MR1048a Continuation of AVON LONGITUDINAL STUDY OF PARENTS AND CHILDREN (ALSPAC) with for the ‘Children’ aspect only

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a transgenerational prospective birth cohort study that recruited women during pregnancy in the early 1990s. ALSPAC is designed to investigate influences on health, wellbeing and development across the life course. To inform these investigations ALSPAC collects information on genetic, epigenetic, biological, psychological, social and environmental exposures and a similar range of health, social and developmental outcomes. ALSPACs primary objective is to manage a long-term relationship with the study families and through this to build a DataBank resource that can be used to inform the investigation of diverse health and social hypotheses across the life course. To achieve this objective, data are collected through postal questionnaires, study clinical assessments, the collection of biological samples and through linkage to routinely collected health and social administrative records (including those held by the NHS Digital). ALSPAC is part of the Population Health Science group within the Bristol Medical School at the University of Bristol. Over £100m has been invested into ALSPAC by UK funding councils, charities (e.g. Wellcome Trust, British Heart Foundation, Asthma UK, Cancer UK), the NHS NHIR and directly from UK Government Departments. ALSPACs primary funding comes from the Wellcome Trust, The Medical Research Council and the University of Bristol.

The study seeks approval to link to, extract and use NHS Digital data (Flagging and Tracing, Hospital Episode Statistics and Mental Health Services Data Set) to inform a set of specific research investigations (listed below). These are specific questions – that require linked data - that have arisen from existing work, are led by University of Bristol investigators and are tied to health service improvements (as described later in the application).

Data provided by NHS Digital will be used by ALSPAC staff to facilitate study administration. Within this, the study will use participant contact details to help trace participants lost to follow-up (NHS contact details will be kept separate from the primary administrative database which will only be updated in the event of a participant responding to a contact request). The database will also be updated with fact of death and date of death in order to stop inappropriate future contact attempts.

This data processing agreement (NHS Digital reference number: MR1048) relates to the records of the ALSPAC index children (i.e. those born in the early 1990s). Eligibility for ALSPAC is defined as all mothers who were pregnant and due to deliver between 01/04/1991 and 31/12/1992 while resident in certain health administrative areas within the County of Avon. There were 19,600 live born children resulting from these pregnancies. At the point where the index children had reached 18 years of age, ALSPAC had enrolled 14,775 live born children from 15,247 pregnancy events. Recruitment of the remaining eligible index children, and members of their extended family units, remains ongoing. The ‘children’ are all now adults (mean 26 years old). Detailed description of eligibility and enrolment into ALSPAC are provided in two ‘Cohort Profile’ publications (http://www.bristol.ac.uk/alspac/researchers/cohort-profile/). This agreement is for data relating to the ~5,000 (precise numbers vary over time as eligible children enrol or, conversely, if enrolled children withdraw) index children who are enrolled into ALSPAC and where consent is the legal basis for these uses of their health service data. The index children have moved across the UK over time, so the cohort is no longer geographically distinguishable and cannot be filtered by geographical area.

All the projects detailed below are considered to be supported through explicit participant consent as a legal basis. The consent statements provide an explicit participant declaration for the linkage, extraction and research use of the records held by NHS digital.

ALSPAC participants are free to object to the studies use of their health records at any time through contacting the study. Records of objections are stored in a central database. ALSPAC will ensure that objectors wishes are upheld and they will not be included in the list of MR1048 participants for whom University of Bristol request records.

Specific purposes

Note: All specified researchers accessing NHS Digital data are University of Bristol contracted staff. Additional researchers and clinicians will advise the research team, but will not have access to individual personal information (i.e. only anonymous tabular information and statistical outputs that has been assessed for disclosure risk before consultation).

1. The effect of substance use in adolescence on mental health

Project: The study will use HES and MHSDS data, along with linked ALSPAC, GP data and education data, to investigate the association between mental health outcomes in young people and substance use in adolescence. The study will consider the use of three of the most widely used substances (alcohol, cannabis and tobacco), and their association with a diagnosis of a mental or psychological disorder in general, and specifically a clinical diagnosis of mood disorder (e.g. depression), anxiety or psychotic disorder (e.g. schizophrenia). ALSPAC collected data will provide information on substance use exposure and NHS Digital and GP data will provide objective assessments of mental health outcomes. NHS Digital and GP data may be used (where possible) to assess reporting accuracy within the self-reported data and to inform strategies to deal with missing data. This research will improve understanding of the risks of substance use, and the patterns of health service use for young people with mental health problems.

2. Chlamydia testing, infection, and sequelae in young people

Project: The study will use HES data, along with ALSPAC Data, GP records and linked National Chlamydia Screening records, to examine which factors influence Chlamydia testing, infection, and sequelae in young people. HES records will be used in the identification of pelvic inflammatory disease, ectopic pregnancy and reduced fertility amongst female ALSPAC participants with different evidence of exposure to Chlamydia (only negative tests, any positive tests, no evidence of testing). Reduced fertility will also be considered for male participants.

3. Assessing the Validity of Self-Reported Hospital Admissions and the Implications of study non-response

Project: The study will investigate and describe 1) the reliability and validity of self-reported hospital admissions and those recorded in HES and MHSDS and 2) assess if individuals with adverse health status profiles are more likely to be missing from study follow-up assessments. Self-reported data suffers from participant reporting bias introduced by factors such as recall error (i.e. the ability to accurately remember and report information) or social desirability (i.e. where perceived social influences impact on the answers individuals give). This project will help inform researchers, public health officials and policy makers as to how to interpret findings generated using self-reported data. Separately, it is known that participants who respond to studies are different to those who do not, and there is potential for health effects to impact on individuals’ likelihood to take part. Findings from this study will improve the understanding of study error (e.g. errors in prevalence estimates introduced where the likelihood of follow-up is differentiated by social, demographic or health conditions).

4. Investigating the accuracy of current estimates of self-harm

Project: The study will use the data to investigate a) the accuracy of current estimates of self-reported self-harm in the community (exploring the impact of non-response bias and misreporting) b) the long-term risk of hospital admission for self-harm in those self-harming in the community. This information is of critical importance to prevent over or under-estimation of the magnitude of self-harm, as policies based on inaccurate estimates may lead to the wrong policy decisions and incorrect prioritisation of particular health risk factors. Findings will also help to identify risk factors for future self-harm hospitalisation, and improve understanding regarding the relevance of findings from population-based studies using self report to clinical practice.

5. Early life causes of adolescent depression and anxiety

Project: The main research objective is to obtain accurate estimates of the association between maternal smoking and binge drinking during pregnancy and depression and anxiety in late adolescence and to investigate how (a) non-response and (b) misreporting in questionnaires affects estimates of this association. GP data will be used to provide depression and anxiety data for those individuals for whom University of Bristol do not have self-reported information (just over 65% of the cohort). The secondary objective is to obtain accurate estimates of the prevalence of depression and anxiety in late adolescence.

