Are Neuroticism, Perceived Stress, and Adverse Life Events Risk Factors for Functional Somatic Disorders: DanFunD
Conditions: Irritable Bowel Syndrome, Fibromyalgia, Chronic Fatigue Syndrome, Somatoform Disorders, Bodily Distress Syndrome, Medically Unexplained Symptoms, Medically Unexplained Syndrome
Sponsor: University of Aarhus

08.11.2022 
 
1 
 
Study protocol 
Official title: Are neuroticism, perceived stress, and adverse life events risk 
factors for functional somatic disorders?  
DanFunD  
 
Background 
Functional somatic disorders (FSD) are common disorders with a multifactorial aetiology involving 
biological, social, and psychological factors (1, 2). An often used explanation of the illness 
mechanisms behind FSD which is provided to the patients is, that FSD may be understood as a multi 
systemic physical response to stress (3). This relationship can be modelled as proposed in the 
Cognitive Behavioural Therapy (CBT) model of emotional distress where several cognitive, 
behavioural and psychological factors are thought to contribute to the onset and perpetuation of FSD 
(4). in the Cognitive Behavioural Therapy (CBT) model of emotional distress where several 
cognitive, behavioural and psychological factors are thought to contribute to the onset and 
perpetuation of FSD. Personality traits e.g. neuroticism contribute to give rise to our cognitive, 
behavioural, and psychological reactions. Furthermore, neuroticism with its heightened reactivity to 
stressors, has shown to be an important predictor of a generic vulnerability to both physical and 
psychological conditions. Having been exposed to previous adverse life events/traumas and 
childhood adversities has also showed to impact the risk of having FSD. This relationship has been 
proposed to be induced by a heightened response to stimuli, i.e. sensitisation, caused by physical and 
emotional distress triggering a hormonal cascade in the hypothalamus pituitary adrenal (HPA) axis 
(4, 5).  
So far, most studies into these aspects have been carried out in selected patient samples, and general 
population-based studies including a large randomly obtained are sparse. In three recent population-
based studies, we have established strong associations between FSD and neuroticism, perceived 
stress, and the accumulated number of experienced adverse life events (ALE), respectively (6). 
However, these studies were cross-sectional, thereby not providing insight to whether these factors 
were risk factors of FSD. More studies are needed for further elucidation on these aspects. 
 
Objective 

08.11.2022 
 
2 
 
The objective of this study is to explore the role of neuroticism, perceived stress, and the accumulated 
number of ALE, respectively, in the development and perpetuation of FSD. 
 
Hypotheses 
1) Higher neuroticism, higher perceived stress, and higher number of ALE at baseline are individual 
risk factors of having developed FSD in the 5-year period from baseline to follow-up:  
 
FSD non-case at baseline → FSD case at follow-up 
2)  Neuroticism, perceived stress, and the accumulated number of ALE positively contribute to the 
perpetuation of FSD from baseline to follow-up:  
 
 
 
 
FSD case at baseline → FSD case at follow-up 
 
Methods 
Study population 
Data from the DanFunD (Danish Study of Functional Disorders) baseline and 5-year follow-up 
investigation cohorts will be included (7, 8). The baseline cohort (gathered in the years 2012-2015) 
is a random sample selected through the National Civil Registration system among people living in 
10 municipalities in the western part of greater Copenhagen, Denmark, ages 18 to 76 years. The 
baseline cohort constitutes data from self-reported questionnaires (n=7,493) and diagnostic 
interviews data (n=1,590). The follow-up cohort (gathered in the years 2018-2020) consists of 
participants all born in Denmark, between 24 and 84 years of age. The follow-up cohort constitutes 
data from self-reported questionnaires (n=4,288) and diagnostic interviews data (n=1,094). 
 
Primary outcome (dependent variables): 
Preferably, if a sufficient number of incident and perpetuating cases are available at follow-up, 
participants with FSD will be defined as follows: 
 Participants fulfilling the criteria of the unifying diagnostic concept Bodily Distress 
Syndrome single- and multi-organ type will be defined with both questionnaires (9) and 
diagnostic interviews (10, 11) 

08.11.2022 
 
3 
 
 Participants with irritable bowel, chronic widespread pain, and chronic fatigue will be 
defined with questionnaires (12-14) 
 
Primary explanatory/independent variables: 
All primary explanatory variables will be self-reported. Neuroticism will be measured with the 
Danish version of the short-form NEO Personality Inventory (NEO-PI-Rsf) (15). Perceived stress 
will be measured with the 10-item Cohen's Perceived Stress Scale (16). The accumulated number of 
ALE will be measured with the Danish version of the Cumulative Lifetime Adversity Measure 
(CLAM) (17).  
 
