Development of a breast cancer risk assessment and primary prevention pathway for women aged 30-39 years: Views of UK primary care providers on the role of primary care.

BACKGROUND: Identifying women aged 30-39 years at increased risk of developing breast cancer would allow them to receive screening and prevention offers. For this to be feasible, the practicalities of organising risk assessment and primary prevention must be acceptable to the healthcare professionals who would be responsible for delivery. It has been proposed that primary care providers are best placed to deliver a breast cancer risk assessment and primary prevention pathway. The present study aimed to investigate a range of primary care provider's views on the development and implementation of a breast cancer risk assessment and primary prevention pathway within primary care for women aged 30-39 years. METHODS: Twenty-five primary care providers working at general practices in either Greater Manchester or Cambridgeshire and Peterborough participated in five focus groups (n = 18) and seven individual interviews. Data were analysed thematically and organised using a framework approach. RESULTS: Three themes were developed. Challenges with delivering a breast cancer risk assessment and primary prevention pathway within primary care highlights that primary care are willing to facilitate but not lead delivery of such a pathway given the challenges with existing workload pressures and concerns about ensuring effective clinical governance. Primary care's preferred level of involvement describes the aspects of the pathway participants thought primary care could be involved in, namely co-ordinating data collection for risk assessment and calculating and communicating risk. Requirements for primary care involvement captures the need to provide a training and education package to address deficits in knowledge prior to involvement. Additionally, the reservations primary care have about being involved in the management of women identified as being at increased risk are discussed and suggestions are provided for facilitating primary care to take on this role. CONCLUSIONS: Despite optimism that primary care might lead a breast cancer risk assessment and primary prevention pathway, participants had a range of concerns that should be considered when developing such a pathway.

Feasibility and acceptability of offering breast cancer risk assessment to general population women aged 30-39 years: a mixed-methods study protocol.

INTRODUCTION: Breast cancer incidence starts to increase exponentially when women reach 30-39 years, hence before they are eligible for breast cancer screening. The introduction of breast cancer risk assessment for this age group could lead to those at higher risk receiving benefits of earlier screening and preventive strategies. Currently, risk assessment is limited to women with a family history of breast cancer only. The Breast CANcer Risk Assessment in Younger women (BCAN-RAY) study is evaluating a comprehensive breast cancer risk assessment strategy for women aged 30-39 years incorporating a questionnaire of breast cancer risk factors, low-dose mammography to assess breast density and polygenic risk. This study will assess the feasibility and acceptability of the BCAN-RAY risk assessment strategy. METHODS AND ANALYSIS: This study involves women undergoing risk assessment as part of the BCAN-RAY case-control study (n=750). They will be aged 30-39 years without a strong family history of breast cancer and invited to participate via general practice. A comparison of uptake rates by socioeconomic status and ethnicity between women who participated in the BCAN-RAY study and women who declined participation will be conducted. All participants will be asked to complete self-report questionnaires to assess key potential harms including increased state anxiety (State Trait Anxiety Inventory), cancer worry (Lerman Cancer Worry Scale) and satisfaction with the decision to participate (Decision Regret Scale), alongside potential benefits such as feeling more informed about breast cancer risk. A subsample of approximately 24 women (12 at average risk and 12 at increased risk) will additionally participate in semistructured interviews to understand the acceptability of the risk assessment strategy and identify any changes needed to it to increase uptake. ETHICS AND DISSEMINATION: Ethical approval was granted by North West-Greater Manchester West Research Ethics Committee (reference: 22/NW/0268). Study results will be disseminated through peer-reviewed journals, conference presentations and charitable organisations. TRIAL REGISTRATION NUMBER: NCT05305963.

"I don't know what I'm feeling for": young women's beliefs about breast cancer risk and experiences of breast awareness.

BACKGROUND: Younger women are often diagnosed with advanced breast cancer. Beliefs about risk are instrumental in motivating many health protective behaviours, but there may be confusion around which behaviour is appropriate to detect breast cancer earlier. Breast awareness, defined as an understanding of how the breasts look and feel so changes can be identified early, is widely recommended. In contrast, breast self-examination involves palpation using a specified method. We aimed to investigate young women's beliefs about their risk and experiences of breast awareness. METHODS: Thirty-seven women aged 30-39 years residing in a North West region of England with no family or personal history of breast cancer participated in seven focus groups (n = 29) and eight individual interviews. Data were analysed using reflexive thematic analysis. RESULTS: Three themes were generated. "Future me's problem" describes why women perceive breast cancer as an older woman's disease. Uncertainty regarding checking behaviours highlights how confusion about self-checking behaviour advice has resulted in women infrequently performing breast checks. Campaigns as a missed opportunity highlights the potential negative effects of current breast cancer fundraising campaigns and the perceived absence of educational campaigning about breast cancer for this demographic. CONCLUSIONS: Young women expressed low perceived susceptibility to developing breast cancer in the near future. Women did not know what breast self-checking behaviours they should be performing and expressed a lack of confidence in how to perform a breast check appropriately due to limited knowledge about what to look and feel for. Consequently, women reported disengagement with breast awareness. Defining and clearly communicating the best strategy for breast awareness and establishing whether it is beneficial or not are essential next steps.

