that younger people have fewer problems in the physical than in the
mental dimensions of HRQoL, but for the elderly it is the other way around
[17].

Regarding sex, it is today recognised that women often receive lower scores on
measures of HRQoL than men [18]. One possible explanation is that men and
women think about different things when they assess their own health.
Women have been suggested to be more inclusive than men, or at least to put
different emphasis on things though including the same things. While men
tend to rate disease, lifestyle and function ability as most important, women
tend to give more weight to emotional factors that are not always disease-
related [19]. Another possibility is of course that women in fact have a lower
HRQoL, perhaps due to worse life conditions and/or a more vulnerable social
role (gender research) [20, 21]. Nevertheless, many studies of HRQoL only
adjust for the effect of sex, and differences between men and women are
seldom further explored.

12
 Introduction

Psychosocial determinants
Several types of psychosocial factors have been suggested to influence HRQoL
[14]. Psychosocial factors may be divided into extrinsic (social environment,
social support) and intrinsic (individual, psychological characteristics). The
latter, in turn, can be subdivided into 1) those resources that enhance health
and HRQoL, and 2) factors associated with increased risk of disease. Such risk
factors include negative emotions (e.g., anxiety and depression) and cognitions
(e.g., hopelessness and hostility), while coping ability, sense of coherence, and
perceived control over life are examples of resources [14]. Many studies have
shown that psychological resources are positively related to patients’ HRQoL,
while psychological risk factors are negatively related [22-31], but there are
few population-based studies [32-34].

Lifestyle and biomedical factors

Studies regarding the influence of lifestyle factors (i.e., smoking, physical
activity, etc) on HRQoL are still in dispute and no firm conclusions can be
made at present [35-40].

The presence of disease has, maybe self-evident for many people, repeatedly
been shown to have an inverse relation to HRQoL [17, 41-46], and medical
symptoms such as pain (which is probably the most common symptom in a
general population) are also known to relate to a poorer HRQoL [47, 48].
However, if the main objective of health care is to optimise the HRQoL for
each patient, it may not be that self-evident for presence of disease and
medical symptoms to invariably have a negative impact on HRQoL?

Models of Health-Related Quality of Life

In 1995, Wilson & Cleary developed a causal model of HRQoL [49]. This was
prompted by the need for a model that could be used in planning health care
interventions to improve patients’ HRQoL, indicating the relations between
the determinants as well as identifying them. The Wilson & Cleary model was
further revised by Ferrans et al in 2005 [50]. This revised model presents five
ordered domains of patient outcomes, from biological function (e.g. presence
of disease) via symptoms, functional status, and general health perceptions to
overall quality of life, implicating a one-way main causal relation. The
characteristics of the individual (demographic, biological, e.g. genetics, and

13
Introduction

psychological factors) as well as characteristics of the environment (social and

physical factors), are furthermore described to affect, in a one-way direction,
all of the five outcomes, thereby completing the model (Figure 1).

Figure 1. Causal model of HRQoL, revised by Ferrans et al (2005) from the original model by
Wilson & Cleary (1995). Reprinted with the permission of publisher John Wiley and Sons.

However, though claiming to be a model of HRQoL, the term is actually not

visible in the model. Instead the term used is QoL, which may be an example
of the confusion in the usage of the terms described earlier (chapter - The
concept of Health-Related Quality of Life). Furthermore, lifestyle factors are
not explicitly included in Characteristics of the individual, which may be the
most reasonable box to place them in.

The Wilson & Cleary model has furthermore been criticised for over-
emphasising the influence of what the authors refer to as health-related factors
(the factors in the central boxes) on QoL [51]. According to Anderson &
Burckhardt [51], such factors only have indirect effects on QoL, while
psychosocial factors exert direct effects, and therefore should be in the centre
of the model. Moreover, Anderson & Burckhardt raises the issue of QoL as a
suitable outcome for health care. If so interventions ought to address
psychosocial factors to a greater extent, in order to better achieve the goal of
improved QoL of patients. According to the authors, the medical interventions
of today, which are mainly directed towards disease symptoms and functional
ability, will only affect QoL if they first result in changes in self-perception,
perceived social support etc.

14
 Introduction

Though the best known, the Wilson & Cleary model is not the only model of
HRQoL. For example, Ashing-Giwa [52] argues that models of HRQoL should
have a stronger focus on ethnical and cultural differences than is the case
today. Valderas & Alonso [53] has presented a model based on the Wilson &
Cleary model together with the WHO classification systems ICD (International
Classification of Diseases and causes of death) and ICF (International
Classification of Functioning, disability and health). In their model the final
right box is actually changed from QoL to HRQoL, but also expanded to
contain other related outcomes, such as satisfaction with care and resilience
(coping ability, handling stress and illness). The intention behind the
development of this model was that it should constitute a conceptional basis to
support the choice of patient-reported outcome (as represented by the four
boxes Symptoms, Functional status, General health perceptions, and Health-
Related Quality of Life).

Health-Related Quality of Life as a determinant of

mortality

The final outcome of the Wilson & Cleary/Ferrans model is QoL (HRQoL).
However, low HRQoL has been shown to predict mortality [54-56], similarly
to what earlier was shown for low self-rated health (SRH) [57, 58], a term used
to denote a single-item measure of global health, in contrast to the use of
multi-dimensional, multi-item measures of HRQoL [59].

Regarding SRH, four main hypotheses exist to explain its ability to predict
mortality, even after adjustment for present disease [58].
• SRH catches symptoms from yet undiagnosed diseases and unmeasured
illness or specific co/multimorbidity concerns
• SRH measures the anticipated future health (health trajectories)
• low SRH is related to poorer health behaviour (including lifestyle
factors)
• SRH reflects pathological psychosocial stress

Are the same hypotheses applicable to the wider concept of HRQoL? If so, to
all dimensions or just some? While SRH allows the respondent to be as
inclusive as he or she wishes, most measures of HRQoL contain the
dimensions assumed by researchers and health professionals to be relevant for

15
Introduction

the patients (as further discussed in the chapter Measures of Health-related

Quality of Life).

Psychoneuroimmunology
Regarding the above hypothesis that low SRH (and low HRQoL?) predicts
mortality because it reflects psychosocial stress, knowledge from the field of
psychoneuroimmunology about behavioural-neural-endocrine-immune
system interactions [60], might shed some light on the matter. Psychosocial
stress and negative emotions are known to predict illness and mortality [61],
but they are also related to increased levels of inflammatory cytokines, e.g.
interleukin (IL)-1β and IL-6 [62, 63].

Interleukins
The name interleukin was originally given to cytokines secreted by, and acting
on, leukocytes. Cytokines are low molecular weight proteins secreted by cells
to regulate other cells, in either an autocrine (acting on the cell that secreted it),
paracrine (acting on nearby cells) or endocrine (acting on distant cells through
spreading via the blood circulation) fashion. Cytokines can be categorised in
families according to function or structure. They may affect both the innate
and the adaptive immune systems [64].

Interleukin (IL)-6 is a monomer made up of 184 amino acids and belongs

structurally to the hematopoetin family [64], and is secreted by T-cells,
macrophages and endothelial cells. Activators of the IL-6 gene expression
include IL-1β and Tumor Necrosis Factor (TNF) α [65]. Together these three
(IL-1β IL-6 and TNFα) are known as the pro-inflammatory cytokines [64].
However, they also seem to have anti-inflammatory qualities, and furthermore
seem to both up- and down-regulate each other [66, 67]. The facts that the
regulation of IL-6 seems very complicated and that elevated levels of IL-6 is
implicated in several diseases, such as cardiovascular disease, cancer, diabetes
mellitus/insulin resistance, and rheumatoid arthritis [68], imply a strong need
for the body to keep this potent interleukin under strict control. IL-6 induces,
among other things, the production of acute-phase proteins from the liver,
such as the C-reactive protein (CRP). CRP opsonises bacteria by binding to the
phosphorylcholine portion of lipopolysaccharides in the bacterial cell-walls. It
also activates the classical complement (C) cascade, by binding to cascade

16
 Introduction

factor C1q [64]. Though the effects of CRP in some instances can be regarded
as echoing those of IL-6, CRP and IL-6 also have their own properties.

Upon activation of the hypothalamus by the pro-inflammatory cytokines the

so called “sickness behaviour” is provoked, affecting, among other things,
sleep, eating behaviour and mood states, making a person experience feelings
of “sickness”, discomfort and low energy [69]. The hypothesis is that elevated
levels of the pro-inflammatory interleukins are meant to lead to behaviour
changes in order to keep the body out of danger until it has recovered, i.e. you
should crawl back to your cave and rest, not engage in new fights or
exhausting food searches. Interestingly, the same kinds of symptoms are
associated with low SRH [70, 71], which in turn is known to correlate with IL-
1β and/or IL-6 [70, 72, 73].

Furthermore, IL-1β and IL-6 activate the HPA (hypothalamus-pituitary-

adrenal)-axis, a system that is also known to be activated during stress,
leading to an increase in the cortisol production in the adrenal cortex. Cortisol,
in turn, has an anti-inflammatory effect, through inhibiting the production of
the pro-inflammatory interleukins. However, prolonged stress could
presumably lead to down-regulation of cortisol receptors, or otherwise
interfere with normal HPA axis/cortisol responses, with a subsequent chronic,
low-grade inflammation as a result [71, 74]. This inflammation is called low-
grade because the production of cytokines during prolonged stress does not
reach the same high level as during the response to microorganisms, rather it
stays at a maximum level of 3-5 times the normal. Though the stress reaction is
necessary for survival in acute stress situations, the pro-inflammatory effects
of a dysfunctional HPA-axis during prolonged stress are potentially harmful,
as elevated levels of cytokines are implicated in the pathogenesis of several
diseases (see above) and have been found to predict mortality in older people,
independently of the presence of disease [75, 76].

Inflammation and health-related quality of life

Studies so far about the relation between inflammatory biomarkers and
HRQoL have mainly been patient-based, and often relatively small. Besides
IL-1β and IL-6, other cytokines investigated in these studies are for example
IL-10, a general inhibitor of inflammatory reactions, and the pro-inflammatory
chemokine CXCL8 (chemokine (C-X-C motif) ligand 8, formerly known as IL-
8). Although some significant associations have been found for cytokines and
measures of HRQoL in some of the studies, the results are still inconclusive

17
Introduction

and no trend is discernible [77-87]. Similarly, inconclusive results have also

been found regarding the relation between HRQoL and CRP [83, 88-91].