Analytical plan  
All analyses will be performed using STATA version 17.0 (18).  
Descriptive statistics will be presented for all the three continuous explanatory variables across FSD 
diagnoses. Depending on data distribution, descriptive statistics will be presented as means and 
standard deviations or medians and interquartile ranges. 
 
Depending on number of incident and perpetuating cases at follow-up, a range of analyses will be 
conducted with the purpose of investigating if higher neuroticism, higher perceived stress, and higher 
accumulated number of ALE at baseline  
1) are individual risk factors for the development of FSD from baseline to follow-up 
2) are positively contributing to the perpetuation of an FSD from baseline to follow-up 
 
The first choice of analyses 
For hypothesis one, multiple logistic regression models will be performed with incident FSD cases at 
follow-up as primary outcome and baseline neuroticism, perceived stress, and accumulated number 
of ALE as explanatory primary variables. The effect of neuroticism, perceived stress, and the 
accumulated number of ALE will be reported from the same analysis as the effect when controlled 
for the effect from the other primary explanatory variables. Odds ratio (OR) with 95% confidence 
intervals (CI) will be used as measure of association; an OR > 1 supports the hypothesis. The reference 
group will constitute participants without FSD at both baseline and follow-up. Reference value of 
neuroticism, perceived stress, and the accumulated number of ALE will be set as the median value of 

08.11.2022 
 
4 
 
the total sample. In each analysis there will be controlled for the confounding effect of sex (with male 
as reference) and age (the median value of the total sample). 
 
For hypothesis two, multiple logistic regression models will be performed with FSD cases 
perpetuating from baseline to follow-up as primary outcome and baseline neuroticism, self-perceived 
stress, and accumulated number of ALE as primary explanatory variable. The effect of neuroticism, 
perceived stress, and the accumulated number of ALE will be reported from the same analysis as the 
effect when controlled for the effect from the other primary explanatory variables. Odds ratio (OR) 
with 95% confidence intervals (CI) will be used as measure of association; an OR > 1 supports the 
hypothesis. The reference group will constitute participants with FSD at baseline but without FSD at 
follow-up. Reference value of neuroticism, perceived stress, and the accumulated number of ALE 
will be set as the median value of the total sample. In each analysis there will be controlled for the 
confounding effect of sex (with male as reference) and (the median value of the total sample). 
 
The second choice of analyses 
If number of incident and perpetuated cases at follow-up are too low to perform the above multiple 
logistic regression models with incorporation of the three primary explanatory variables in one 
analyses per FSD definition, it will be investigated if the confounding primary explanatory variables 
can be reduced into one variable and incorporated in separate analyses instead. Hence, instead of 
performing one analysis per FSD definition, three logistic regression analyses will be performed for 
each FSD definition: 
1. An analysis investigating the effect of baseline neuroticism (primary explanatory variable) as risk 
factor for incident FSD/contributor to perpetuating FSD (primary outcome) with adjustment for 1) 
perceived stress and the accumulated number of ALE reduced into one variable, 2) sex, and 3) age. 
2. An analysis investigating the effect of baseline perceived stress (primary explanatory variable) as 
risk factor for incident FSD/contributor to perpetuating FSD (primary outcome) with adjustment for 
1) neuroticism and the accumulated number of ALE reduced into one variable, 2) sex, and 3) age. 
3. An analysis investigating the effect baseline accumulated number of ALE (primary explanatory 
variable) as risk factor for incident FSD/contributor to perpetuating FSD (primary outcome) with 
adjustment for 1) neuroticism and perceived stress reduced into one variable, 2) sex, and 3) age. 

08.11.2022 
 
5 
 
To find out if the confounding primary explanatory variables can be reduced into one variable, 
principal component analyses will be performed.  
The third choice of analyses 
If the second set of analyses cannot provide us with meaningful variables describing the primary 
explanatory variables, separate logistic regression analyses investigating the effect of neuroticism, 
perceived stress, and the accumulated number of ALE, respectively, will be performed with pre-
defined prioritisation of confounders. The prioritisation will be as follows (depending on the primary 
explanatory variable): 1) neuroticism, 2) perceived stress, 3) accumulated number of ALE, 4) sex, 
and 5) age.  
Dissemination of results 
Results from this study will be presented as an original research article published in an international 
peer-reviewed journal. 
 