6. Investigating the association between IQ and self-harm

Project: The main research objective is to obtain a more accurate estimate of the association between IQ and suicidal and non-suicidal Self-harm among adolescents and to investigate how (a) nonresponse and (b) underreporting in questionnaires affects estimates of this association. GP, hospital admissions and A&E data will be used to provide self-harm data for those for whom the study does not have self-reported information. ALSPAC self-reported data will provide information on IQ and linked education records will provide proxy information on educational attainment. The GP and hospital data will also be used to correct for any under-reporting. The secondary research objective is to examine the extent to which adolescents seek GP help for self-harm and suicidal feelings.

7. Enabling the cross validation of asthma diagnosis using combinations of symptom and physiological data with GP and Hospital records

Project: The study will use the data to investigate a) the accuracy of current estimates of self-reported asthma in the community (exploring the impact of non-response bias and misreporting) and b) to calculate the extent of asthma severity from recorded hospital attendance/admissions as well as primary care emergency visits and treatment steps. There is concern that asthma may be socially patterned and that it is known that key exposure and confounders collected through observational studies certainly are. Therefore the concern is that assumptions made about the associations and confounding structures of relationships between environmental exposures and asthma outcomes may not be valid. Insights into the accuracy of ALSPAC self-reported and study clinic assessed asthma and the severity of asthmas will support University of Bristol's investigations into the genetic and environmental influences of asthma and current work into the impact of traffic pollution on asthma. The study will investigate i) the natural history of early wheeze in relation to later asthma outcomes; 2) the relationships between early wheezing and later clinical records to determine if a severe asthma profile can be detected in early childhood; 3) compare the impact of smoking and biomarker data from ALSPAC and respiratory function; 4) investigate the relationships between childhood infections and wheezing phenotypes with asthma and lung function in later childhood; 5) compare exposure to traffic pollution and asthma incidences (included A&E and admitted care). These projects may help confirm an association (identified elsewhere between early respiratory infection and decreased lung-function during childhood that may be antecedent to adult respiratory morbidity and possibly mortality; and, 6) investigate the relationships between treatment for asthmas in primary care, adherence to treatment and outcomes of asthma and lung function in later childhood and early adulthood.

8. Antecedent factors predictive of later ear disease

Project: Serious ear disease in later childhood and adulthood is distressing and burdensome on those effected and incurs treatment costs on the NHS. This project will investigate whether early signs of ear disease identified in ALSPAC at age 9 (categorised from photographs of the ear drum) are predictive of the development of serious ear disease requiring hospital treatment in later childhood and adulthood (as identified through HES).

9. Parental and child alcohol use and later criminality and injury outcomes

Project: The number of children who are affected by parental alcohol misuse is largely unknown

although estimates suggest a third of all UK children live with at least one parent who uses

alcohol hazardously. How this impacts on their health, mental health and education is

unclear. ALSPAC has multi informant measures of parental alcohol use reported by the mothers and partners during pregnancy and throughout childhood (allowing comparison of maternal and paternal effects) and child self-reported alcohol use. Self-reported and linked health and social outcome data will be assessed to help understand associations between parental alcohol use, child alcohol use and child cognitive, behavioural and emotional development. This research will study child engagement in criminal activities and injury. Linked HES records will contribute information on admission rates, accidents and injuries.

10. Understanding drug use pathways and resulting accident and injury

Project: When reaching their early twenties, almost 60% of ALSPAC participants have reported cannabis use at some point in their life, one in five has used ecstasy, and around one in ten young adults has used amphetamines, cocaine, or magic mushrooms. Given the adverse effects of adolescent drug use on adult outcomes, these numbers are alarming. This project will seek answers to the following questions:

• Why do so many young people experiment with drugs?

• How many of them are regular users?

• Is the use of illicit drugs systematically linked to alcohol and tobacco use?

• How are temporary and chronic use reflected in psychosocial adjustment and accomplishment of normative development milestones?

• Can protective factors be identified that increase the likelihood for youngsters to abstain and users to desist from using drugs before they can leave lasting damage?

HES data will be used in combination with ALSPAC self-reported data and data from linked GP and Education records. The linked HES data will contribute outcome data on A&E admissions patterns and injury outcomes.

11. Understanding drug use pathways and resulting mental health outcomes.

Project: When reaching their early twenties, almost 60% of ALSPAC participants have reported cannabis use at some point in their life, one in five has used ecstasy, and around one in ten young adults has used amphetamines, cocaine, or magic mushrooms. Given the adverse effects of adolescent drug use on adult outcomes, these numbers are alarming. This project will seek answers to the following questions:

• Why do so many young people experiment with drugs?

• How many of them are regular users?

• Is the use of illicit drugs systematically linked to alcohol and tobacco use?

• How are temporary and chronic use reflected in psychosocial adjustment and accomplishment of normative development milestones?

• Can protective factors be identified that increase the likelihood for youngsters to abstain and users to desist from using drugs before they can leave lasting damage?

HES and MHSDS data will be used in combination with ALSPAC self-reported data and data from linked GP and Education records. The linked HES and MHSDS data will contribute outcome data on mental health (cognitive function, depressive symptoms, psychotic symptoms).

12. Parental and child alcohol use and later mental health and development outcomes

Project: The study will use the data to investigate the associations between maternal substance use in pregnancy (where 'substance use' is defined as alcohol, tobacco, medicinal and recreational drug use and other stimulants (e.g., caffeine)) on child physiological, developmental and mental health outcomes. This component of ELASTIC will extend University of Bristol's research into child health and social outcomes of parents with differing alcohol consumption patterns by using linked HES and MHSDS records to study mental health outcomes including self-harm, suicide, addiction, anxiety, depression and psychosis. Linked education records will allow assessment of impacts on educational attainment and attendance.

13. Investigating the incidence and aetiology of psychosis.

Project: Psychotic experiences (PEs) are reported by around 5-10% of the general population. Although usually transient, they are associated with increased risk of schizophrenia over time, but the natural progression of PEs and transition to schizophrenia in adulthood has not been examined in detail previously. This study will:

i) Examine the proportion of children and adolescents with PEs who transition to clinical disorder in adulthood, and estimate the extent to which these individuals are identified by primary/secondary care services (i.e. highlighting potential unmet needs)

ii) Use detailed data on ALSPAC participants to identify those at highest risk of transition to psychotic disorder and inform tools for prediction

iii) Examine the extent to which associations observed between risk factors (e.g. cannabis use) and psychosis outcomes in ALSPAC and other cohort studies are likely to be over- or under-estimated due to selective loss to follow-up.

Linkage to primary and secondary care (HES and MHSDS) records is necessary to accurately identify individuals who have sought help for psychotic psychopathology, estimate the unmet public health needs of non help-seeking individuals with PEs, and examine the extent of potential biases in identifying risk factors. Access to full mental health data within primary care records will enable us to identify early (prodromal) symptoms in individuals who have not yet transitioned into a full-blown illness, to inform identification of those at highest risk of developing psychosis, and where closer medical supervision might therefore be appropriate.