Another inflammatory biomarker of theoretical interest since it has recently

been shown to have an association to all-cause mortality [92], is the matrix
metalloproteinase 9 (MMP-9), an extra-cellular matrix degrading enzyme.
MMP-9 has shown high activity in inflamed atherosclerotic plaques, implying
a role in plaque instability and ischemic cardiac disease [93-96]. The enzyme is
up-regulated by inflammation, and higher MMP-9 levels have been related to
poorer lifestyle and psychosocial status [97, 98], but it has not been studied in
the HRQoL context.

The first box in the causal Wilson & Cleary/Ferrans model of HRQoL is
Biological function. The content of this box is only generally described, but more
biologically detailed models are available. McCain et al have presented a
PsychoNeuroImmunology (PNI) framework to explain how psychological
stress and coping relate to health outcome (in this case quality of life,
psychosocial functioning, and physical health), via the neuroendocrine and
immune systems, in that order [99]. The N (both the HPA and the
Sympathetic-Adrenomedullary systems) and the I (interleukins etc.)
components are regarded as mediators, while the P component is seen as a
moderator. Just as in the Valderas & Alonso model, the framework is intended
to provide a guide for both interventions and measurement regarding chronic
and severe diseases, facilitating a holistic view of health and disease
management, as exemplified by McCain et al in the cases of cancer and HIV
(human immunodeficiency viral) disease.

18
 Introduction

Measures of Health-Related Quality of Life

Today, there is an abundance of so-called HRQoL-instruments (validated

questionnaires), either generic, i.e. measuring general health problems, or
disease-specific, i.e. measuring health issues of vital importance for a certain
disease or condition. The former allows the possibility of comparing different
patient groups, and may give answers to questions about the patient’s
situation that nobody has thought to ask, while the latter may be necessary to
cover all disease symptoms and functional limitations of already known
importance for a certain disease. However, it has been argued that this
distinction is actually less clear-cut, since many of the disease-specific
instruments contain generic domains as well [53].

Internationally well-known and widely used generic HRQoL-instruments

include the Quality of Well-Being Index (QWB) and the Sickness Impact
Profile (SIP) from the 1970s, the Nottingham Health Profile (NHP) and the
Quality of Life Index (QLI) from the 1980s, and the Medical Outcome Study
Short Form-36 (SF-36) and the EuroQol Index (now EQ-5D) from the 1990s.
Numerous disease-specific HRQoL-instruments exist, and will not be
expanded on here. ProQolid is an international free access database, which is
intended to provide an overview of existing patient-reported outcome
measures such as the HRQoL-instruments, and to facilitate the choice of
appropriate instruments (http://www.proqolid.org/). Articles guiding the
choice are also available [100-102].

The majority of HRQoL-instruments consist of predetermined health

dimensions, chosen by the researcher to cover the concept of HRQoL and to
get the patients’ view of their health situation, i.e. yield patient-reported
outcome. However, these instruments have been criticised for not being as
patient-centred as one would think, since a true patient-centred instrument
would let the patients themselves decide which dimensions were of
importance for them [103]. One example of such an instrument is the Schedule
for Evaluation of Individual Quality of Life (SEIQoL) [104].

The most used generic HRQoL-instruments in Sweden today are two of the
newer instruments, the EQ-5D and the SF-36. Older instruments, such as the
NHP and the SIP, are often considered to have comparatively more

19
Introduction

disadvantages, such as being lengthy, having binary response alternatives

(leading to low responsiveness), etc. However, the choice of instrument should
always depend on the context in which it is to be used.

EQ-5D

The EQ-5D (EuroQol 5 Dimensions) [105], formerly known just as EuroQoL

(the name of the European research group from five different countries,
including Sweden, that created the instrument), was initially developed to
create a summary index to use for health economics, comprising the five
dimensions considered most important to patients, four physically oriented
and one psychologically oriented. Originally, the EQ-5D was intended to be a
self-administered complement to other, more comprehensive HRQOL
instruments, but is nowadays increasingly used as a stand-alone instrument.
(http://www.euroqol.org)

The EQ-5D has two parts, one in which the respondent states his or her
present functional ability within each one of the five health dimensions, and
one in which the respondent rates his or her present general health on a
vertical scale from 1-100 (sometimes referred to as the EQ-5D thermometer).
The five health dimensions are mobility, self-care, daily activities, pain/discomfort,
and anxiety/depression.
Each dimension includes three statements, indicating no, some or severe
problems in that dimension. One of these statements is chosen for each of the
five dimensions, resulting in a total of 35=243 different combinations of
answers. Every combination has then received a “quality of life weight”,
which means that the combination has been valued in relation to full health
(using e.g. the Time Trade-Off method). The weighting procedure has
sometimes been criticised for using people from the general population for the
valuation procedure instead of persons in the actual health states [106]. The
reason for this criticism is that it is well known that healthy persons tend to
rate their quality of life for fictitious diseases lower than patients do, a
phenomena called response shift (adaption to the situation, coping; change of
internal standards) [107-110]. The population weights were meant to reflect
the opinion of the general tax payers (and future patients), since the EQ-5D
was created to allow for health economic analyses, but it could be argued that
patient-based valuations are more veridical, and they might be superior in
health outcome studies in routine health care [106].

20
 Introduction

Finally, a summary index value is calculated, for use in health economic

analyses.

Besides the index value, EQ-5D may be presented by using the five
dimensions directly, which gives the opportunity to see in which dimensions
the problems lie, as opposed to just using means values of the EQ-5D index.
Devlin et al have proposed the Pareto method to yield more useful
information in outcome studies, where using only the mean values of the
index value may hide important variation in the material [111]. The Pareto
method divides the change in each of the five dimensions into only
improvement, only worsening, no change, and undecided change (some
dimensions have improved, but others have deteriorated).

Concurrent criterion validity tests of the EQ-5D have shown an acceptable

correlation to the SF-36, while construct validity tests have shown that EQ-5D
discriminates in the expected way between different groups, e.g. with and
without disease. However, it might work less well in a population with a
lesser amount of disease severity [112]. The reliability has been tested using
the test-retest method, showing good stability [113, 114].

Besides its validity and reliability, the responsiveness of the instrument is vital
when it is used in outcome studies. EQ-5D is known to have ceiling and floor
effects (=too few and/or skewed response alternatives, leading to too many
respondents choosing the best or worst response alternative, respectively).
Since you only can choose between no, moderate or severe problems, you may
well have improved, but not enough to change from moderate to no problem.
To improve responsiveness and overcome the ceiling and floor effects the
EuroQol group has developed a new, improved version, the EQ-5D-5L, with
five response alternatives instead (no, slight, moderate, severe, or extreme
problems). The EQ-5D-5L has been shown to be valid and reliable, but studies
confirming the improved responsiveness have still not been published
(January 2012) [115]. Correspondingly, the original version is now called EQ-
5D-3L. Additionally, a version for children has been developed, the EQ-5D-Y,
for children 7 to 12 years old [116, 117].

A novelty is the use of so called dimension extensions (or bolt-ons), where extra
items of relevance to a specific patient group are added to the five original
ones. In general, the use of combinations of generic and disease specific

21
Introduction

HRQOL-instruments is increasing, allowing a more complete picture of the

patient’s situation to be obtained.

SF-36

The SF-36[10], which was developed in the United States of America, is

probably the internationally most used generic measure. It originates from a
more comprehensive instrument used in the RAND Corporation (an American
non-profit research organisation) Medical Outcomes Study, MOS
(http://www.rand.org/health/surveys_tools/mos.html), and which has 40
subscales and more than 100 items, and is intended to cover the WHO
definition of health. However, to allow the instrument to be used in routine
health care, a shorter and more user-friendly instrument was created, with 36
items in eight subscales, chosen among other things for their strong correlation
to disease. The still relatively large number of items was considered necessary
to cover all important aspects in each subscale. The eight subscales are

• PF Physical Functioning
• RP Role functioning - Physical
• BP Bodily Pain
• GH General Health
• VT Vitality
• SF Social Functioning
• RE Role functioning – Emotional
• MH Mental Health

The eight subscales are divided into physically (PF, RP, BP & GH) or
psychosocially oriented scales (VT, SF, RE & MH), sometimes brought
together into two summary scores (initially created using factor analysis), the
PCS (Physical Component Scale) and the MCS (Mental Component Scale),
respectively [118]. However, the principle behind these algorithms has been
criticised [119]. PCS will receive high scores not only if levels on the physically
oriented scales are high, but also if levels are very low on the psychosocially
oriented scales. Thus, if the psychosocially oriented scales have very low
levels, a high PCS might reflect this fact instead of genuine high levels for the
physically oriented scales. The reverse is true for MCS. Therefore it is
important to always interpret PCS and MCS together with all eight subscales.
Furthermore, it has recently been shown that three summary scores are

22
 Introduction

superior to two [120]. It is the three role function subscales, RP, SF, and RE,
that form a third summary score, the RCS (Role Component Summary), and to
form a third summary score also improves the performance of the remaining
PCS and MCS summary scores. The above study setting was the general
population in Japan and it is still to be investigated whether three summary
scores also outperform the traditional two summary scores in other
populations.

Construct validity tests of the SF-36 have shown good or acceptable ability to
distinguish the healthy from the sick, and to discriminate between physical
and psychiatric disease groups, major common disease groups and disease
stages and severity. The structure of the SF-36 allows for further reliability
testing besides test-retest (which has shown acceptable stability). Testing the
internal consistency of the SF-36 has yielded Cronbach α>0.70 for all subscales,
and some of them even reached 0,90 or more, a level usually required for
analyses on the individual level [113, 114, 121, 122]. For the new improved SF-
36 version 2, even more subscales have acquired α>0.90, and the
responsiveness is also enhanced (fewer ceiling and floor effects), since some of
the items have changed from two to five response levels (in role functioning
subscales RP and RE) [123].

The SF-36 belongs to a family of instruments that besides the SF-36 currently
include the SF-12 (and SF-12 version 2), SF-8, and SF-6D. These instruments
are appropriate in different research situations (according to the research
question, sample size, population characteristics etc.). The SF-6D, like the EQ-
5D, yields an index value that may be used for health economics [124].
Furthermore, there is an algorithm for SF-6D that may be applied to SF-36
datasets as well, i.e. you do not have to use the actual SF-6D to obtain an index.
It should be kept in mind that comparative studies have shown that the EQ-5D
and the SF-6D do not produce identical results [125, 126].

