This systematic review aims to gather the necessary information to help us put a lifetime cost on ACEs. It is divided into two parts of investigation. The first part of the review investigates odds and relative risk ratios in the way ACEs affect the diseases identified later in this review. The second part aims to gather the evidence base for the cost of illness of the five main diseases in the UK that can be said to be partly caused by ACEs. This will allow the calculation of lifetime costs attributable to different denominations of ACEs. The question of attribution is key here.
The methodology we will be using, in a further study, to calculate the attributable cost of ACEs is population attributable fractions (PAF). This was first proposed by Levin  and developed by Miettinen  and others into what is known today as population attributable fractions. The idea is that there is seen to be a causal relationship between risk factors (ACEs) and adverse outcomes (disease). Then we can try to find out how much of the disease burden in any given population is reduced if we eliminate the causal factors. That is, how much of the disease would be eliminated if we got rid of ACEs entirely. Put another way it can be thought of as how much of a given disease is caused by ACEs.
“PAF is defined as the fraction of all cases of a particular disease or other adverse condition in a population that is attributable to a specific exposure”
(Mansournia et al,  p 1)
It is then possible to take the costs of a certain disease and calculate how much of that cost is attributable to ACEs by multiplying the PAF with the cost. The formula for PAF is as follows:
Where P = percentage of ACE endorsed in the sample and RR= relative risk ratio.
Usually in epidemiologic studies the relative risk or odds ratio is used to measure the strength of association between risk factors and outcomes. PAF takes this further and considers the prevalence of the risk factor into thus allowing for consideration of the importance of the risk factor. To populate this equation and to get estimates of PAF for different ACE counts we need information on the relative risk of diseases that can be partly attributed to ACEs. Further, we need information on the cost of diseases to calculate the cost that is attributable to ACEs. This is what this review seeks to achieve.
The main objective of this review was to provide evidence of the association between ACEs and the top five diseases in the UK in terms of expenditure. This was done by performing a meta-analysis of odds ratios that linked ACEs with these diseases. Another priority was to determine the lifetime costs associated with the diseases that were partly caused by ACEs.
According to the Nuffield Trust  as can be seen in figure 1.1 the main diseases, in terms of expenditure, in the UK are as follows: Mental Disorders, Circulatory disorders, cancer, muscoskeletal disorders and genitourinary disorders.
The questions asked in this systematic review are as follows:
- What are the odds ratios of the five disease types that link ACEs with these diseases?
- What are the lifetime costs associated with diseases that are partly caused by ACEs?
- Where do these costs fall (i.e., NHS, society etc)?
- What is the proportion of costs that are direct (i.e., healthcare costs) and indirect (i.e., productivity losses)?
- Is it possible to take costs from international sources and extrapolate them to the UK?
- Is it possible to take costs from one type of disease/condition e.g., cancer and extrapolate them to other types of diseases/conditions to get the total cost of a particular disease/condition?
To address the systematic review questions the Campbell and Cochrane Economics Method Group (CCEMG)  design, methods and processes have been followed. The systematic review is in two parts. The first part of the systematic review describes odds ratios for diseases partly caused by ACEs by searching for meta-analyses in this area; and the second part describes cost of illness studies for the five main diseases in terms of expenditure.
2.1 Inclusion and exclusion criteria – Part A of systematic review
Part A of the systematic review includes any study that discusses the odds ratios of how ACEs can partly cause those diseases. It does not include any RCTs or other trials of interventions to reduce the prevalence of these diseases. Systematic reviews are included as they give an idea of other studies that may have been overlooked in the systematic search. The time frame for the studies considered is not limited as the relationship between ACEs and the diseases is not considered to have changed much over time. Studies from areas outside Europe and the US are included in this review as the likelihood of ACEs causing these diseases is not considered to be vastly different based on geographical area.
2.2 Inclusion and exclusion criteria – Part B of systematic review
Part B of the systematic review includes any study that discusses the costs of those diseases identified in this chapter. It does not include any RCTs or other trial interventions to reduce the prevalence of these diseases but merely the economic costing of these diseases. Systematic reviews are excluded due to the volume of information included in them. The time frame for the studies considered is not limited as cost figures are inflated to reflect current (2020) prices. Studies from areas outside Europe and the US are excluded as are those that are not in the English or Welsh languages. Grey literature was also searched including official costing documentation, local authority and charity reports, intervention evaluations not subjected to peer review etc. This was to reduce publication bias in the results.
2.3 Types of outcome measures
Any evidence on the relative risk of those diseases due to the three categories of ACEs and the costs of diseases. The following are the outcomes we will consider under each part:
Part A: Relative risk evidence: risk ratios, odds ratios; diseases/conditions: mental illness, circulatory, cancer, muscoskeletal, genitourinary; ACEs - emotional, physical, and sexual abuse; neglect; household dysfunction.
Part B: Cost evidence: direct and indirect cost of illness, mental illness, circulatory, cancer, muscoskeletal, genitourinary; year of publication; cost year; methodology; time period; perspective
Figure 1.2 shows the systematic review flow chart. Both parts of the systematic review are guided by the CCEMG . The CCEMG framework has been used to create the search process and terms directly from the objectives. The databases, chosen for their relevance, are JSTOR, PubMed, Embase, Medline, Web of Science and Psycinfo.
A Bangor University health sciences librarian was consulted to define the search terms, in terms of Medical Subject Heading (MeSH) keywords and to help identify relevant databases. These keywords were grouped, and groups of keywords were linked using Boolean operators (and, not, or). The search terms for part A of the systematic review identified were:
Adverse childhood experience AND disease type (e.g., cancer)
Search terms for part B were as follows:
Cost of illness AND disease type (e.g., cancer)
Burden of illness AND disease type (e.g., cancer)
Cost* of disease AND disease type (e.g., cancer)
Economic burden of disease AND disease type (e.g., cancer)
Ancestral or hand searching was performed by searching the reference list of the chosen manuscripts. A search log was created to keep track of how the searching was conducted – this lists the search terms used and in which database they were used. This can enable the search to be replicated.
2.4 Selection of studies
Two researchers independently screened and identified paper title and abstracts for their relevance. After the initial screening those articles considered relevant were obtained. These remaining studies were further scrutinised according to the inclusion/exclusion criteria by the two reviewers so that they were finally included/excluded.