14. Antecedents and health outcomes of intellectual disabilities and autism.

Project: The overarching aim of this project is to make use of HES and MHSDS data in conjunction with GP data, education records and ALSPAC parent and self-reported and clinic measures, to understand the i) prenatal and early life antecedents and ii) later life outcomes children with intellectual (learning) disabilities and autism. ALSPAC data will be used to identify prenatal and early life antecedents including maternal stress, anxiety and depression, substance use (including smoking, alcohol, cannabis and other drugs). The linked data will be used to cross validate individuals with intellectual disability and autism identified through questionnaire/clinic data and school records and identify further cases which may have been missed. Later life outcomes will include questionnaire and clinic measures of mental health as well as health service usage and diagnoses recorded in the linked data. The study will use the wealth of socioeconomic and lifestyle data collected in ALSPAC as potential confounders or mediators as appropriate. This research will further the understanding of the causes and adolescent and early adulthood outcomes including health needs and health inequalities of children with intellectual disabilities and autism.

15. Patterns of engagement with health and education services as predictors of child looked-after or in-need status.

Project: University of Bristol will use HES and MHSDS data, along with ALSPAC self-reported data and extracted general practice data, to examine whether patterns of health service engagement (e.g. missed routine appointments, regular attendance at A&E or out-of-hours services, receipt of care for real or alleged ‘accidental’ injuries) are useful predictors of a child becoming in need or looked-after. The study will also use HES and MHSDS data to investigate health outcomes and health service usage in ALSPAC participants who were in need or looked-after as children. Both mental and physical health will be considered. ALSPAC are engaged with the nascent National Child Looked After Observatory and local (Bristol) safeguarding teams in order to effectively disseminate the findings. Findings will also be published in appropriate academic journals and through conferences and local workshops (in partnership with the South West BRC, NHS CLHARC West and Bristol Health Partners).

16. Comparison of proposed HES extract with ALSPACs historical HES extract.

Project: ALSPAC has previously extracted HES records on ~3,000 consenting participants. This extract has informed published scientific investigations (e.g. Mars et al 2016: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841016/). In line with established scientific method it is necessary for ALSPAC to retain data supporting these investigations to support scientific challenges or replication studies. NHS Digital have expressed their preference that this historical extract is now securely destroyed. This project will compare – for the subset of consenting participants – if the initial extract is fully replicated in the proposed extract (bar change introduced through participants withdrawing consent) and if the data within these records are exact matches. If it is found that the historic extract is fully represented in the proposed extract then ALSPAC commit to securely destroying the historic extract (following the methodology provided in the security documentation). If it is found that the historic extract differs from the proposed extract then ALSPAC will securely archive the historic extract within the ‘safe haven’ and only make it available for scientific challenge/replication with prior consultation and approval of NHS Digital. It is not the intention to publish findings of this evaluation as it is for internal data management purposes.

As described above, this study is of great public and scientific interest. This work therefore relies on Articles 6(1)e (processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller) and 9(2)j (processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes) as the GDPR legal basis for processing the data disseminated under this Agreement.

The University of Bristol is the sole Data Controller under this Agreement; no other organisations have any involvement in determining the purpose for which the data supplied under this Agreement is used. ALSPAC make use of a secure research infrastructure developed to support the SAIL databank of Welsh routine health and administrative records by contracting the University of Swansea to provide a copy of the infrastructure to host ALSPAC data and data linked to ALSPAC. In this contractual arrangement, the University of Swansea is the Data Processor working to instruction from the University of Bristol who is the Data Controller (the contract will bind the University of Swansea to the same conditions (where relevant) as the University of Bristol have agreed to in their contract with the NHS Digital). Therefore, the University of Swansea are listed as the sole Data Processor under this Agreement.

Process Stage 1: Linking ALSPAC participants to the NHS/NHS Digital demographic database

(this stage has already taken place and further linkage will only be applicable for those cohort participants not originally linked)

ALSPAC have provided the NHS Digital (then NHS IC) with the personal identifiers of its study participants. NHS Digital commissioned linkage of the ALSPAC identifiers to the NHS central demographic register (now the NHS Spine). The product of this linkage (a link between ALSPAC MR1048 ID to NHS ID for each participant) is stored by NHS Digital and can be used to identify ALSPAC participants amongst NHS Digital records. Additional linkage may be required for newly enrolled cohort participants (approximately 15,000 of 20,000 eligible families are enrolled, but small numbers of the remaining 5,000 continue to enrol). A new Study ID will be allocated to these records.

ALSPAC will securely provide NHS Digital with separate lists identifying (by Study ID) the MR1048:consent participants. The lists will be filtered for up-to-date consent/dissent/withdrawal from ALSPAC status prior to sending.

Process Stage 2: NHS Digital Extraction of Records

HES and MHSDS records of ALSPAC participants will be identified using the existing MR1048 link and NHS Digital will extract copies of participants records where found (with the same processing for ‘new’ cohort participants).

MR1048 extracts will be sent to the ALSPAC Data Safe Haven. The extracts will be identified by Study ID and a check identifier (Date of Birth) to allow validation of the linkage. The extract will be sent to ALSPAC via the NHS Digital secure methodology (e.g. secure download site in an encrypted file). As ALSPAC are able to map MR1048 ID back to the ALSPAC administrative database these data extracts should be considered as being identifiable (even if pseudonymised).

The extracts will be received into the ALSPAC Data Safe Haven; which is managed by a small, specialist, team of ALSPAC health informatics experts (employed by the University of Bristol). The data will be stored on a secure encapsulated virtual machine located at the University of Bristol. The safe haven is kept separately from the ALSPAC administrative database (which contains participant identifiers). The Data Safe Haven design has been adopted to restrict access to identifiable data used for secondary purposes and to support the de-identification of the data prior to the bulk of the data uses. The Data Safe Haven governance arrangements have been reviewed and approved by an NHS Research Ethics Committee (REC) and the Health Research Authorities Confidentiality Advisory Group (HRA CAG). The Data Safe Havens security arrangements have been independently audited and certified to the NHS IG Toolkit and ISO27001 security standards (described below).

Process Stage 3: Data processing in the ALSPAC Data Safe Haven

The ALSPAC Data Safe Haven was designed in accordance with NHS policy [3]. Incoming, identifiable, data is stored in an encrypted format on encrypted and firewalled demarcated server space. Access to this server space is restricted to the Data Safe Haven team (by user access controls and access is only permitted from a small number of desktop computers based in secure offices at the University of Bristol). On entry to the Data Safe Haven a copy of the data is archived. The data are processed for the following purposes:

i. Assess Data & Data Linkage Quality: The data extract is compared against the agreed extract specification to ensure the content (both in terms of variables supplied and patients included) is correct. The linkage between ALSPAC participant and NHS record is quality checked using check variables (e.g. NHS ID to ALSPAC ID link is checked using date of birth and gender). The data values will be subject to logical error checks to assess if the value is consistent with the expected values (as defined in the source documentation). Inconsistent values will be recoded to missing (i.e. ALSPAC will not attempt to infer a correct value);