Both the SF-36 and the EQ-5D are, in research situations, known to be useful as
health outcome measures, but the question remains whether they are as good
in routine health care, especially if used for the purpose of improvements in
health care, and not only for follow-up or health economics. Will these, and
other, instruments be able to help in identifying patients whose HRQoL has
not improved, or even has deteriorated, despite the health care given, and who
is in need of further (e.g. after a seemingly successful surgical procedure) or
altered (e.g. during the lifelong management of diabetes) interventions?

23
Introduction

Health-Related Quality of Life as patient-

reported outcome in routine health care

Health care outcomes research came into fashion in the United States in the
early 1980s, as the more academic counterpart to health policy research [127].
Outcomes research studies “the impact of health care on the health outcomes of
patients and populations” [127]. Hence, this research spans from developing new
health-related outcome measures (beyond traditional outcome measures such
as hospital readmission rates, laboratory test results, treatment complications
and death) to implementation of the results of outcomes research in the health
care system. The latter means that the research setting is the real-life world as
opposed to controlled clinical trials, i.e. effectiveness rather than efficacy
research, to find out which medical treatments actually worked, and in which
situations. Furthermore, variations in medical practice have been discovered
that cannot be explained by known patient characteristics or by the medical
resources in a community, and traditional measures have been rendered
insufficient when the treatment goal was the improvement of HRQoL rather
than the (unattainable) cure of a disease, as in patients with multiple chronic
conditions and functional limitations. The final goal is the creating of highly
functional Outcomes Management Systems within health care [128, 129].

Casemix problems, especially co/multimorbidity

Measurement of HRQoL was considered a key factor and a catalytic element
in the implementation of Outcomes Management [128], making the
interpretation of the results of these measurements a crucial step in the
implementation process. An important issue when interpreting the results of
HRQoL measurements, and especially when using generic instruments, is the
casemix-problem. Other factors, such as sex, age, disease severity, disease
history, comorbidity, socioeconomic status, and social support, are likely to
influence the result, and therefore adjustments are necessary [100, 130-132].

Regarding co/multimorbidity there are a number of adjustment methods [133,

134]. Rather uncomplicated ways are to simply recognize the presence of
multi-morbidity or to add up the number of diseases, but these methods do
not take into consideration that diseases may differ in severity and health
impact. To address these aspects comorbidity indicies, giving different
weights to different diseases and conditions, were developed. In mortality risk

24
 Introduction

studies a common way to adjust for comorbidity is to use the Charlson

Comorbidity Index (CCI) [135, 136], but in HRQoL outcome studies the CCI
performs less well [137], and it has been criticised for not including all
potentially important conditions [138]. Therefore, other solutions have been
presented, such as having a single comorbidity measure but with different
algorithms depending on the nature of the outcome [138], or developing
comorbidity indices for explicit use in HRQoL studies, like the Health-Related
Quality of Life Comorbidity Index (HRQL-CI), which is still in need of further
validation [139]. Although the terms co- and multimorbidity are sometimes
used interchangeably, a difference is that the latter takes into consideration all
of the patient’s diseases, while the former is used for all of the patient’s
diseases besides the disease of interest, the index disease [140]. Furthermore, it
has been suggested that diseases related to the index disease, i.e.
complications, should not be regarded as comorbid diseases [138].

A related issue in interpreting the results of HRQoL measurements is how to

decide what is the minimum change in the score of the HRQoL instrument
that will be perceived by patients as important, the so-called Minimal
Important Difference (MID), also known as Minimal Clinically Important
Difference (MCID), Minimal Important Change (MIC), etc. [141-143]. Probably,
different study populations and contexts will require different MID’s for one
and the same HRQoL-instrument, but more research is needed in the area.

Usefulness of measures of Health-Related Quality of

Life

Higginson & Carr [144] have presented the following motives for using
HRQoL measures in routine health care:
• identifying and prioritising problems
• facilitating communication
• screening for hidden problems
• facilitating shared clinical decision-making
• monitoring changes or responses to treatment

There are a small but increasing number of scientific articles being published
regarding evidence for the usefulness of measures of HRQoL for health care
improvements [130, 144-153], and especially in the field of cancer. This is not
very surprising, since the number of people surviving cancer is greater than

25
Introduction

ever, and they will have to live with the sequelae of both the disease and the
treatment, perhaps for the rest of their lives, and this will often affect their
health-related quality of life and functional ability. The use of measures of
HRQoL has proved to be beneficial for the patient - health professional
encounter and communication, e.g. if doctors have the results of the HRQoL
measurement available during the patient encounter it allows the most
important current health issues for the patient to be directly addressed [130,
144-153]. Patients are also reported to feel more empowered maybe because
the use of this kind of measurements encourages them to reflect upon their
situation, thereby increasing self-awareness, and it also indicates that the
health care professionals will be interested in listening to their problems [154].

Evidence for its ability to enhance HRQoL is still poor, and more and better
designed studies are needed. Some impact on health that have been reported
in organisations using patient-reported outcome measurement are lower
incidence of pain at four-week follow-up (higher prescription of analgesics)
and lower incidence of depression at six-month follow-up when using early
screening for mental illness [145]. Others have reported discovering unknown
problems in their patient groups, such as pain being a common symptom
among patients with chronic obstructive pulmonary disease [155-157].
Suggested explanations to this lack of evidence are that the medical treatments
may already be optimal or only small improvements possible, and therefore
the responsiveness of the chosen HRQoL-instruments is crucial; that the
results of the measurements are difficult to interpret; or that the results are not
presented to the “right” persons, i.e. those responsible for the treatment plans,
often the physicians [158]. It is important that the results are presented in a
way that is easy to understand and draw conclusions from. For example, to
present the result from before-and-after measurements in the form of Pareto
changes (as described above for the EQ-5D) instead of just mean values would
facilitate identifying the nature of the patient’s problem.

In an overview of RCT:s (Randomised Clinical Trials) including the SF-36 as

one (and the only patient-reported) of the outcome measures, the results of the
HRQoL measurements in several cases differed from the results of the
traditional medical outcome measures, but this fact seldom affected the
conclusions [159]. This lack of impact of patient-reported outcome measures
on medical and managerial decision makers in the health care was discussed
already in the 1990s in terms of Outcome management and Outcomes research
[160-163]. Greenhalgh et al [164] have suggested that it is caused, at least in

26
 Introduction

part, by lack of theory, since, over the years, researchers have focused more on
the development of new instruments than on reflecting upon the theoretical
background of them and why they should be useful for health care
improvements. Thus, we need to learn more about what we actually measure.

McClimans [165] has suggested that although researchers are aware of that
questions used in measures of HRQoL may be context-dependent and their
theoretical construct imperfectly understood, the consequence of this insight,
i.e. that today’s quantitative instruments may not be optimal outcome
measures, is ignored. She suggests a parallel use of qualitative data, both as a
means for constant revision of existing instruments, and as a tool for
interpreting quantitative data.

Using patient-reported outcomes can be regarded as a sort of feedback to the

clinicians from the patients [166]. Carlier et al [167] found in a literature search
that using the feedback system Routine Outcome Monitoring (systematic
evaluation of treatment responses during the course of the treatment) had a
significantly positive impact on health care professionals with respect to
earlier adjustments of treatment plans etc., especially in the short term, in the
majority of studies. Communication between professionals and patients was
also improved, and more than half of the studies furthermore showed a
positive impact on mental and/or physical health of the patients. The authors
proposed that feedback theories, such as the Feedback Intervention Theory
(FIT) might explain the positive results. According to the FIT, health care
professionals, when given formerly unknown information about the patient,
will become more focused on the task, and thus health care will improve.
However, the effects of FIT have also been questioned [168].

The patient perspective

There are few studies concerning the patients’ perspective on the perceived
value of HRQoL outcome assessments, or preferred HRQoL-instruments [169,
170]. In the choice of appropriate instruments the patients’ perspective is of
vital importance [171, 172], and questionnaires should preferably be designed
to make every part of the cognitive response process (comprehension of the
question, retrieval of information, judgement based on retrieved information,
and response selection) as easy as possible for the respondent [173]. Related
aspects that are often discussed in the literature are respondent burden
(questionnaire length and effort in answering) and patient perceived validity of
the instrument [113, 174].

27
Introduction

Aims of the thesis

The general aims of the thesis were to study the associations of HRQoL with
psychological and biological factors, and the use of HRQoL as patient-
reported outcome in routine health care.

Specifically, the four papers in the thesis aimed to investigate

• the association between HRQoL (SF-36) and psychological factors in a

normal middle-aged population, especially differences and similarities
between women and men (Paper I)

• the association between HRQoL (SF-36) and inflammatory biological

factors with a known relation to disease and mortality (CRP, CXCL8, IL-
1β, 6, and 10, and MMP-9), in a normal middle-aged population (Paper
II)

• the impact of comorbidity on HRQoL (SF-36 and EQ-5D) in a normal

Swedish population, and to test two different comorbidity indices (one
older and often used, but designed for mortality studies, and one new,
specifically designed for HRQoL studies), using national register data
(Paper III)

• the patients’ point of view on using measures of HRQoL (SF-36

compared with EQ-5D) for health outcome assessments (i.e. as patient-
reported outcome) in routine health care (Paper IV)

28
 Methods

METHODS

Papers I and II

The data used in papers I and II were collected between October 2003 and
May 2004, using random sampling (stratified according to the catchment areas
of ten different primary health care centres, sex, and age at 5-year intervals) of
the population in the county of Östergötland, Sweden. An invitation letter was
sent by post, and by signing and returning a reply form the participants gave
informed consent. The participants were enrolled until the predetermined
sample size of 500 women and 500 men between the ages 45 and 69 was
obtained (five 5-year age-groups with 50 women and 50 men in each), and
finally resulted in 505 women and 502 men, with a response rate of 62.5%. This
constituted the basis of the ongoing, prospective Life conditions, Stress, and
Health (LSH) study (http://www.imh.liu.se/samhallsmedicin/socialmedicin/ lsh-
studien?l=en&sc=true). The LSH study was designed to investigate whether the
relationship between socioeconomic status and coronary heart disease is
mediated through biopsychosocial pathways. Since the primary outcome in
this study is coronary heart disease, the age group 45-69 was chosen to
optimize the number of outcomes. Exclusion criteria were ongoing serious
physical or mental disease, or difficulty in understanding the Swedish
language, but no exclusion for any of these factors became necessary. The
study sample was representative of the population in terms of educational
attainment, immigrant status, and employment rates.

