Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2, previously called Neurofibromatosis type 2) are rare genetic conditions that both cause benign nerve growths, various health problems and reduced life expectancy. Individuals with NF1 often experience difficulties with learning, social interaction and communication. In research studies, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are commonly diagnosed or suspected following screening tests. Surveys undertaken with individuals with NF1 or NF2 often report symptoms of anxiety, depression, and stress. It is not clear how often mental health conditions are diagnosed and treated among individuals with NF1 or NF2 within the NHS.
We will study all individuals diagnosed of NF1 and NF2 as recorded in their GP or hospital record. We will determine how common NF1 and NF2 are diagnosed. We will examine how often these individuals are diagnosed with mental health conditions and prescribed related medication. We will make comparisons between individuals with and without NF1 or NF2. We will look at how these and other conditions occur over time and the causes of deaths. Finally, we will study how often individuals with NF1 or NF2 use healthcare within the NHS (including how often people see their GP and the reasons and frequency of hospital admissions and outpatient appointments).
Working with our Patient and Public Involvement and Engagement partners, we will share our findings widely and make recommendations relevant for health and social care, education, and employment services. Our study will provide a framework for other rare conditions.
Neurofibromatosis type 1 (NF1) and NF2-related schwannomatosis (NF2, formerly Neurofibromatosis type 2) are rare genetic conditions previously considered analogous. NF1 is characterised by cutaneous features, neurofibromas, optic pathway gliomas, variable learning difficulties and elevated malignancy risk. NF2 is considerably less common and causes bilateral vestibular schwannomas, meningiomas and spinal ependymomas. Small studies and questionnaire-based research report adverse physical and mental health outcomes and excess mortality risk in both conditions. No population-based studies have used linked primary care, secondary care and mortality datasets to investigate this further.
Our study population will consist of individuals registered with a CPRD Aurum contributing practice with a diagnosis of NF1 or NF2 recorded in their primary or secondary care record. A comparator group of unaffected individuals will be matched on age, sex and registered GP. Most diagnostic codes do not distinguish between NF1 and NF2, although separate groups will be determined using condition-specific supporting codes. Related approaches were used to establish Denmark’s NF1 registry and examined cancer outcomes using Hospital Episode Statistics.
Three phases of study are planned. Phase 1 will investigate the prevalence and incidence of NF1 and NF2. Phase 2 will investigate mental health outcomes and psychotropic medicine prescriptions from 2000 onwards. Phase 3 will investigate common and condition-specific phenotypes across a life course and cause-specific mortality. Phase 3 will include a nested healthcare utilisation study from 2008 onwards. Outcomes will be stratified by sex, age, ethnicity and Index of Multiple Deprivation quintiles. Cumulative incidence (absolute risk) will be calculated using survival analysis techniques accounting for varying person-time at risk and competing risks. Relative risks will be estimated by Cox regression models.
Working with our Patient and Public Involvement and Engagement (PPIE) partners, we will creatively disseminate our findings, offering cross-sector recommendations. Our study will provide a framework for examining other rare conditions.
• Incidence of psychiatric diagnoses, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), depression, anxiety disorders, obsessive-compulsive disorder (OCD), feeding or eating disorders, personality disorders, post-traumatic stress disorder (PTSD), bipolar affective disorder, schizophrenia, severe mental illness (SMI), dementia, alcohol and drug misuse.
• Prevalence of ASD and ADHD.
• Incidence of self-harm.
• All self-harm episodes (i.e., including first and subsequent recorded episodes; i.e., self-harm repetition).
• Incidence of prescriptions of psychotropic medications with sub-categories including antidepressants, benzodiazepines, antipsychotics, and medications used for dementia, ADHD, and ASD.
• All prescriptions of psychotropic medications with sub-categories (i.e., including the first and subsequent prescriptions).
• Incidence of prescriptions of medication as categorised by BNF chapters.
• All prescriptions of medications, as categorised by BNF chapters.
• Incidence of primary care referrals to mental health services.
• Incidence of psychiatric inpatient care.
• Incidence and/or prevalence of phenotypes of individual conditions, comorbidities and multimorbidity (conditions selected based on clinical association with NF1 or NF2, core conditions, diseases in the Quality and Outcomes Framework (QOF) and ‘Long Term conditions’ (LTC) as defined by the NHS).
• Cause and age of death (all-cause and cause-specific mortality categorised using ICD-10 chapters across the full range).
• Incidence of primary care consultations.
• Incidence and primary diagnosis for inpatient and day-case hospital admissions.
• Incidence and speciality of outpatient hospital consultations.
Incidence for each outcome will be determined on monthly, quarterly, or yearly period, stratified by age group, sex, ethnicity, and patients’ residential neighbourhood-level IMD quintiles. Survival analysis techniques that account for varying person-time at risk and competing risks will be used to calculate cumulative incidence (absolute risk). Cox regression models will be used to model hazard ratios proportional hazard ratios (relative risks).
Darren Ashcroft - Chief Investigator - University of Manchester
Thomas Wright - Corresponding Applicant - University of Manchester
Matthew Carr - Collaborator - University of Manchester
Roger Webb - Collaborator - University of Manchester
Shruti Garg - Collaborator - University of Manchester
Siddharth Banka - Collaborator - University of Manchester
HES Admitted Patient Care;HES Outpatient;ONS Death Registration Data;Patient Level Index of Multiple Deprivation;Practice Level Index of Multiple Deprivation;CPRD Aurum Ethnicity Record;CPRD Aurum Mother-Baby Link;CPRD Aurum Pregnancy Register