ii. Derivation: Derived data are created in order to assist in the de-identification of the data (e.g. Age in days at the time of a health event will be derived from Date of Birth and the event date) and to distil records extracted from multiple sources into a cohort longitudinal record (e.g. age in days will allow accurate sequences of events to be created when combining NHS Digital data with other data), and to assist the research process (e.g. 1) a range of read codes, hospital admissions and prescription data are used to derive an indicator to whether an individual has had any interaction with the NHS relating to/or being coded as asthma, and 2) routine records are used to inform statistical techniques, such as multiple imputation, which can address missing self-reported data). All derivation routines are applied through computer syntax, which is stored along with a documented record of the derivations;

iii. Linkage: The extract is linked to the internal ALSPAC individual ID numbers. The quality of the match is checked (see above). Linkage success or failure is assessed and documented within the data set (e.g., University of Bristol attempt to distinguish between failure to link due to a patient not seeking consultation, with failure to link due to insufficient identifiers and failure to link as the individual is resident outside of the catchment area of the data extract in question). The extract is processed to ensure it is harmonised with the ALSPAC longitudinal data set;

iv. De-Identification: The Safe Haven de-identification processes are designed to minimise the risks of disclosure through either: direct identification of an individual from a dataset (either accidentally or maliciously); through inference or through the potential of variables in combination to identify individuals; or the potential of inappropriately described outputs to identify individuals. The data are pseudonymised through removing NHS ID, name and address (where present). The extract is stored, within the Data Safe Haven, until information from it is requested for a research investigation.

v. Consent status checks: To account for changes in consent status over time the data extract is compared against a master consent list before being de-identified and made available for research (where further consent check stages are used, see Process Stage 6);

vi. Collation, Storage & Archiving: Copies of the data shared with researchers will be held securely within the Data Safe Haven. These will be used for audit purposes, to keep a record of research project sample selection (in order to allow follow-up assessments) and to fulfil the requirements that peer-reviewed findings are reproducible.

The identifiable data are only used for these data processing purposes, i.e. to facilitate and support research. The Identifiable data are not used in research investigations.

Process Stage 4: Participant Tracing Data

Where the data extracted from the NHS Digital relates to participant contact details and status (e.g. left England and Wales, fact of death) the members of Data Safe Haven staff will swap the ID used to extract the data for ALSPACs internal system ID and will then pass the information to the ALSPAC team whose role it is to maintain communications and relationships with participants. Neither NHS IDs or clinical data (beyond ‘alive/deceased’ status) will be provided to this team. The details are then used to update ALSPACs administrative database. These details are not provided to researchers, although address information is used to derive spatial identifiers and other values which are used in some research projects in a non-disclosive form.

ALSPAC will use a MRC Farr Institute ‘UK Secure eResearch Platform (UKSeRP) as a ‘secure research environment’ to combine records from different sources and to manage access to effectively anonymous sub-sets of combined records to specific researchers at a project level. UKSeRP is the technological infrastructure which supports the SAIL databank of Welsh routine health and administrative records. UKSeRP was developed by the Welsh MRC Farr Institute and is operated by two organisations: The NHS Wales Informatics Service (NWIS) and the University of Swansea Health Informatics Research Unit (HIRU). HIRU, through the MRC Farr Institute are making the UKSeRP infrastructure available to other research organisations. This means ALSPAC can make use of the full advantages of the secure research infrastructure developed to support SAIL by contracting the University of Swansea to provide a copy of the infrastructure to host ALSPAC data and data linked to ALSPAC. In this contractual arrangement, the University of Swansea will be Data Processor working to instruction from the University of Bristol who will be Data Controller (the contract will bind the University of Swansea to the same conditions (where relevant) as the University of Bristol have agreed to in their contract with the NHS Digital). UKSeRP has ISO27001 certification. This principle has been previously agreed as suitable for hosting linked NHS Digital records.

Process Stage 5: Linking ALSPAC participants to the UKSeRP

(this stage has already taken place and will not need repeating).

UKSeRP operates on a ‘split file’ approach to handling data; where identifiers are handled separately from clinical or individual attribute data. Identifiers are processed by NWIS (within the confines of the NHS); where they are processed by an algorithm which consistently converts incoming identifiers (e.g. NHS ID, name, date of birth) into an encrypted ‘Anonymous Linkage Field’ (ALF). In this way identifiers relating to the same person coming from multiple sources can be linked to the same ALF.

ALSPAC have already sent the identifiers to NWIS along with an externally meaningless ID number (KEY ID). NWIS have used the identifiers to create ALF IDs for ALSPAC participants. This is managed in such a way that 1) neither ALSPAC nor HIRU (who manage clinical data) are able to trace back ALF to a person’s identity and 2) ALSPAC are able to send clinical and other attribute data linked to KEY ID into the system which can then be automatically replaced with ALF in a ‘black box’ process.

Process Stage 6a & 6b: Sending NHS Digital and ALSPAC data from ALSPAC into the UKSeRP

ALSPAC research staff will replace the IDS on the de-identified data from the ALSPAC resource with the Key ID. The research staff will then securely (using AES-256bit encryption) send the data into the ALSPAC UKSeRP via the automated ‘gateway’ upload appliance.

ALSPAC data safe haven staff will also conduct the same process on the de-identified (see Stage 3) HES and MHSDS data. The HES and MHSDS data with Key ID into the ALSPAC UKSeRP will then be sent securely (using AES-256bit encryption) via the automated ‘gateway’ upload appliance.

Process stage 7:

The UKSeRP automated gateway system automatically replaces Key ID on incoming data with ALF ID (yet the system has no access to identifiers of the individuals used to produce ALF as these never leave the NWIS trusted third party). The data are then deposited in the ALSPAC UKSeRP. Meaning the ALSPAC staff have no means of linking ALF back to the ALSPAC databases, yet can use ALF to join records coming in from different sources or at different times (e.g. longitudinal updates).

Process Stage 8: Sub-setting and further anonymization of data prior to analysis

The researchers with approval to access the ALSPAC HES and MHSDS data will be created project specific ‘containers’ in UKSeRP that they can access. ALSPAC Data Safe Haven staff will sub-set the extracted data to minimise it to only the information needed to conduct the project investigation. Each project data set will be given its own unique ID. The researchers will not have access to the ALSPAC administrative database and therefore – given the technological, contractual, training and data management steps involved – the data can be considered to meet the Information Commissioner’s Office ‘effectively anonymous’ requirements (as defined in the ICO Anonymisation Code Of Practice – the University of Bristol include a separate document describing how their process meets the ICO requirements). Information about these hypotheses – and the use of NHS data sourced from the NHS Digital – will be posted on the study website:

- www.bristol.ac.uk/alspac/participants/young-people/.

Participants have been notified about this information, and each study newsletter includes updates and reminders (e.g. page 2 of:

- www.bris.ac.uk/alspac/external/newsletters/Childrenofthe90s_familynewsletter_2015.pdf )

Participants are able to opt-out of each individual study (before the study starts). This mechanism for providing on going fair processing information was developed with the HRA CAG with input from the Information Commissioners Office.