As part of the protocol of the LSH study, participants visited their primary
healthcare centres, where anthropometric and blood pressure measurements,
in addition to blood, urine, and saliva samples, were obtained. All samples
were collected in a fasting state. Out of the 1007 participants, blood samples
were eligible for analysis from 961 participants (paper II). Patients were
instructed to reschedule their appointment if they were currently experiencing
any acute infections, e.g. a common cold. At the visit, information about the
voluntary nature of participating in the study was given verbally. In order to
ensure standardization of the data collection, the nurses collecting data at the
ten primary healthcare centres were trained together. All other measures in

29
Methods

papers I and II, except for sex and age, were self-reported (from
questionnaires).

Disease, lifestyle, and psychosocial factors

Self-reported disease data in the LSH-study were obtained using a checklist.
The participants were asked if they had ever been diagnosed by a physician
with any of the medical conditions in the list: myocardial infarction, angina
pectoris, stroke, chronic obstructive pulmonary disease, cancer,
asthma/allergy, dyspepsia/peptic ulcer, kidney disease, celiac disease,
hypertension, hyperlipidemia, or diabetes mellitus. An open question asking
about the presence of other medical conditions than the above concluded the
checklist. The questionnaire also contained a question about the presence of
musculoskeletal pain in the back of the neck and/or in the back (henceforth
referred to as back pain). Lifestyle factors included smoking habits, alcohol
consumption (from a validated food and beverage questionnaire) [175],
physical activity [176], and Body Mass Index (BMI; used as a measure of
weight control).

Psychosocial factors
The questionnaires in the LSH study included a broad range of instruments
measuring psychosocial variables, including the following five validated
instruments representing psychological resources (higher scores favourable)
and risk factors (with lower scores being favourable). (1) Self-esteem [177]
referred to a positive attitude towards oneself, while (2) Sense of Coherence,
SOC [178], reflected the extent to which one felt one’s own life to be
comprehensible, manageable, and meaningful. (3) Perceived Control included
11 statements adapted from the Whitehall II Study [179] and the New
Barometer studies [180, 181] regarding perceived control over health and
perceived control over life. (4) The Center for Epidemiologic Studies Depression
scale (CES-D) [182] was developed in the 1970s to capture depressed moods in
epidemiological studies. (5) Cynicism was one of six subscales from the
Hostility Scale [183], reflecting a generally negative view of humanity, which
depicts others as unworthy, deceitful, and selfish. Social support in terms of
the availability of social contacts in the wider social context (social integration)
and of close social relationships (emotional support) was measured using
validated abbreviated forms of two subscales: the availability of social
integration and the availability of attachment, both from the Interview
Schedule for Social Interaction [184].

30
 Methods

Health-Related Quality of Life

The Swedish version 1 of the internationally widespread instrument SF-36 was
used to measure health-related quality of life, defined as physical and
psychosocial well-being and functioning. [185].

Biomarkers (paper II only)

Plasma levels (EDTA plasma) of IL-1β, IL-6, IL-10, and CXCL8 were measured
with ultrasensitive bead kit technology (Invitrogen Co, Carlsbad, CA, USA)
according to the manufacturer’s instructions and analysed on a Luminex®
100TM system (Austin, TX, USA). The lower limit of detection was 0.38, 1.68,
1.36, and 0.64 pg/mL for IL-1β, IL-6, IL-10, and CXCL8, respectively. The
corresponding proportions of samples with detectable levels were 50%, 40%,
14% and 97%, respectively. Samples below the detection levels were given a
value that was half the limit of detection.

C-reactive protein (CRP) was measured in EDTA-plasma by a highly sensitive

latex-enhanced turbidimetric immunoassay (Roche Diagnostics GmbH,
Vienna, Austria) with a lower detection limit of 0.03 mg/L and interassay
coefficient of variance (CV) of 1.7%. Detectable levels were found for all
samples but one, which received a value of zero.

Concentrations of MMP-9 were measured in EDTA-plasma by human Biotrak

ELISA systems (Amersham Biosciences, Uppsala, Sweden). The lower
detection limit was 0.6 ng/ml, CV was 7.2 to 7.9 %. Detectable levels were
found in all samples.

o
Aliquots of plasma (0.5 mL) were stored at -70 Celsius for approximately 18
months before laboratory analysis of MMP-9, and approximately 40 months
before analyses of CRP, interleukins and chemokines.

Statistical analyses
Correlation and partial correlation analyses were used to explore the relations
between the SF-36 and psychological factors (paper I) and inflammatory
biomarkers (paper II), adjusting for sex, age, disease, lifestyle and/or
(psycho)social factors in different ways. Prior to the analyses, biomarker
outliers were excluded from the study base. Cut-off levels were set on the
basis of the biomarker distribution. Fischer r-z transformation was used to
investigate differences in correlation coefficients between women and men
when separate analyses were performed.

31
Methods

Linear regression analyses were used to further explore the relation between
the SF-36 and the explanatory variables used in the regression analyses i.e. sex,
age, disease, lifestyle, and/or (psycho)social factors, and, in paper II,
biomarkers.

Paper III

The data used in paper III were collected from a random sample of 10 000
persons from the general population, aged 20-74, in the county of
Östergötland (275 000 persons; total population 410 000 in 1999), which in
spring 1999 was sent a public health survey from the county’s Public Health
Centre for the purpose of monitoring the general health in the county
(including HRQoL-instruments SF-36 version 1 and EQ-5D), with a final
response rate of 60.93% (6093 participants). Of these responses, 6086 contained
useful data for the study. Corresponding data on diseases (diagnoses) and
causes of death were obtained from the Swedish National Inpatient Register
(discharge data from hospitals; 1987 through 2009) and the Causes of Death
register (1999 through 2009). The data was in the form of ICD codes; ICD-9
codes 1987 through 1996, and ICD-10 codes from 1997.

Charlson Comorbidity Index (CCI)

The CCI [135] includes 19 medical conditions, each given a weight of 1, 2, 3, or
6, according to severity. The sum of the weights constitutes the index value
(range 0-37), with higher levels indicating an increased risk of death from
comorbid diseases. Conditions can be collected manually from charts, but also
with computer aid, by using ICD codes from administrative systems. In
Sweden, administrative data are also recorded in mandatory national
registries, the source of data in paper III. Since the date of transition from ICD-
9 to ICD-10 codes in Sweden was the 1st January 1997, the study base in paper
III contains both types of codes, and we attempted to achieve maximum
agreement between them to ensure high validity of the study. Many different
adaptation algorithms of both ICD-9 and ICD-10 codes to the CCI weights
exist, all with their own features. Starting by identifying a common core in the
existing adaptations, ICD-9 and ICD-10 adaptations were compiled, using the
Swedish ICD-9/10 Translation Modules.

32
 Methods

Health-related quality of Life Comorbidity Index (HRQL-CI)

As opposed to the uni-dimensional CCI, the HRQL-CI [139] is divided into
two sub-indices, one covering the physically-oriented dimensions of health-
related quality of life (including 20 medical conditions), and one covering the
psychosocially-oriented dimensions (including 15 conditions). The conditions
were originally selected from a larger set, and some conditions became
included in both sub-indices, though they may have been given different
weights (1-3) in the different sub-indices (e.g. diabetes has the weight 1 in the
psychosocial sub-index, but the weight 2 in the physical), while others were
included in only one of the sub-indices. Sex-specific medical conditions, such
as diseases of the genital organs, were excluded to make the index
generalisable. The sum of the weights form two index values (range 0-35 and
0-25, for the physical and psychosocial sub-indices respectively), with higher
scores predicting lower health-related quality of life because of comorbidity.
The HRQL-CI was originally created based on so-called Clinical Classification
Codes (grouping similar diseases), not ICD codes directly, and no ICD
adaptation algorithm is currently available. Therefore, instead of having a
record of all possible codes matching all conditions in the HRQL-CI (which is
the case for the CCI), only the ICD codes present in our own study database
were matched with suitable medical conditions in the HRQL-CI.

Statistical analyses
A two-tailed t-test and an ANOVA analysis, with one-tailed Bonferroni post
hoc corrections between selected CCI and HRQL-CI index levels (where a
gradient was expected), or with two-tailed Tukey post hoc corrections (where
a gradient was not expected) were used to study the relation between the
comorbidity indices and HRQoL as well as mortality.

Linear regression analyses were used to further explore the impact of

comorbidity on health-related quality of life. Physically-oriented (PF, RP, BP,
GH) and psychosocially-oriented dimensions (VT, SF, RE, MH) of the SF-36
were investigated separately and only in relation to either the physical or the
psychosocial sub-indices of the HRQL-CI. To test the construct validity of the
CCI and the HRQL-CI, the known groups technique was used, analysing
differences between groups, for example different comorbidity index values
for those who had died and those who were still alive ten years after
answering the questionnaire [186].

33
Methods

Paper IV

The data used in paper IV were collected from the Swedish WHO-network
Health Promoting Hospitals (HPH) Health Outcome Assessment Project. In
2004, all Swedish member hospitals (23 at the time) were invited to find
interested clinics to participate in this multicentre project. Preferably, these
clinics cared for patients suffering with the following five common diagnoses:
ischemic heart disease, chronic obstructive pulmonary disease, rheumatic
disease, chronic pain, and knee/hip disorder. The staff then chose suitable
patient intervention groups from within the clinic’s ordinary practice. Thus,
the study design is a form of convenience sampling.

All patients in the chosen intervention groups were then asked to enter the
project (after giving informed consent), thus creating a number of local sub-
projects within the Health Outcome Assessment Project. Exclusion criteria
were: <16 years old, patient was confused or demented, or had difficulties
understanding the Swedish language. Each sub-project planned to include
about 20 patients. This recruitment resulted in participation by 18 hospitals,
comprising 573 patients divided into 31 sub-projects (1–4 sub-
projects/hospital; 7-50 patients in each subproject). The majority of the
intervention groups were so called patient education groups. Such multi-
professional groups are designed to enhance patients’ capability to deal and
cope with their own disease while improving their HRQoL. In addition to the
five suggested diagnostic groups, three further groups were included (one
sub-project of each); cardiac insufficiency, cardiac arrhythmia, and diabetes.

Patients were asked to respond to the HRQoL-instruments EQ-5D and SF-36

version 1 (in that order) before and after the interventions at the hospital in
connection with the intervention. Of the 573 patients, 463 (80%) completed
both measurements, and at the time of the second measurement they were
asked to complete an evaluation form. The five evaluation questions
concerned the cognitive response process (1. Understanding and 2. Responding
to the items in the EQ-5D and the SF-36; five response alternatives each),
patient-perceived content validity (3. Whether the instruments gave patients the
ability to describe their health in a comprehensive way; five response
alternatives), and patients’ perspectives on health outcome assessment (4. Was
this kind of health outcome assessment within health care perceived as
valuable in the future, and 5. If so, which instrument would they prefer?; three

34
 Methods

response alternatives each). An open-ended question giving patients the

opportunity to expand their answers concluded the evaluation form.