References 
1. 
Burton C, Fink P, Henningsen P, Lowe B, Rief W. Functional somatic disorders: 
discussion paper for a new common classification for research and clinical use. BMC Med. 
2020;18(1):34. 
2. 
Henningsen P, Gundel H, Kop WJ, Lowe B, Martin A, Rief W, et al. Persistent Physical 
Symptoms as Perceptual Dysregulation: A Neuropsychobehavioral Model and Its Clinical 
Implications. Psychosomatic medicine. 2018;80(5):422-31. 
3. 
Saunders CT, H; Rask, MT; Pedersen, H; Rask, C; Burton, C; Frostholm, L The ways 
we explain functional somatic symptoms. Under preparation. 2022. 
4. 
Deary V, Chalder T, Sharpe M. The cognitive behavioural model of medically 
unexplained symptoms: a theoretical and empirical review. Clinical psychology review. 
2007;27(7):781-97. 
5. 
McEwen BS. Allostasis and the Epigenetics of Brain and Body Health Over the Life 
Course: The Brain on Stress. JAMA Psychiatry. 2017;74(6):551-2. 
 
 
 

08.11.2022 
 
6 
 
6. 
Petersen MC, TBW; Frostholm, L; Wellnitz, KB; Ørnbøl, E; Lamm, TT; Dantoft, TM; 
Eplov, LF; Jørgensen, T; Fink, P. Neuroticim and adverse life events are important determinants in 
functional somatic disorders. The DanFunD study. Scientific Reports In review. 2022. 
7. 
Dantoft TM, Ebstrup JF, Linneberg A, Skovbjerg S, Madsen AL, Mehlsen J, et al. 
Cohort description: The Danish Study of Functional Disorders. Clin Epidemiol. 2017;9:127-39. 
8. 
Jørgensen T, Dantoft TM, Weinreich Petersen M, Benros ME, Poulsen CH, Falgaard 
Eplov L, et al. Examine the public health impacts of functional somatic disorders using the DanFunD 
study. Scand J Public Health. 2022;50(7):988-94. 
9. 
Budtz-Lilly A, Fink P, Ørnbøl E, Vestergaard M, Moth G, Christensen KS, et al. A new 
questionnaire to identify bodily distress in primary care: The 'BDS checklist'. Journal of 
psychosomatic research. 2015;78(6):536-45. 
10. 
Fink P, Toft T, Hansen MS, Ørnbøl E, Olesen F. Symptoms and syndromes of bodily 
distress: an exploratory study of 978 internal medical, neurological, and primary care patients. 
Psychosomatic medicine. 2007;69(1):30-9. 
11. 
Petersen MW, Schröder A, Jørgensen T, Ørnbøl E, Dantoft TM, Eliasen M, et al. RIFD 
- A brief clinical research interview for functional somatic disorders and health anxiety. Journal of 
psychosomatic research. 2019. 
12. 
Kay L, Jorgensen T. Redefining abdominal syndromes. Results of a population-based 
study. Scandinavian Journal of Gastroenterology. 1996;31(5):469-75. 
13. 
White KP, Harth M, Speechley M, Ostbye T. Testing an instrument to screen for 
fibromyalgia syndrome in general population studies: the London Fibromyalgia Epidemiology Study 
Screening Questionnaire. The Journal of rheumatology. 1999;26(4):880-4. 
14. 
Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, et al. 
Development of a fatigue scale. Journal of psychosomatic research. 1993;37(2):147-53. 
15. 
Hansen HM, EL. Dokumentation for den danske udgave af NEO PI-R og NEO PI-R 
Kort Version.  NEO PI-R Manual - Klinisk. Frederiksberg Bogtrykkeri A/S: Hogrefe Psykologisk 
Forlag A/S; 2004. 
16. 
Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health 
Soc Behav. 1983;24(4):385-96. 
17. 
Carstensen TBW, Ornbol E, Fink P, Jorgensen T, Dantoft TM, Madsen AL, et al. 
Adverse life events in the general population - a validation of the cumulative lifetime adversity 
measure. Eur J Psychotraumatol. 2020;11(1):1717824. 

08.11.2022 
 
7 
 
18. 
StataCorp. Stata Statistical Software: Release 17. College Station, TX: StataCorp LLC: 
College Station, TX: StataCorp LLC.; 2021.