Project specific datasets are risk assessed and disclosure control is applied as deemed appropriate. Further disclosure control ranges from suppression of rare values and outliers to a state where the possibility of disclosure is rendered so challenging that the data can be considered as being effectively anonymised in line with the HSCIC Anonymisation Standard for the publication of Health and social Care Data [4]. Case selections will be assessed for risks of disclosure through inference (e.g., where a sample selection is made on the basis of a health condition), where this is a risk the Safe Haven staff will add control or masking cases.

The ALF used in the hypothesis specific dataset will undergo secondary encryption (reversible by ALSPAC) using an algorithm specific to each project. This means that a researcher with multiple projects will not be able to join data across the different datasets using ALF.

Participant consent status is checked as a final stage before making the data available to researchers.

Process Stage 9: Researcher access to data

Researchers are all contracted to University of Bristol (as described below). They will only be able to access the sub-partition(s) of the ALSPAC UKSeRP where their project specific data set is located. The UKSeRP technology restricts the actions that researchers can take, for example, it is not possible to plug in a USB stick, or to copy and paste or to connect from within UKSeRP to the internet. These restrictions – in conjunction with the training and binding agreements the researchers enter into – ensure good governance is maintained. Furthermore, the anonymization processes undertake (stages 3 and 6) are sufficient to reduce the risks of participant identifiably to a point that they are so remote that the data can be appropriately treated as effectively anonymous.

Researchers are allowed to remove data outputs (e.g. statistical findings, graphs, tables of aggregated findings) from UKSeRP through a controlled process where each output is reviewed and assessed for disclosure risk by ALSPAC Data Safe Haven staff prior to being released. ALSPACs Data Access policies require that researchers submit all publications, prior to submission for publication, to the ALSPAC Executive. The Executive Committee assess the publications for issues including checks for potential disclosure risks (e.g. tables summarising statistical outputs containing small cell counts). Disclosure checks will ensure compliance with the small number suppression rules contained within the HES Analysis Guide.

Data Specification: ALSPAC require life-course data from birth (i.e. maternity HES from 1990-1993) to the most recent finalised datasets (the University of Bristol appreciate that the records contained within different HES domains start at different points in time). This will allow the assessment of changing health status over time, changing severity of health status and the precursor health events leading up to health outcomes. ALSPAC require detailed information about these in order to build event sequence records comprising study collected information, linked health and social care records from NHS Digital and linked records from other providers (e.g., national pupil database records). The data request is limited to the cohort participants, but not limited geographically (given that participants have moved away from the original cohort catchment area).

Information Security: ALSPAC are committed to maintain high standards of information security and recognise that this is a key component of the trust relationship with participants and data owners alike. To achieve these standards ALSPAC have developed an Information Security Management System and associated management and governance structure that has been certified as meeting the ISO/IEC 27001:2013 Information Security standard. ALSAPC have submitted an NHS IG Toolkit assessment (edition 14: 2016/2017) which scored 97% in the last assessment.

Participant Consent: ALSPAC have provided fair processing materials to all participants via a postal campaign (those University of Bristol failed to contact will be excluded from the data extract request). The fair processing materials included a form through which participants could provide an explicit decision as to how they wanted their records to be used (returning this form was optional and the materials clearly described how ALSPAC would proceed with data sharing in the event of non-response). While the ‘fair processing’ campaign has concluded (having completed the REC approved protocol), ALSPAC continue to provide fair processing information via newsletters, the website and social media. Where participants are met up with (e.g., at a study data collection clinic), researchers ask them to complete a form outlining their explicit preferences.

In the event the participant changes their mind, then ALSPAC have a defined ‘withdrawal of consent’ protocol, which is available to participants via the study website:

- http://www.bristol.ac.uk/alspac/participants/

The policy allows participants to tailor their involvement in the study; either by altering permissions for the use of their health records in a specific project, the use of their health records in general, or their continued involvement in the study.

Research Purposes: Observational epidemiology aims to build a body of evidence related to any given topic. The investigations detailed below are designed to add to the relevant evidence base within that field. In themselves, these will typically not directly change NHS process. However, if replicated elsewhere and found to be important through systematic review then this could lead to policy change (e.g., NICE guidelines are frequently developed using systematic reviews of evidence). This is in contrast to other types of research (e.g., randomised controlled trial interventions or drug trials) that may provide stronger evidence of causation and can hence can lead to more immediate impact. To ensure full potential for impact on health and social care system, University of Bristol will ensure that the findings of investigations are well placed to feed into this process through ensuring publication in peer-reviewed journals that are fully indexed (e.g., pubmed, medline) and contain strong descriptive keywords (i.e., the findings will be discoverable by those conducting systematic reviews). This is the standard pathway to impact for observational research. Where possible, University of Bristol will also directly feed findings into national or local health care initiatives, and describe this where relevant (see below).

The ALSPAC Data Safe Haven team who will process the data are University of Bristol contracted staff. The Safe Haven team will prepare the data extracts and also give ‘Data Science’ input into the research process (i.e., through offering expert guidance on ALSPAC, data linkage processes, and on the interpretation and statistical processing of linked records within an epidemiological context). As such they will undertake processing which from data management to research analysis.

Previous data extracts

ALSPAC received flagging and tracing extracts for many years. The study also, in 2013, received an extract of HES records for ~3,000 consenting index children. This extract was envisaged to be a technical pilot and to investigate exemplar hypotheses. While successful (see https://understandingpatientdata.org.uk/case-study/investigating-self-harm-young-people), this extract had restricted potential due to its small sample size. The overlap between the data extract requested in this application and this past application will be evaluated. If the data are found to be exact duplicates then the previous extract will be securely destroyed. If they are not equivalents, then the previous extract will be encrypted and archived. It will not be made available for new research but may be used if previously published work is challenged. Once the recommended period for retaining data is complete, it will then be securely destroyed.

All investigations are due to be conducted between 2018 and 2020. Timings of the dissemination via journal articles will be constrained by the nature of the peer-review system. ALSPAC employ dedicated communications experts to assist with dissemination and engagement. Public and professional publicity (e.g., press releases, twitter posts, newsletter and Facebook articles) will be coordinated with the publication of findings. Dissemination via conferences and workshops will occur throughout the project period using interim results. For all the investigations, University of Bristol are committed to feeding back findings to participants. Participants will be informed through the ALSPAC print and social media newsletters. ALSPAC have a strong track record of running study engagement events which are designed with input from participants. In recent years, University of Bristol have held ‘data linkage’ themed evening lectures (e.g., http://www.bristol.ac.uk/alspac/external/presentations/how-we-are-using-your-records.pdf) and ‘ResearchFest’ (http://www.bristol.ac.uk/alspac/events/researchfest2012/), a day-long event with a wide series of public lectures in Bristol. Periodically the study produces a book (e.g., http://www.bristol.ac.uk/alspac/go/21st-book/) or YouTube videos (https://www.youtube.com/user/children90s) that describe findings and how University of Bristol use participant data. University of Bristol work with national and local media to disseminate findings, along with local attractions such as the MSHED museum of Bristol Life. Study findings from the applications described in this application will be incorporated into future activities.