Statistical analyses
The answers to each of the first three evaluation questions (cognitive response
process and patient-perceived content validity) regarding EQ-5D were compared
with answers regarding SF-36, and the differences in the chosen response
alternatives were used to compute a respondent satisfaction difference score,
ranging from +4 (EQ-5D very easy/good and SF-36 very hard/bad) to –4 (SF-36
very easy/good and EQ-5D very hard/bad). Then these three scores were
added together, forming a respondent satisfaction summary score (range +12
to –12). This summary score was further transformed into a category variable;
in favour of EQ-5D (positive score) or SF-36 (negative score), or equal (zero
score, i.e. no differences or differences that cancelled each other out). Only
patients with complete data for all three respondent satisfaction questions for
both SF-36 and EQ-5D (n = 392) were included in the analyses.

The two-sided McNemars’ test with Yate’s continuity correction or, when the
number of discordant pairs was <10, the two-sided sign-test were used to test
statistical significance for differences in respondent satisfaction and
preferences between SF-36 and EQ-5D, in the total sample population as well
as in the sample population categorised by sex and age (younger than 65 years
old vs 65 or older)

The responses to the open-ended question were first sorted according to

whether they discussed the value of health outcome assessment in routine
health care (n = 27) or discussed their preference of instrument (n = 62), and
then further sorted into groups, referred to as categories. Each category was
illustrated by citations.

35
Results

RESULTS

Associations of Health-Related Quality of Life

with psychosocial and biological factors

Papers I and II addressed the issue of associations of HRQoL instruments

with psychosocial and biological (inflammatory biomarkers) factors, to better
understand what it is we actually measure by these HRQoL-measures.

Significant sex differences were seen for many of the variables. Back pain
occurred significantly more often among women than men (46% vs 37%).
More men than women had BMI>25 (72% vs 55%), and more men than women
had high alcohol consumption (26% vs 8%). Regarding the SF-36 and the
psychosocial instruments, men generally scored significantly more favourably
than women, except with regard to Cynicism and Emotional Support, where
women scored more favourably. Because of these sex differences, analyses
were first carried out separately for men and women. However, in paper II
Fischer r-z transformation did not show any significant differences in the
HRQoL-biomarker correlation coefficients for women and men, and
separating the analyses by sex did not change the main findings, but affected
power. Hence, further analyses were adjusted for sex, but not performed
separately for men and women in paper II.

In paper I the main results were that partial correlation coefficients for the
relations between HRQoL and psychological resources (Self-esteem, SOC, and
Perceived Control), as well as psychological risk factors (CES-D), were almost
all significant and in the expected directions, i.e. higher score on resources and
lower scores on risk factors in relation to higher HRQoL. They were generally
lower for the physically-oriented SF-36 subscales (PF, RP, BP, GH; significant
r=|0.11 - 0.38|) than the psychosocially-oriented subscales (VT, SF, RE, MH;
significant r=|0.13 - 0.60|). CES-D generally displayed the highest correlation
coefficients. In general, the results were similar for men and women, but
women had significantly greater r values than men (p = 0.05) in the following
correlations: Self-esteem–VT, Self-esteem–SF, Perceived Control–RE, SOC–RE,

36
 Results

and CES-D–SF. The SF-36 subscales showing sex differences are therefore all
psychosocially-oriented and predominantly role-functioning ones.
Furthermore, multiple linear regression analyses were performed in order to
verify the impact of psychological factors on HRQoL. For all subscales of SF-
36, the addition of the five psychological instruments en bloc into the
regression model resulted in significant R2 changes for both men and women.
The lowest explained variance was seen for RP and the highest for MH (for
men and women alike), though among the physically-oriented scales RP
showed the highest relative R2 change (Table 2) regarding psychological
factors, especially for men.

Table 2. Total explained variances (R2) and R2 change; multiple regression analyses
exploring relations between health-related quality of life (SF-36) and psychological
factors for middle-aged men and women.
PF RP BP GH VT SF RE MH
Men
(n=502)
∆R2 other 0.22 0.10 0.29 0.21 0.20 0.05 0.06 0.11
∆R2 psych 0.05 0.07 0.05 0.15 0.23 0.18 0.23 0.36
Total R2 0.27 0.17 0.34 0.36 0.43 0.23 0.29 0.47
Women
(n=505)
∆R2 other 0.31 0.18 0.36 0.36 0.34 0.15 0.11 0.20
∆R2 psych 0.02 0.08 0.03 0.13 0.21 0.26 0.33 0.36
Total R2 0.33 0.26 0.39 0.49 0.55 0.43 0.44 0.56
Other=age, disease, pain, lifestyle (smoking, alcohol, BMI, and physical activity), and social
support
Psych=psychological factors (sense of coherence, self-esteem, perceived control, depression,
and cynicism)

In paper II the main results were that significant negative correlation

coefficients for every subscale of the SF-36 (adjusting for sex and age) were
found for IL-6 (r=-0.103 - -0.170; p<0.001), whereas CRP showed significant
negative coefficients for all scales (r=-0.073 - -0.155; p<0.05) except the MH scale
(r=-0.025; p=0.458). For MMP-9, significant negative correlations were seen for
five out of the eight SF-36 scales (PF, BP, GH, SF, and MH; r=-0.072 - -0.097;
p<0.05), although they were weaker than for IL-6 and CRP. In contrast, no or
only scattered significant correlations were found for IL-1β, IL-10, and CXCL8.
Based on these results, further regression analyses involving biomarkers were
only conducted for IL-6, CRP and MMP-9.

37
Results

The regression analyses were performed in five different ways; 1) adjusting for
age and sex, 2) additionally adjusting for a) only lifestyle factors, b) only
presence of disease/back pain, c) only psychological factors, and d) for all
factors together (full model). Both IL-6 and CRP revealed significant beta
coefficients for all subscales of the SF-36 when initially adjusting for age and
sex (except the MH scale for CRP). Coefficients regarding IL-6 were somewhat
attenuated (e.g. for PF the beta coefficients for the five analyses described
above were -3.7, -2.8, -3.0, -3.3, and -2.2 respectively) after including the other
explanatory factors, especially in the full model, although they only became
non-significant for the VT and the RP scales (and only in the full model).
Unlike IL-6, the beta coefficients for CRP became non-significant when
adjusting for lifestyle factors for half of the subscales, and for VT when
adjusting for the other explanatory factors as well. The full model yielded non-
significant beta coefficients for CRP for all subscales except PF and RP.
Regarding MMP-9, significant beta coefficients were found for the PF, BP, GH,
and SF subscales after initial adjustment for age and sex. After further
adjustments all coefficients became non-significant, except for the PF, BP, and
GH scales when adjusting for the presence of disease/back pain. The results of
the regression analyses regarding IL-6, CRP, and MMP-9 are seen in Table 3.

Table 3. Beta coefficients for the initial and full models, and total explained variances
(R2) for the full model; multiple regression analyses exploring relations between
health-related quality of life (SF-36) and inflammatory biomarkers IL-6, CRP, and
MMP-9 for middle-aged men and women (n=729-791). Beta coefficients expressed as
change in SF-36 scale per SD increment of the biomarker.
PF RP BP GH VT SF RE MH
IL-6
β -3.7*** -4.2** -3.2*** -3.6*** -2.7** -3.2*** -5.0*** -2.2***
β full model -2.2*** -1.9 -2.0** -1.7** -1.1 -1.9** -3.2** -1.1*
Total R2 0.36 0.18 0.32 0.38 0.43 0.32 0.29 0.50
CRP
β -2.8*** -4.6*** -2.8** -2.9*** -1.6* -1.7* -2.8** -0.3
β full model -1.0* -2.9* -1.5 -1.2 -0.4 -0.8 -1.8 -0.01
Total R2 0.32 0.16 0.31 0.36 0.43 0.29 0.29 0.49
MMP-9
β -1.3* -1.8 -1.8* -2.0** -0.7 -1.3* -1.3 -1.0
β full model -0.2 -0.2 -0.5 -0.2 -0.7 -0.2 -0.3 -0.1
Total R2 0.34 0.17 0.30 0.36 0.43 0.30 0.28 0.49
β = adjustments only for sex and age
β full model = adjustments for sex, age, disease, pain, lifestyle (smoking, alcohol, BMI, and
physical activity), and psychological factors (sense of coherence and depression)
*p<0.05, **p<0.01, ***p<0.001

38
 Results

Use of Health-Related Quality of Life as a

patient-reported outcome in routine health care

Papers III and IV addressed the issues of casemix problems when interpreting
the results of HRQoL measurements, and the patient-perceived usefulness and
feasibility of HRQoL instruments as patient-reported outcomes.

In the study population in paper III, investigating the impact of comorbidity

on HRQoL, 3183 persons (52.3%) had been registered in the Inpatient register
with ≥1 ICD codes before the public health survey was conducted, i.e. before
1st July 1999. The majority had not been registered with codes that were
included in any of the comorbidity indices; 478 (15.0%) and 664 (20.8%)/418
(13.1%) persons out of the 3181 had been registered with ≥1 codes included in
the CCI and the HRQL-CI physical/psychosocial, respectively.

Table 4. Linear regression analyses, with SF-36 and EQ-5D as outcome and the
comorbidity indices CCI and HRQL-CI as explanatory variables for the participants
registered with ≥1 ICD code between 1987 and the 30th June 1999 (n=3183). All β were
significant (p<0.001).
PF RP BP GH VT SF RE MH
CCI
Total R2 0.067 0.028 0.014 0.062 0.016 0.016 0.005 0.004
HRQL-CI ph
Total R2 0.161 0.052 0.033 0.094
HRQL-CI ps
Total R2 0.018 0.028 0.024 0.026

EQ- EQ
VAS index
CCI
Total R2 0.031 0.022
HRQL-CI ph
Total R2 0.049 0.051
HRQL-CI ps
Total R2 0.040 0.035
CCI=Charlson Comorbidity Index
HRQL-CI ph=Health Related Quality of Life-Comorbidity Index, physical subindex
HRQL-CI ps=Health Related Quality of Life-Comorbidity Index, psychosocial subindex

39
Results

The results of the linear regression analyses revealed HRQL-CI to have a

stronger explanatory power (higher R2) than the CCI regarding the impact on
health-related quality of life. However, all R2-values were generally very low,
with the PF and GH subscales of the SF-36 showing the highest values for both
indices (Table 4).

