Investigating the epidemiology of CFS/ME in children using the ALSPAC cohort.

CONTEXT: Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) in adolescents is relatively common and causes significant suffering. 1% of secondary school children miss one day a week because of CFS/ME, and 0.1% are so severely affected they are unable to attend school at all. More than half of children are bed bound at some stage, losing on average one academic year of schooling. Despite the importance of paediatric CFS/ME to those affected, their families and society, little is known about how common CFS/ME is in adolescents, what causes it and what the chances are of an adolescent recovering without treatment. In addition, little is known about the different types of CFS/ME in adolescents. If there are different types, these may suggest different causes and may need different treatments. So far, researchers have been hampered in their research in to the causes of CFS/ME because this needs reliable information about children before they develop CFS/ME.These type of studies also need to be large enough to answer these types of questions. This lack of knowledge prevents the development of interventions to prevent or treat paediatric CFS/ME in adolescents. The MRC understands the importance of understanding the mechanisms of CFS/ME in children and knowing more about the different types, and have asked researchers for studies to investigate these areas in the recent CFS/ME highlight notice.

The Avon Longitudinal Study of Parents and Children (ALSPAC) provides a unique opportunity to investigate the risk factors for CFS/ME. It has enough data so that we can define CFS/ME at 3 ages (13, 16 and 17). Information on possible risk factors has been collected before the onset of CFS/ME from pregnancy to adolescence, and the number of children is sufficiently large that there is enough power to explore the causes of CFS/ME in adolescence in unprecedented detail.

AIM: to describe CFS/ME in adolescence in order to understand more about the mechanisms that cause it and develop ideas on how to treat and prevent CFS/ME in this age group.

OBJECTIVES
1. Find out how common CFS/ME is at 15 and 17 and whether it is more common in girls or boys. Describe whether CFS/ME in adolescents gets better if untreated.
2. Investigate the different types of CFS/ME in adolescents and whether it overlaps with chronic pain disorders which have similar features.
3. Investigate risk factors for CFS/ME at 13, 16 and 17 years. We will investigate factors that have been shown to be associated with CFS/ME in either adults or children such as activity, patterns of sleep, anxiety and depression and see whether they increase the risk of developing CFS/ME or are secondary to it.
4. Investigate "maintaining factors". We will compare children who have persistent fatigue between the time points with those that recover, to understand whether there is a difference in risk factors between the two groups.

POTENTIAL APPLICATIONS AND BENEFITS:
Clinicians and commissioners need to know how common adolescent CFS/ME to be able to plan CFS/ME services. Knowing whether CFS/ME gets better without treatment is important for clinicians, adolescents with CFS/ME and their carers who need to decide whether to have treatment. Information on the different types of CFS/ME is important as it may help us understand more about the mechanisms involved in different types. If there are different types of CFS/ME, it is important that researchers know this so they can study the same type of illness if they need to. Understanding what the risk factors are for CFS/ME should help researchers know more about the mechanisms that cause CFS/ME and prevent recovery. This should help researchers develop better treatment and prevention trials.

We will use data ALSPAC, a birth cohort (www.alspac.bris.ac.uk).
OBJECTIVE 1. Describe the prevalence and persistence of CFS/ME in adolescence
We will estimate the prevalence (total and by gender) of CFS/ME at 16 and 17 years by identifying adolescents with CFS/ME at 16 years. We will combine data with prevalence at 13 years and define adolescents with persistent fatigue at > 2 time points. We will examine the receiver-operator characteristics curves, of the Chalder fatigue scale to determine a threshold for severe fatigue.

OBJECTIVE 2. Investigate the heterogeneity of CFS/ME in adolescence
We will use latent class analysis (fitted with MPlus software) to identify symptom based phenotypes of CFS/ME at 17, compare these with a specialist clinic cohort and investigate whether associations of risk factors for CFS/ME differ between phenotypes. We will describe how many 17 year olds with CFS/ME fit the definition for chronic pain syndrome.

OBJECTIVE 3. Investigate risk factors for incidence of CFS/ME at 13, 16 and 17 years
We will investigate risk factors for CFS/ME at 13, 16 &17 years. We will use: logistic regression to relate each of the potential risk factors adjusted for age and sex; directed acyclic graphs (DAGs) to identify confounding and mediating factors; fractional polynomials to investigate the linearity of the relationship between activity and CFS/ME; linear regression to examine the continuous outcome (Chalder fatigues score) at age 16. For exposures measured at multiple times, we will create categorical variables coded as 0, 1, 2 or 3+ episodes, identify critical periods that are biologically plausible and compare regression models using likelihood ratio tests.

OBJECTIVE 4. We will use logistic regression to investigate predictors of persistent fatigue
Missing data: Where multiple imputation is appropriate, we will generate 50 imputed datasets, and combine estimates using Rubin's rules and we will explore whether weighting is helpful

This study will tackle two research areas that the MRC considers to be "important and tractable for research" according to the recent MRC highlight notice. Most of this research grant will be used to "improve the unerstanding of the mechanisms that lead to the early onset of the disease" by investigating risk factors for CFS/ME at 13, 16 and 17. We will also use this study to "improve the sub-phenoytping and stratification of CFS/ME" in adolescence as we agree that this will eventually lead to "better targeting of treatment".

The main research outputs will be: prevalence data for CFS/ME at 16 and 17, information on the natural history of CFS/ME and a detailed understanding of the risk factors for CFS/ME. Additional outputs will be exploration of the phenotypes at 17 and analyses of the appropriate threshold for the Chalder Fatigue Scale used in the diagnoses and treatment of adolescent CFS/ME in the UK. The main beneficiaries are adolescents with CFS/ME and their families/carers. Other beneficiaries are, policy makers, commissioners, clinicians and clinical service providers, CFS/ME researchers and the wider research community.

Adolescents with CFS/ME (and their families) will benefit:
a) In the short term (2014-'15) by increased awareness of how common CFS/ME and what the natural history is. Understanding the prevalence is helpful for adolescents and their families. Understanding the natural history will enable adolescents and their carers make informed choices about treatment.
b) In the medium/long term (2018-2022) understanding the aetiological risk factors and maintaining factors will enable us to understand more about disease mechanisms in CFS/ME. This should lead to the development and evaluation of new treatments, before they are assessed in large-scale clinical trials. Understanding what the risk factors are for the development of CFS/ME will enable us to explore whether strategies to prevent the development of CFS/ME are feasible before testing them in large scale trials. Because the health resource use and societal costs of this illness are so large, interventions to prevent the development of CFS/ME or improve treatment outcomes in children are likely to have a significant impact on the nation's wealth.

Paediatricians and clinicians that either work in specialist services or see children with CFS/ME in paediatric services including paediatric physiotherapists, occupational therapists and psychologists will benefit in the short term from:
1. understanding how common CFS/ME is, and which children are most likely to have CFS/ME. This will enable clinicians and commissioners to target services more appropriately.
2. Understand what the natural history is and what maintaining factors prevent children with CFS/ME getting better. This will enable clinicians to adapt treatment more appropriately.
3. If we identify modifiable risk factors, clinicians will be able to target these in treatment.

In the long term, identifying risk factors and the mechanisms of adolescent CFS/ME may lead to more effective different treatments or strategies to prevent the development of CFS/ME.

The CFS/ME research community will benefit from bringing new leaders of research from obesity, activity, sleep, psychology, psychiatry in to CFS/ME as well as training a post-doctoral researcher who will be encouraged to apply for a post-doctoral fellowship in CFS/ME at the end of the study.
The wider research community will benefit from the collaborations that will result.