Our specific project level dissemination plans are:

Project 1 (The effect of substance use in adolescence on mental health): The findings will be disseminated through appropriate epidemiological and public health academic journals (e.g. Addiction, International Journal of Epidemiology, Epidemiology, Wellcome Open) and findings (including interim results) at conferences (e.g. Society Academic Primary Care, MRC Farr Institute). The study will also work with members of the NHS Bristol Health Impact Team – Directed by the Professor in Public Health and Epidemiology & Head of Population Health Sciences - to feed findings to local service providers.

Project 2 (Chlamydia testing, infection, and sequelae in young people): This research will lead to a better understanding of sexual health and testing behaviours in young adults. It therefore has the potential to impact on public health policy. Findings will be published in an appropriate epidemiology journal(s) or those dedicated to sexual health findings (e.g. International Journal of Sexual Health) and presented at conference (e.g. Society of Academic Primary Care).

The Deputy Chair of the NICE Public Health Advisory Committee ((PHAC-F) - a committee responsible for the development of NICE public health guidance) - who is also the Director of the NHS Bristol Health Partners sexual health for population and patients health integration team, will lead professional dissemination.

Project 3 (Assessing the Validity of Self-Reported Hospital Admissions and the Implications of study non-response): Insights from this work will be published in an appropriate epidemiology/survey methods journal (e.g. Society of Longitudinal and Life Course Studies, BMC Medical Research Methodology, Survey Research Methods), at similar conferences and via ALSPAC study website and the CLOSER longitudinal research consortium website. To ensure this information is fed back to the NHS, University of Bristol will send the project findings to the Care Quality Commission Survey Coordination Centre who facilitate NHS Surveys.

Project 4 (Investigating the accuracy of current estimates of self-harm): Results from the study will be published in a suitable epidemiology/psychiatry journal and via the ALSPAC study website. Preliminary work (based on those participants who provided consent to link their data with medical records) has been published in Archives of Suicide Research (http://dx.doi.org/10.1080/13811118.2015.1033121), and has been selected as a case study by the understanding patient data taskforce that is developing mechanisms to communicate recommendations from the third Caldicott Review to the public (https://understandingpatientdata.org.uk/case-study/investigating-self-harm-young-

To ensure this information is fed back to the NHS, University of Bristol will communicate the project findings to the Bristol Health Partners Improving Care in Self-Harm ‘STITCH’ Health Integration Team. The Professor of Epidemiology is the academic lead for STITCH and also a member of both England’s and Bristol’s Suicide Prevention Advisory Groups and works closely with Public Health England, and will feed back relevant findings into NHS and Public health strategy.

Project 5 (Early life causes of adolescent depression and anxiety): Outputs will be published in academic journals (e.g. BMJ Open, International Journal of Epidemiology) and will inform methodological understanding of self-reported and public policy development. The Investigators will work with the Professor in Public Health and Psychiatry (University of Swansea, who will not have access to the data) to disseminate findings.

Project 6 (Investigating the association between IQ and self-harm): Findings will be published in academic publications topical to the condition and/or epidemiological methods (e.g., BMC Medical Research Methodology). The researchers will work with the Professor of Epidemiology and the Professor in Public Health and Psychiatry to ensure wide dissemination of study findings within relevant NHS community (see Projects 4 and 5).

Project 7 (Enabling the cross validation of asthma diagnosis using combinations of symptom and physiological data with GP and Hospital records): Findings will improve the understanding of asthma research based on the ALSPAC study and other studies using similar methodologies. Understanding will be disseminated via the Medical Research Council and Asthma UK funded STELAR asthma research consortium. Findings will help support research by the Medical Research Council and Natural Environment Research Council ERICA study that will assess associations between traffic pollution exposure and asthma outcomes in ALSPAC index children. The findings will support the Professor of Paediatric Respiratory Medicine’s programme of work, as a part of which he was a lead contributor to the Royal College of Physicians Every Breath We Take report into the lifelong impacts of air pollution (https://www.rcplondon.ac.uk/file/2914/download?token=qjVXtDGo). Study findings will be disseminated through the network of clinical respiratory paediatricians.

Project 8 (Antecedent factors predictive of later ear disease):

The Senior Research Associate in Medical Statistics and the Professor of Community Child Health will use the data to conduct the research evaluation. Clinical expertise will be provided by a Research Fellow in Social and Community Medicine and a Lecturer/NHS ENT surgeon, neither of whom will be provided with access to the data. Academic findings will be published in journals (e.g. International Journal of Audiology, BMJ Open, PLoS ONE). Study findings will be disseminated via the ENT liaison with the local CCGs Clinical Policy Review Groups. On a national level the ENT Specialty Lead for the NIHR Clinical Research Network: West of England will disseminate via the ENT National specialty group.

Project 9 (parental and child alcohol use and later criminality and injury outcomes): This work has been funded by the UK Medical Research Council and findings will be disseminated through academic routes (i.e. public health and health practitioner journals such as the BMJ as well as conferences such as the Society of Academic Primary Care), press releases and feedback to Department of Health policy makers. The Director of the NHS Bristol Health Partners ‘Drug and Alcohol’ Health Impact Team and will feed findings through into local care providers via this network.

Project 10 (Understanding drug use pathways on accident and injury)

We will publish in academic journals (e.g. Injury, Injury Prevention) and present at conferences (e.g. Society Academic Primary Care). The Director of the NHS Bristol Health Partners ‘Drug and Alcohol’ Health Impact Team and will feed findings through into local care providers via this network.

Project 11 (Understanding drug use pathways on mental health outcomes)

We will publish in focused academic journals (e.g. Drug and Alcohol Review) and present at similarly focused conferences (e.g. Managing Drug & Alcohol Problems in Primary Care Conference). The Director of the NHS Bristol Health Partners ‘Drug and Alcohol’ Health Impact Team and will feed findings through into local care providers via this network.

Project 12 (parental and child alcohol use and later mental health and development outcomes): Findings will be disseminated through academic routes (i.e. public health and health practitioner journals such as the BMJ as well as conferences such as the Society of Academic Primary Care), press releases and feedback to Department of Health policy makers. The Director of the NHS Bristol Health Partners ‘Drug and Alcohol’ Health Impact Team and will feed findings through into local care providers via this network. Findings relating to self-harm and suicide will be disseminated via the Professor of Epidemiology and the Professor in Public Health and Psychiatry.

Project 13 (Investigating the incidence and aetiology of psychosis). The Professor of Psychiatry and the co-director of the NHS Bristol Health Partners Psychosis Health Impact Team will use their clinical networks to disseminate findings. In addition to these clinical routes, the team will disseminate findings via academic publication (e.g. Psychological Medicine, Social Psychiatry and Psychiatric Epidemiology, European Psychiatry, Journal of Affective Disorders, Biological Psychiatry) and conferences (e.g. RCPsych International congress, IMFAR, Society for Epidemiological Research, The International Society for Developmental Origins of Health and Disease).