The ANOVA-analysis (post hoc contrasting one index level with the next)
showed that both the CCI and the HRQL-CI consistently received lower scores
for the EQ-5D and the SF-36 scales for all index levels compared with the
index level 0 (i.e. ≥1 ICD code registered before 30th June 1999, but none that
were included in the index), but the expected gradient was undecided.
Significant differences between the other index levels were noted mostly for
the physically-oriented dimensions of the two health-related quality of life
instruments, especially the PF and GH scales, and the EQ-5D VAS.

Between 1999 and 2009, 371 (6.1%) persons in the study population died, and
25 died within one year of answering the questionnaires (i.e. before 1st July
2000). Almost all (22) of these 25 had been registered with ICD codes before
answering the questionnaires. The CCI showed a clear, highly significant
gradient between those who died within one year, up to ten years after the
survey, or were still alive after ten years, while the trends for the HRQL-CI
were less apparent, though the differences between those alive in 2009 and
those who had died within one year were significant (Table 5).

Table 5. Mean values of the CCI and the HRQL-CI (for participants with ICD codes
between 1987 and the 30th June 1999; n=3183), regarding those who died within one
year or up to ten years after the survey, or who were still alive after ten years.
Died before 1st July Died 1st July 2000- Alive 31st December
2000 31st December 2009 2009 (n=2923)
(n=22) (n=238)
mean (SD) mean (SD)
mean (SD)
CCI 2.4 (2.3)* 1.0 (1.3) 0.1 (0.5)
HRQL-CI phys 0.9 (1.4)* 1.7 (2.1) 0.3 (0.9)
HRQL-CI psych 0.5 (0.9) 0.7 (1.3) 0.1 (0.6)
CCI=Charlson Comorbidity Index
HRQL-CI phys=Health Related Quality of Life-Comorbidity Index, physical sub-index
HRQL-CI psych=Health Related Quality of Life-Comorbidity Index, psychosocial sub-index
*significant differences (p<0.05) between deaths before and after 1st July 2000; all differences
between those alive and those who died (before as well as after 1st July 2000) are significant
(p<0.05)

40
 Results

The majority of the 392 patients in paper IV with complete data pertaining to
the respondent satisfaction questions found both SF-36 and EQ-5D easy to
understand (70/75%; p=0.005) and respond to (54/60%;p=0.001), even if EQ-5D
was found to be significantly easier, particularly among women aged >65
years. While 7/4% found the instruments hard to understand, 12/8% found
them hard to respond to. The ability to describe their health in a
comprehensive way was also found to be mainly good for both instruments
(68/68%), though 10/9% of patients regarded them as poor in this regard.

The three categories of the respondent satisfaction summary score were

distributed in the following way; 20% in favour of EQ-5D, 13% SF-36, and 67%
equal (mostly due to identical judgements for SF-36 and EQ-5D and not to
different judgements cancelling each other out). Men aged >65 years were
more often in favour of SF-36, while women aged >65 years were more often in
favour of EQ-5D.

Of these 392 patients, 385 answered the question about the perceived value of
health outcome assessment within routine health care, and 219 (57%) answers
were found to be positive, while 15 (4%) were negative. Of the 219 patients
giving positive answers, 210 answered the question about which instrument
they would prefer for use in routine health care. Though the majority (68%,
142) stated no preference, three times as many preferred the SF-36 (25%, 52) as
the EQ-5D (8%, 16), and usually these were men and women aged <65 years,
while women aged ≥65 years showed no significant differences in preferences.
In Table 6 this preference data was cross-tabulated with the respondent
satisfaction summary score, showing that respondents with an equal summary
score or a score in favour of SF-36 preferred the SF-36 for use in routine health
care, while no significant difference was seen for those with a summary score
in favour of EQ-5D.

41
Results

Table 6. Patients’ preferences of HRQOL-instruments (SF-36 and EQ-5D) for use in

routine care versus the respondent satisfaction summary score, among those
responding positively towards health outcome assessments and who had answered
the question about preference (n=210).
Preference of instrument for use in routine care
Respondent Prefer SF-36 Prefer EQ-5D No preference P (SF-36 vs EQ-
satisfaction % (n) % (n) % (n) 5D)
summary score
In favour of SF- 47 (16) 3 (1) 50 (17) < 0.001
36 (n=34)
In favour of 26 (9) 32 (11) 41 (14) 0.82
EQ-5D (n=34)
Equal score 19 (27) 3 (4) 78 (111) < 0.001
(n=142)

Answers to the open-ended question contained both positive and negative

reflections on health outcome assessment and the HRQoL-instruments. Some
examples of citations are seen below.

Positive towards health outcome assessment:

“It saves time at consultations”
“To find ill-health earlier”
“Someone cares!”

Negative towards health outcome assessment:

“I prefer health care to questionnaires!

The SF-36 was considered to have more and better response alternatives, but
was also more likely to cause confusion. The EQ-5D was considered quicker
and easier to answer, but also to have too few response alternatives, and one
person felt “too healthy for the questions” in the EQ-5D.

42
 Discussion

DISCUSSION

Associations of Health-Related Quality of Life

with psychosocial and biological factors

Both papers I and II confirmed that HRQoL is not an isolated measure of

trivial importance, but instead that it has essential links to both psychological
and biological factors of known value for health and disease.

Regression analyses in paper I revealed positive associations between HRQoL

(as measured by the SF-36) and psychological resources, and negative
associations regarding psychological risk factors, also after adjusting for of
disease, pain, lifestyle, and social support. In a similarly designed study as
ours on haemodialysis patients (though we conducted separate analyses for
women and men, while they adjusted for sex), the explained variance
increased considerably after the addition of psychosocial variables, as with our
results [27]. However, an even greater impact of psychosocial factors on the
physically-oriented scales than ours was noted, but there was a smaller effect
on the psychosocial scales. For patients afflicted with severe diseases,
psychosocial factors may play a greater role in their perceptions of physical
performance, as compared with a normal population. Discrepancies of this
sort are important to identify in order to reduce the possible bias of
generalising findings for populations with varying degrees of disability or
disease. Further research is needed to investigate if and how systematic
psychosocial interventions, together with medical treatments, will improve
patients’ HRQoL. Examples of such interventions are patient education
designed to enhance the coping abilities among patients with chronic illness
and disease, or screening for comorbid depression among patients where the
anticipated improvement in HRQoL did not occur.

We found fewer sex differences than expected, especially for two subscales, SF
and RE. It was notable that both of these are role-oriented. SF measures
“restrictions in social activities due to physical and mental health problems”
and RE describes “restrictions in daily activities because of mental health
problems”. Both of these scales had stronger correlations to measures of

43
Discussion

“mood” (depression) and “confidence in oneself” (Self-esteem, SOC, and

Perceived Control) among women, i.e., psychological factors seem to be more
important for perceived social functioning for women compared with men. In
a study investigating whether different factors explained global self-rated
health in women and men in a normal population, Undén and Elofsson [187]
found that women and men seemed to consider similar factors (including
psychological ones, such as self-esteem and depression) when judging their
self-rated health, although some sex differences were found for the strength of
the relationships between psychological factors and self-rated health, in line
with the results in paper I. Undén and Elofsson [187] concluded that an
individual’s perspective is probably more important than a gender perspective
when trying to improve self-rated health. A related subject is the importance
of coping as a determinant of HRQoL, and women with myocardial infarction
have been found to use a greater diversity of coping strategies than men,
including more passive strategies [188].

The third role-oriented scale, RP, represents restrictions experienced in daily

activities due to the respondent’s physical condition. This subscale showed a
large relative increase in explained variance with the addition of psychological
factors, especially for men. It is known that psychological factors may lead to
avoidance of physical activity, as in kinesiophobia and “fear of movement”
[189, 190]. As physical activity is increasingly recognized as a method for both
rehabilitation and prevention, and “fear of falling” has in fact been shown to
be a key predictor for functional recovery after hip fracture surgery, the above
findings may be of importance when planning interventions regarding
physical activity.

In a biomarker context, the LSH-study can be considered to have included a

large number of participants. In paper II the relation between HRQoL and
inflammatory biomarkers was investigated and the hypothesis was that if a
relation could be found, it would be explained by factors of known importance
to HRQoL (age, sex, disease/symptoms, lifestyle, and psychological factors).
However, the SF-36 was found to be significantly and independently related to
two well established measures of inflammation, IL-6 and CRP, especially the
former (though beta coefficients for the biomarkers were attenuated after
inclusion of the explanatory factors).

CRP is a “down-stream” molecule of IL-6, and therefore to a substantial extent

reflects IL-6. However, IL-6 is a very pleiotropic cytokine, affecting several

44
 Discussion

biological processes besides the induction of CRP. Accordingly, IL-6 could be

expected not to act identically to CRP. Another reason for including CRP as
well as IL-6 is that CRP is an often used biomarker in clinical medicine, where
CRP levels of <10mg/l traditionally have been regarded as normal, but the
high-sensitivity CRP assays have made it possible to measure levels even
below 1mg/l. Lower levels of CRP have been shown to have a graded
association (<1 low risk, 1—3 average risk, >3 high risk) with myocardial
infarction, though it is not established whether CRP is a mediator or just a risk
marker [191]. Although no traditional clinical levels of low grade
inflammation exist for the other biomarkers, the study blood sample levels
indicated present inflammation to be low grade, and the few individuals who
had high values (indicating highly active inflammation) were excluded from
the analyses in paper II.

A novel finding in the study was that MMP-9, a new candidate in the research
on inflammatory biomarkers and HRQoL, showed significant associations
with several of the SF 36 scales (when adjusting for age and sex), all in the
same direction as for IL-6 and CRP. This observation merits further
investigation. The reason the other included biomarkers (IL-1β, IL-10, and
CXCL8) did not show relations to HRQoL is not evident. Some of them might
be too down-stream in the hierarchical process of inflammation for use in
population studies, or they may be mainly induced in other routes, not related
to factors included in paper II.

The hypothesis that a relation between HRQoL and inflammatory biomarkers

would be explained by age, sex, disease/symptoms, lifestyle, and
psychological factors was not fully supported by the results in paper II. For
IL-6, the beta coefficients became non-significant in the full regression model
only for the RP and VT scales but were still significant, though attenuated, for
the other six scales of SF-36. This independent effect of IL-6 on HRQoL
remains unexplained, but vital explanatory factors might still be missing.
These could include yet undiagnosed diseases among the participants, other
aspects of psychological stress besides those included in the present study, or
other lifestyle factors, such as dietary factors with effects on the inflammation
system. In the present study, the included lifestyle factors seem to be the
explanatory factor of most importance in the case of CRP. Since all three
biomarkers (IL-6, CRP, and MMP-9) are known to be associated with lifestyle
factors [192-197] the reason for this finding is not obvious, but one explanation
might be that IL-6, unlike its weaker reflector CRP, induces sickness

45
Discussion

behaviour, which possibly exerts more influence on HRQoL than lifestyle

factors do.