Project 14 Antecedents and health outcomes of intellectual disabilities and autism) Research findings will be disseminated via appropriate academic journals in the field of medicine, psychiatry, epidemiology and public health (e.g. BMJ, British Journal of Psychiatry, International Journal of Epidemiology, Wellcome Open) with findings and preliminary results being presented at conferences (e.g. RCPsych International congress, IMFAR, Society for Epidemiological Research, The International Society for Developmental Origins of Health and Disease). University of Bristol will also engage clinicians and service users through a variety of routes including ALDERN (Avon Learning Disability Education and research network- a network of clinicians, researchers and people with learning disabilities and their families. The lead investigator is an NHS consultant psychiatrist with extensive NHS roles.

Project 15 (Patterns of engagement with health and education services as predictors of child looked-after or in-need status.

Research findings will be disseminated by the emerging National Family Justice Observatory and the Children Looked After and In Need strands of the Administrative Data Research Network. University of Bristol will publish findings in relevant academic journals (e.g., Epidemiology, Wellcome Open, Child & Family Social Work, British Journal of Social Work, Adoption and Fostering). University of Bristol will disseminate relevant project findings to charities (e.g., NSPCC) and the NHS England ‘National Looked After Children Safeguarding Sub Group’.

Project 16 (Comparison of proposed HES extract with ALSPACs historical HES extract). The findings will not be disseminated but will be used internally to determine further data management options.

The described investigations have defined primary objectives to improve the understanding amongst some of the most concerning and prevalent areas of adolescent health; i.e., those relating to depression, psychosis, self-harm and suicide and substance use. Through this innovative use of a cohort study of adolescents linked to health records, University of Bristol can study exposure/outcome associations in marginalised groups (i.e., those in need/in care and those suffering from mental health conditions). Secondary objectives relate to a better understanding of self-reported measurement error which will be used to inform interpretation of evidence emerging from longitudinal research studies and therefore improve the accuracy of evidence informing health and social care policy development.

The project level anticipated benefits include:

Project 1 (The effect of substance use in adolescence on mental health):Based on study findings being disseminated in public health academic journals and conferences outlined in the Outputs for Project 1 This research will lead to a better understanding of the risks associated with substance use in adolescence, and the aetiology of mental health difficulties. It therefore has the potential to impact on public health policy.

Project 2 (Chlamydia testing, infection, and sequelae in young people): Effective reduction of adverse sexual health outcomes depends in part on an understanding of the factors and processes that predispose an individual to experience these outcomes. Such understanding depends on the ability to consider the influence of exposures acting across the life course from early childhood. Based on study findings being disseminated in public health academic journals and conferences outlined in the Outputs for Project 2 this research will lead to a better understanding of sexual health and testing behaviours in young adults. It therefore has the potential to impact on public health policy and General Practice administration of testing and testing guidance. The Deputy Chair of the NICE Public Health Advisory Committee ((PHAC-F) - a committee responsible for the development of NICE public health guidance), will lead professional dissemination

Project 3 (Assessing the Validity of Self-Reported Hospital Admissions and the Implications of study non-response): This methodological work that will support interpretation of ALSPAC data in other research projects (including the studies listed in this application). The work also has potential to support wider understanding and interpretation of bias in self reported health status (e.g. in the NHS Survey of Mental Health and Wellbeing). This is increasingly important as ‘Big Data’ approaches in contemporary Data Science are being used to inform health policy development through the analysis of combined study data and routine records. Study findings are to be disseminated via the appropriate academic journals and conferences outlined in the Outputs for Project 3 The potential benefits of Project 3 are illustrated by Project 4 and 5. While Project 3 will look at this in broad terms, Projects 4 and 5 will study some of the same issues at more depth within the context of specific health status.

Project 4 (Investigating the accuracy of current estimates of self-harm): Outputs from this project are of critical importance to prevent over or under-estimation of the magnitude of self-harm, as policies based on inaccurate estimates may lead to the wrong policy decisions and incorrect prioritisation of particular health risk factors. Findings will also help to identify risk factors for future self-harm hospitalisation, and improve understanding regarding the relevance of findings from population-based studies using self-report to clinical practice. . Study findings are to be disseminated via the appropriate academic journals and conferences outlined in the Outputs for Project 4. Preliminary work (based on those participants who provided consent to link their data with medical records) has been published in Archives of Suicide Research (http://dx.doi.org/10.1080/13811118.2015.1033121), and has been selected as a case study by the understanding patient data taskforce that is developing mechanisms to communicate recommendations from the third Caldicott Review to the public

Project 5 (Early life causes of adolescent depression and anxiety): Rates of anxiety and depression among children and adolescents in the UK have increased markedly in recent decades. Maternal smoking and alcohol consumption during pregnancy have been shown to be associated with many adverse psychological and behavioural outcomes among children, including in ALSPAC. The study would like to find out if these are risk factors for adolescent depression/anxiety. It is possible that the predictors of depression/anxiety may be different among individuals for whom self-reported data is held, compared to those who are no longer participating in the study. Study findings are to be disseminated via the appropriate academic journal outlined in the Outputs for Project 5 and will inform the methodological understanding of self-reported depression and anxiety and public policy development.

Project 6 (Investigating the association between IQ and self-harm): Findings from the research will add value to epidemiological research on self-harm and have wider benefit for the scientific community as it will increase knowledge of how best to combine self-harm data from different sources. With the inclusion of GP data, it will build on work being undertaken by colleagues and allow researchers to make appropriate decisions regarding missing self-reported data in their analyses. This research also has the potential to impact on public health policy as it will lead to a better understanding of who is at greatest risk of self-harm. This is important in terms of the appropriate design and targeting of interventions.

Project 7 (Enabling the cross validation of asthma diagnosis using combinations of symptom and physiological data with GP and Hospital records): Findings will improve the understanding of asthma research based on the ALSPAC study and other studies using similar methodologies. Specifically, longitudinal approaches will allow greater understanding on precursor GP reporting (e.g. presenting with wheeze) prior to diagnosis of asthma status. Accurate asthma status informed by objective assessment and therapeutic data will enable more accurate assessment of the environmental and genetic development influences of asthma and other respiratory conditions and be disseminated through the network of Clinical Respiratory Paediatricians.

Project 8 (investigating early signs of ear disease): Information about the prognosis of these early signs and their likely development into serious disease will inform clinical decision making about the need for early preventative surgical intervention, which is currently not known. Study findings will be published in appropriate journals and presented locally and nationally through specialist Networks.

Project 9 (parental and child alcohol use and later criminality and injury outcomes): In part, this research will address the evidence gap on in utero substance use exposure on child outcomes. The importance of this work has recently been highlighted in a systematic review of the effects of maternal alcohol consumption in pregnancy on later child outcomes (see http://www.bris.ac.uk/news/2017/september/drinking-during-pregnancy.html for more details), and the confusion this generates with conflicting press reporting of 'safe' levels of substance use public health guidance for pregnant women. The research will also consider childhood exposure to parental alcohol consumption and later child/adolescent/young adult alcohol consumption and resulting patterns of criminality and personal injury. Evidence of complex health and social associations is lacking due to the challenge of building sufficiently rich and diverse data to inform these investigations. The aim is that linked ALSPAC-HES-General Practice-Education records may inform understanding in this area and allow dissemination via relevant journals, press releases and appropriate networks as outlined in Outputs for Project 9.

Project 10 (Understanding drug use pathways on accident and injury)

Answering questions addressed in this research programme is crucial to understand drug use pathways and their antecedents and outcomes, through the life course. Contemporary and robust evidence drawn from large population samples is challenging given the complex and illicit subject matter. The aim is through linking a large scale population cohort (ALSPAC) with rich information on drug use with routine medical records (HES), University of Bristol will be able to improve the understanding of the impact of drug use on accident and injury. The intention is that this evidence will help inform effective policy development and to help understand the resource burden on A&E and other injury treatment services resulting from drug use.

Project 11 (Understanding drug use pathways on mental health outcomes)

Answering questions addressed in this research programme is crucial to understand drug use pathways and their antecedents and outcomes, through the life course. Contemporary and robust evidence drawn from large population samples is challenging given the complex and illicit subject matter. The aim is through linking a large scale population cohort (ALSPAC) with rich information on drug use with routine medical records (HES and MHSDS), University of Bristol will be able to improve the understanding of the impact of drug use on mental health and inform effective policy development.

Project 12 (parental and child alcohol use and later mental health and development outcomes): In part, this research will aim to address the evidence gap on in utero substance use exposure on child outcomes. The importance of this work has recently been highlighted in a systematic review of the effects of maternal alcohol consumption in pregnancy on later child outcomes (see http://www.bris.ac.uk/news/2017/september/drinking-during-pregnancy.html for more details), and the confusion this generates with conflicting press reporting of 'safe' levels of substance use public health guidance for pregnant women. The research will also consider childhood exposure to parental alcohol consumption and later child/adolescent/young adult alcohol consumption and resulting patterns of mental health and development outcomes. Evidence of complex health and social associations is lacking due to the challenge of building sufficiently rich and diverse data to inform these investigations. Via dissemination of study findings through the appropriate academic journals, press releases and local networks outlined in the Outputs for Project 12, the aim is that linked ALSPAC-HES-MHSDS-General Practice-Education records will inform understanding in this area.

Project 13 (aetiology of psychosis)

The main research objective is to obtain accurate estimates of how common psychosis-related outcomes are in the general population at the age of 24 years, and to use data from primary and secondary care to test whether the Psychosis-like Symptoms (PLIKS) interview used in the ALSPAC cohort is a valid measurement of psychosis. This will inform the interpretation of evidence from other studies using the PLIKS assessment. The secondary research objectives of this study are: i) to use the data from primary and secondary care to examine whether individuals lost to follow-up in the ALSPAC cohort are more or less likely to have a psychotic disorder, to help us understand to what extent research into psychosis in the ALSPAC cohort may be subject to bias; and ii) to identify early symptoms (prodromes) that occur in individuals who subsequently develop a psychotic disorder. The identification of prodromes may inform future initiatives to develop predictive algorithms and other tools to aid early identification of individuals with psychotic tendencies and study findings will support this via dissemination in relevant academic publications’ as detailed in the outputs for Project 13.

Project 14 (antecedents and health outcomes of intellectual disabilities and autism): Despite being disabling long term conditions, there is still very little research done on the causes or later life consequences of intellectual disabilities using unselected samples. Much of the research comes from clinical populations without control groups and thus liable to selection bias and confounding. This research will enhance the understanding of the antecedents and outcomes of these neurodevelopmental conditions including health inequalities. The project will improve the evidence base, and highlight issues that will be important for public health, service planning and commissioning. Dissemination routes detailed in outputs for Project 14

Project 15 (Patterns of engagement with health and education services as predictors of child looked-after or in-need status.

It is known that children in care have poorer health and education outcomes than those not in care. Early identification of children at risk of care status will aid early intervention. If the project identifies strong predictors it will investigate the potential for them being incorporated into a predictive tool to be used by health or social care professionals. Such a tool could be embedded in clinical software and improve the early identification of risk, a key challenge in the safe-guarding of children.

There have been >2,000 articles published using ALSPAC data; details of these can be found on the ALSPAC study website. A lay summary of some of the key ALSPAC findings is available here:

http://www.nature.com/news/children-of-the-90s-coming-of-age-1.10396

Notable examples of how ALSPAC findings have informed health and social policy include the following: (i) providing evidence to help persuade policy makers to support the ‘back to sleep’ policy change. This campaign started in the UK prior to ALSPAC's initiation, and initially advised parents not to place their babies to sleep in the prone position to reduce the risk of cot death. ALSPAC reassured sceptical health professionals and policy makers to proceed to recommending the supine position by demonstrating that this position was not associated with factors detrimental to child health.This finding also helped to persuade the US National Institutes of Health to carry out their own ‘Back to Sleep’ campaign that started in 2004. (ii) The finding that the application of skin creams containing peanut oil as a base ingredient to broken skin sensitized children to peanut allergy has led to some manufacturers altering the composition of the creams and the Committee on Safety in Medicines recommending that warning labels be included on all medicinal products containing peanut oil. (iii) ALSPAC has contributed to the debate on the consumption of fish during pregnancy. Established advice in the UK and USA was that on balance the risks of consuming toxins while eating more than two portions of fish per week outweighed the known benefits of eating fish. ALSPAC findings have influenced UK and US guidelines concerning fish consumption in pregnancy by demonstrating that benefits to child behaviour and verbal IQ, early development and visual stereoacuity outweigh potential harm of neurotoxicity from mercury and other sources of contamination. (iv) Evidence from ALSPAC including the influence of socio-economic position on life chances and aspirations were used to support the Independent Review on Poverty and Life Chances by Frank Field MP ‘The Foundation Years: Preventing Poor Children becoming Poor Adults’ and the Marmot Review Fair Society, Healthy Lives.

Genetic investigations using the candidate approach to studying gene variation and phenotypic outcome have described the influence of the filaggrin gene (FLG) on child susceptibility to atopic eczema and asthma. ALSPAC was the largest follow-up sample in the discovery that variation at the FTO gene is associated with increased adiposity and predisposition to obesity; using DXA assessment measures ALSPAC showed that the association was only present for fat mass and not lean mass. ALSPAC holds DNA collected at multiple time points, allowing researchers to explore DNA methylation and epigenetics. To realize the full potential of the resource ALSPAC is involved in genetic consortium studies including UK10K and EGG (early growth genetics).

Environmental studies have explored the antecedents of asthma where environmental exposures including prenatal maternal anxiety and paracetamol use, exposure to a range of cleaning products and excessive hygiene regimes have been found to influence the development of asthma in the child. Analysis of early life influences including maternal age, diet and smoking do not appear to influence blood pressure in the child although maternal weight gain in pregnancy is associated with increased risk of child adiposity and adverse cardiovascular risk factors. ALSPAC has also shown that fat mass contributes to higher bone mineral density.

Full references available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600618/