The inclusion of both IL-6 and CRP gives no conclusive answer to the question
of whether CRP, which is easier and cheaper to analyse, could replace IL-6 as
an inflammatory biomarker in this kind of study/analysis. The choice between
CRP and IL-6 should be determined in each individual case by the context and
the research question.

Although the Wilson & Cleary/Ferrans model of HRQoL [49, 50] unifies social
science and biomedical perspectives of HRQoL, it does not include
psychoneuroimmunology aspects. On the other hand, biological models such
as the PNI Framework [99] are weak on the social and environmental aspects.
Therefore, they seem to complement each other. Optimally, a new, combined
model could be created. The results in papers I and II support the idea that
biology may affect HRQoL in a direct manner, through sickness behaviour
mechanisms, and not only through the chain depicted by the Wilson &
Cleary/Ferrans model. The results also show that lifestyle factors may have a
more apparent role than previously described in the models. Furthermore, the
fact that low HRQoL has been shown to predict mortality (which is not
included in the models), independently of present disease [54-56] is important
to keep in mind, since it will affect the patients’ prognoses.

Use of Health-Related Quality of Life as patient-

reported outcome in routine health care

The use of measures of HRQoL as patient-reported outcome is still poorly

implemented in routine health care, and results of measurements seldom
make a difference when making individual treatment plans, or when planning
health care at large [164].

Paper III addressed an issue often pointed out by health care professionals as
an obstacle to the implementation of the use of HRQoL-instruments, namely
the casemix problem when interpreting general HRQoL data, and especially
the case of the impact of comorbidity on HRQoL. Two different comorbidity
indices were tested; the often used Charlson Comorbidity Index, CCI

46
 Discussion

(designed for mortality studies), and the new Health-Related Quality of Life
Comorbidity Index, HRQL-CI (designed for HRQoL studies).

Linear regression analyses investigating the explanatory power of the two

comorbidity indices on HRQoL showed results at the level of the original
study on HRQL-CI, i.e. the explained variance (R2 values) was rather low, but
higher for the HRQL-CI than for the CCI. The fact that R2 values were
generally higher regarding physical dimensions is in line with the results of
paper I, where presence of disease had a higher explanatory power for the
physically oriented scales of the SF-36 than for the psychosocially oriented (in
relative numbers).

The expected gradient in HRQoL for different levels of the comorbidity indices
was not very visible, especially not for the CCI, although such indices were
created to consider not only multimorbidity but also the severity and
individual impact of different diseases, and therefore higher comorbidity
index values could be anticipated to lead to lower scores on the HRQoL-
instruments. A larger study might have resulted in more patients with higher
index levels, facilitating more meticulous gradient studies. Another
explanation for the lack of clear gradients is that there is too little disparity
between the existing levels, and that the merging of the index levels was not
optimal. Furthermore, a larger study would have allowed the identification of
index diseases, to study true comorbidity; in the present study it is instead
multimorbidity that is being considered. However, using comorbidity indices
is an appealing way to study multimorbidity in the general population.

Unlike the CCI, the HRQL-CI does not include cancer. Since three quarters of
those who died within a year of answering the survey died of cancer, this
exclusion may explain why the index value gradient when dividing the
participants into three groups (died within one year, died within ten years or
still alive after ten years) was more obvious for the CCI (Table 5). Cancer was
originally excluded from the HRQL-CI because in comparison with other
diseases the HRQoL of cancer patients was rather high, which was also the
case in our data material. Still, it was lower than for persons without disease,
which might be due to the use of a 12-year look-back period leading to many
of the persons with cancer-related ICD codes being cancer survivors, who
often have been found not to reach the same high HRQoL as healthy controls,
but more research is necessary [198, 199]. Perhaps cancer should be divided

47
Discussion

into subgroups in this kind of study, e.g. cancer patients receiving curative
treatment, patients with metastatic cancer, cancer survivors, etc.?

Self-reports are often used as a measure of disease and comorbidity, and are
considered an acceptable method and the most realistic solution when
trustworthy charts and/or administrative medical data are difficult to acquire,
but may be impractical in larger studies [200, 201]. Sweden has a number of
mandatory national health databases (based on personal identity numbers for
all Swedish residents) which are attractive to use in health services research.
One of these registries is the Swedish National Inpatient Register, which
contains all hospital discharge data in Sweden from 1987 onwards. Validity
aspects to keep in mind when interpreting data from the Inpatient Register
include coding errors (the patient may have been given an incorrect ICD code,
or even an incorrect diagnosis, by the health care professional, or the
translation of codes from the medical chart to the register may have failed), the
changing proportions of in- and outpatients over time, coding patterns in
different hospitals, recent financial incitements to include more secondary
codes, etc. [202-204]. The validity of the Inpatient Register has been found to
vary among diagnoses, although considered to be high in many cases, and it
has been suggested that the Inpatient Register may be better suited for large
scale population studies, especially long-term, than for studies of specific
diagnoses, where additional data sources and expert knowledge about the
medical conditions are required [202-204]. This variance of validity among
diagnoses is also true for another mandatory national register, the Causes of
Death register. However, less than 1% missing deaths was found when
comparing data from the Causes of Death register with data from the Swedish
Tax agency, the public authority where all deaths are registered in Sweden, i.e.
the coverage is very high [205], which is also the case for the Inpatient Register
[202].

Paper IV introduces a new concept, respondent satisfaction. The idea is that

respondents are not only concerned about things such as the burden of
answering questionnaires, but also like to feel satisfied with their contribution.
The results in Paper IV indicate, contrary to the belief of many health care
professionals, that patients find the use of measures of HRQoL valuable
enough to take the time and effort to answer them, and that the longer SF-36
was as easy to answer as the shorter EQ-5D. The finding that women aged >65
years found EQ-5D easier was in line with earlier findings that the elderly, and

48
 Discussion

especially women, have reported difficulties with the (self-administrated) SF-

36 [206-208].

The fact that 39% of the patients chose not to take a stand about the usefulness
of health outcome assessments may have been because they did not
understand the objective of these assessments. However, answers to the open-
ended question indicate that they did, e.g. ‘‘gives a better insight into the
patient’s experience’’ or ‘‘it is in everyone’s interest if it leads to positive
effects and changes’’. A more possible explanation could be that patients are
unaccustomed to their health being measured in routine health care, or do not
think they have enough knowledge to have a say. Furthermore, the way we
use the respondent’s own judgement as an indicator of the quality of an
answer may be seen as somewhat questionable by those who argue that
people are not very good at judging and reporting their ability to understand
or correctly answer a survey question [209]. Nonetheless, the respondent’s
feelings are never unimportant or insignificant. Again, answers to the open-
ended questions show that the respondents brought up aspects such as the
importance of being able to give truthful answers and of seeing the usefulness
of their answers, in support of the concept of respondent satisfaction.

Measurement of Health-Related Quality of Life as an

innovation

One explanation of why the implementation of the use of HRQoL-instruments

has not been more successful might be that their use in routine health care is
still regarded as an innovation by the supposed adopters, i.e. the health care
professionals, if they are even aware of their existence. In Everett Rogers’
implementation theory, “Diffusion of innovations” [210], an innovation is
defined as the object that is to be implemented, and that is perceived as new
by the adopters, even though it may not be literally new. Adopters are all
people (or organisations) that make a decision to accept and use the
innovation. According to Rogers, the adoption of an innovation is influenced
by its attributes; relative advantage, compatibility, complexity, trialability, and
observability.

The relative advantage of using patient-reported outcome measures such as

HRQoL instruments (compared with only using profession-reported

49
Discussion

measures) is that they systematically provide the patients’ perspectives about

their health and the results of the health care given.

The compatibility may be favourable regarding the values of the health care
professionals and in the health care system in general, since the knowledge
needed to evaluate both the overall goal of health care in Sweden, i.e.
“assuring the entire population of good health” (Swedish Health and Medical
Services Act), and the individual goal of health care professionals “good
health for your patient” is exactly the kind of knowledge that the use of
measures of HRQoL may add. It has been proposed that a health care system
has moral implications to measure and show consideration for patients’
HRQoL [211]. The fact that the patients in Paper IV found health outcome
assessments valuable broadens compatibility to also incorporate patients.
Moreover, patients in favour of using measures of HRQoL in routine health
may actively advocate the idea, for example through patient organisations,
though these organisations have traditionally focused on waiting times and
communication issues.

However, compatibility also concerns how compatible the innovation is with

existing routines in the organisation, which may need to change, even
physically, to adopt an innovation. Luckily, starting to use PROM does not
require very great investment. Some sort of computer aid is needed, scoring
software, perhaps touch screens, web applications etc. Furthermore, personnel
have to be designated to take care of all practical issues [212]. It is possible the
innovation itself may have to change somewhat, in order to better meet the
needs of the organisation in question. In fact, this is an important part of the
implementation process, making the innovation more familiar to its potential
users. However, the single most important action is for the organisation to be
prepared to change the given care according to the results of the
measurements if patients’ experiences are not the anticipated and/or desired
ones.

One such practical issue is the identification of the optimal time points for
measurements for particular patient groups, integrating the measurements in
clinical guidelines and care plans. The use of continuous routine health
assessments has been questioned on the grounds of being costly and time-
consuming [213]. If health care professionals do not experience a direct
usefulness of the assessments in the daily care of individual patients,
implementation will be difficult (especially in practices where patients already

50
 Discussion

have established benefits from the treatments given). Instead, the use of
periodic internal quality control measurements of patients’ HRQoL has been
suggested, e.g. when new procedures are introduced [213, 214]. This is of
course true for all outcomes measurements, not only for measurements of
HRQoL. An advantage of continuous measurements is that they can be used
in the individual encounters with all patients, as a basis for individual
treatment plans.

Even if many patient-reported outcome measures at a glance may seem very

straightforward, the complexity might be regarded as high; Which of all the
hundreds or thousands of instruments should we choose, how should we
collect and process data, how do we interpret the results of the measurements
and handle the casemix problem, etc.? To use for example the HRQL-CI to
adjust for comorbidity in casemix-analyses will help to moderate the
complexity.

Trialability is less of a problem; it is very easy to start with small scale

measurements, testing different patient-reported outcome measures.

Finally, observability refers to the visibility of the results of the innovation. First,
the results of the measurements have to be presented to health care
professionals in a way that is quick and easy to understand, and must be
integrated with other medical data [212]. Then, most importantly, the
usefulness of measures of HRQoL must become visible, and evident, i.e. using
measures of HRQoL to gain a more holistic view of the patient and to point
out possible areas for health gaining interventions must be shown to have
improved health care and thereby the HRQoL of patients.

Methodological discussions

In all the papers, parametric methods suitable for variables with continuous
and normal distributions were used, although the SF-36 (and the psychosocial
instruments in papers I and II) are known to produce data that have discrete,
bounded, and often skewed distributions (although assumed to reflect an
underlying continuous conception). However, nonparametric methods
showed similar results for all bivariate tests, and linear relationships were
further supported by the bivariate scatter diagrams (not shown). Moreover, it

51
Discussion

has been shown for the SF-36 that in larger studies (n > 100), multiple linear
regression is fairly robust against violations of non-normality, probably as a
result of the central limit theorem [215].

Another common problem is that the number of analyses performed may lead
to a risk of mass significance, such as in the significance tests for differences
between women and men in paper I. However, all sex differences found with
respect to the correlation coefficients were in the same direction, i.e.,
psychological factors were of more importance to women than men, and were
found in roughly the same scales of the SF-36, regardless of the psychological
factor tested. This implies that the differences found were genuine. The
general message seems to be that women and men are affected by the same
range of psychological factors but may differ in the importance they tend to
ascribe to them.

A limitation of both papers I and II was the cross-sectional study design, i.e.
causality could not be investigated. Another limitation of paper II was that the
proportions of samples with detectable plasma levels for IL-1β, IL-6, and IL-10
were low, which might have negatively influenced the correlation and
regression analyses.

Unlike the other papers in this thesis, which have cross-sectional designs,
paper III has a longitudinal design, where participants are observed both up
to 12 years before and ten years after answering the questionnaire, enabling
researchers to study change over time and cause-and-effect relationships. A
12-year look-back period was used in the study, which means that all data
from the start of the Swedish National Inpatient Register in 1987 was included.
A shorter look-back period might have been more appropriate to ensure that
all codes pertained to diseases affecting the individuals at the time of
answering the questionnaire, but this was not possible due to sample size.
However, the diseases included in the indices are mostly chronic, severe
diseases and are likely to impact a person’s life for a long time (though the
impact may vary over time). The fact that the HRQL-CI does not include
cancer may render it more useful than the CCI when used with longer look-
back periods.

The long look-back period also had the consequence that we had to include
both ICD-9 and ICD-10 codes in the material. Although, for the most part, the
codes are similar they may also differ substantially (given the widespread

52
 Discussion

expansion in the ICD-10). However, the main results in paper III are not likely
to be seriously influenced by any incongruities, because we did not have any
problems in assigning the codes in the study material to either the ICD-9 or the
ICD-10 systems.

The study design in paper IV can be seen as a kind of convenience sampling,

and thus may suffer from two main problems; possible systematic bias and
lack of external validity. However, this is also a multi-centre study, which is
known to have a number of advantages; possibility to include a large number
of participants in a short period of time, include people from different
geographic locations (wider distribution of demographic factors) and a wider
range of patient groups, and not at least, to give the possibility to compare
results among centres. All these aspects will increase the generalisability of the
study, i.e. the external validity. On the other hand, multi-centre studies require
firm control regarding compliance to the protocol, and a highly developed
coordinating centre.

Pre-selecting five different patient groups served two purposes, to allow for
comparisons between patient groups in different hospitals but also to ensure
that more than a few patient groups were represented, thereby increasing
generalisation and reducing bias due to patient characteristics. Nevertheless,
some important patient groups are missing, for example cancer patients, and
thus the study cannot claim to represent patients in general. However, the
chosen groups do cover five large and common, but quite dissimilar, patient
groups. Furthermore, the health care professionals involved in the project
were probably somewhat more favourably disposed towards health outcome
assessments than in general, and it would have been very interesting to have
had a more negative group to compare with, since the attitude of the health
care professionals may influence the views of the patients. Also the patients in
this sample were probably somewhat more positive towards questionnaires
and health measurements than patients in general, since more hesitant
patients presumably would be less likely to have agreed to participate in the
project. On the other hand, not all our patients were positive and one would
expect those who were more negative to prefer the shortest instrument (i.e.
EQ-5D) when asked to choose. In our result, no definite answer can be gained
by looking at those patients who were indifferent or negative towards health
outcome assessment in routine health care. Compared to those who were
positive, fewer patients (5% vs. 25%) preferred SF-36, but at the same time

53
Discussion

about the same proportion of patients preferred EQ-5D (10% vs. 8%), i.e. more
patients did not state a preference for either instrument.

Another point to be noted about paper IV is that conclusions about the

preferences of HRQoL-instrument versus the respondent satisfaction
summary score are based on a relatively small number of participants.
Moreover, the validity of the respondent satisfaction summary score has not
been tested on another material than that described in this paper.

54
 Discussion

Summary

The following is a brief summary of the results in relation to the aims of the
thesis:

• Psychological resources (Self-esteem, SOC, and Perceived Control) as

well as psychological risk factors (CES-D) were found to relate
independently to HRQoL (SF-36) in the expected directions (positive
relations for resources and negative relations for risk factors), but with
fewer sex differences than expected. (Paper I)

• Low HRQoL (SF-36) was found to relate to higher levels of

inflammatory biological factors (CRP, IL-6, and MMP-9), and, especially
regarding IL-6, many association remained significant, though
attenuated, after adjustment for age, sex, disease, lifestyle and
psychological factors. (Paper II)

• The new comorbidity index HRQL-CI received higher R2 values than the
commonly used CCI regarding the impact of comorbidity on HRQoL
(SF-36 and EQ-5D). However, regarding mortality the CCI showed a
more obvious gradient between those who died within a year of
answering the questionnaires, within ten years, or who were still alive
after ten years. (Paper III)

• Using measures of HRQoL for health outcome assessments (i.e. as

patient-reported outcome measures) in routine health care was regarded
as valuable by the majority of the patients in the study. The respondent
satisfaction summary score was in most cases equal, i.e. SF-36 and EQ-
5D were found to be quite similar regarding the cognitive response process
(understanding and responding to the items in the EQ-5D and the SF-
36) and patient-perceived content validity (if the instruments gave patients
the ability to describe their health in a comprehensive way). (Paper IV)

55
Discussion

Conclusions

The four papers in the thesis investigated different aspects of HRQoL that are
important for the implementation of the use of measures of HRQoL within the
health care system. Hence, in their own way, they all and together, contribute
to removing obstacles in the implementation process.

Specifically, the findings in paper I suggest that, for both sexes, measures of
HRQoL do not merely provide an assessment of absolute function but are also
conditioned by the way people perceive their own ability. The associations
between HRQoL and the inflammatory biomarkers found in paper II present a
possible explanation for the previously observed ability of HRQoL to predict
mortality risk, implying that low HRQoL might be an important sign of
increased biological vulnerability. The results of both papers I and II
emphasize the importance of using patient-reported outcome measures within
the health care system to identify patients with low HRQoL, for further health
promoting interventions aiming at supporting patients psychological
resources, such as coping ability and self esteem.

In paper III the new Health-related Quality of Life Comorbidity Index

(HRQL-CI), explicitly developed for use in HRQoL outcomes studies, was
further validated as a measure of comorbidity. It showed greater explanatory
power than the frequently used Charlson Comorbidity Index (CCI) regarding
impact on HRQoL. However, regarding mortality, the CCI discriminated
better, in line with its original purpose as a mortality predictor. Utilising
morbidity data in the form of ICD codes from mandatory, highly valid
national health data bases (such as the Swedish National Inpatient register)
instead of from medical records were found to be useful in a large study of
this kind (where using data from medical records may be impractical).

Finally, paper IV reported that the majority of patients considered health

outcome assessment within routine health care to be valuable. They found
both HRQoL-instruments SF-36 and EQ-5D easy to understand and answer,
but stated no preference regarding usage in routine health care. Among those
who did state a preference, SF-36 was more often preferred than EQ-5D, even
among those who found the shorter EQ-5D easier to use. Therefore, in the
choice between SF-36 and EQ-5D, this study did not find questionnaire length
and ease of response to be crucial arguments.

56
 Discussion

Future directions

The increased use of HRQoL instruments in health care is often part of an

explicit goal of focusing on health outcomes so that the needs of people may
be served in a more holistic and patient-centered manner. Since these
measurements will be used as a basis for decision-making on health policy and
medical interventions, it is essential that we continually update and re-
evaluate what we are thereby measuring, as in papers I and II. The study
population in paper III might be used as a reference population for patient-
based HRQoL outcomes studies using the HRQL-CI to adjust for comorbidity,
or be used for investigating HRQoL as a predictor of mortality in a general
population, using the comorbidity index CCI for adjustments. The results of
paper IV support the future involvement of patients in the continued
development of patient-reported outcome measures and use of such measures
to improve health care.

Additionally, besides the pressing need for studies specifically designed for
examining the usefulness of HRQoL for quality improvement work,
implementation studies are needed. These should investigate the
implementation of the innovation “using HRQoL-instruments as patient-
reported outcome in routine health care as a means of improving the care
given”.

57
Acknowledgements

ACKNOWLEDGEMENTS
I would like to sincerely thank everyone who in any way has contributed to
the completion of my thesis, and especially my supervisor professor
Margareta Kristenson, my co-supervisor professor Mitra Unosson, my co-
authors (in alphabetical order) Preben Bendtsen, Madeleine Borgstedt-Risberg,
Jan Ernerudh, Peter Garvin, Lotti Orwelius, Folke Sjöberg, and Marika
Wenemark, and also Sven Almér and Kristina Burström for valuable
discussions and John Carstensen, Nadine Karlsson, Anders Nordlund, Lars
Walter, and Elisabeth Wilhelm for excellent statistical advice through the
years.
Furthermore, I would like to posthumously thank my former co-
supervisors professor Lis-Karin Wahren and Ragnhild Raak, who both sadly
passed away much too early.

Margareta, tack för ändlöst tålamod och ständigt stöd genom åren, och för att
du frikostigt delat ditt stora kunnande inom detta forskningsområde med mig.
Utan dig hade det aldrig blivit någon avhandling!

58
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