Quantifying the effects of risk-stratified breast cancer screening when delivered in real time as routine practice versus usual screening: the BC-Predict non-randomised controlled study (NCT04359420).

BACKGROUND: Risk stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) could provide a better balance of benefits and harms. We developed BC-Predict, to offer women when invited to the NHSBSP, which collects standard risk factor information; mammographic density; and in a sub-sample, a Polygenic Risk Score (PRS). METHODS: Risk prediction was estimated primarily from self-reported questionnaires and mammographic density using the Tyrer-Cuzick risk model. Women eligible for NHSBSP were recruited. BC-Predict produced risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5-<8% 10-year) to have appointments to discuss prevention and additional screening. RESULTS: Overall uptake of BC-Predict in screening attendees was 16.9% with 2472 consenting to the study; 76.8% of those received risk feedback within the 8-week timeframe. Recruitment was 63.2% with an onsite recruiter and paper questionnaire compared to <10% with BC-Predict only (P < 0.0001). Risk appointment attendance was highest for those at high risk (40.6%); 77.5% of those opted for preventive medication. DISCUSSION: We have shown that a real-time offer of breast cancer risk information (including both mammographic density and PRS) is feasible and can be delivered in reasonable time, although uptake requires personal contact. Preventive medication uptake in women newly identified at high risk is high and could improve the cost-effectiveness of risk stratification. TRIAL REGISTRATION: Retrospectively registered with clinicaltrials.gov (NCT04359420).

Accessing psychological therapies following self-harm: qualitative survey of patient experiences and views on improving practice.

BACKGROUND: Psychological therapies following an episode of self-harm should happen quickly to ensure patients receive the care they need and to reduce the likelihood of repetition. AIMS: We sought to explore patients' subjective experience of accessing psychological therapies following self-harm and their views on improving practice. METHOD: Between March and November 2019, we recruited 128 patients and 23 carers aged 18 years or over from 16 English mental health trusts, from community organisations and via social media. Thematic analyses were used to interpret the data. RESULTS: Participants reported long waiting times, multiple failed promises and rejection when trying to access psychological therapies following self-harm. Poor communication and information provision contributed to uncertainty, worsening mental health and further self-harm. Other barriers included: lack of tailored interventions, stigmatising responses, use of exclusionary thresholds to access services, and punitive approaches to treating these patients. Participant recommendations to improve access to psychological therapies included: (a) the importance of compassionate and informed staff; (b) having timely access to aftercare from well-funded and well-resourced teams; (c) continuity of care, improved communication, and support during waiting times and while navigating the referral process; (d) greater information on the availability and benefits of psychological therapies; and (e) greater choice and flexibility over interventions. CONCLUSION: Our findings identify long waiting times and inadequate service provision as barriers to high-quality and safe aftercare for patients who have self-harmed. Consistent with clinical guidelines, all patients should receive prompt aftercare and access to tailored psychological treatments following a self-harm episode.

Optimising the delivery of breast cancer risk assessment for women aged 30-39 years: A qualitative study of women's views.

BACKGROUND: Identifying women aged 30-39 years at increased risk of developing breast cancer could allow them to consider screening and preventive strategies. Research is underway to determine the feasibility of offering breast cancer risk assessment to this age group. However, it is unclear how best to deliver and communicate risk estimates to these women, in order to avoid potential harms such as undue anxiety and increase benefits such as informed decision-making. OBJECTIVES: This study aimed to investigate women's views on, and requirements for, this proposed novel approach to risk assessment. DESIGN: A cross-sectional qualitative design was used. METHODS: Thirty-seven women aged 30-39 years with no family history or personal history of breast cancer participated in seven focus groups (n = 29) and eight individual interviews. Data were analysed thematically using a framework approach. RESULTS: Four themes were developed. Acceptability of risk assessment service concerns the positive views women have towards the prospect of participating in breast cancer risk assessment. Promoting engagement with the service describes the difficulties women in this age group experience in relation to healthcare access, including mental load and a lack of cultural awareness, and the implications of this for service design and delivery. Impact of receiving risk results focuses on the anticipated impacts of receiving different risk outcomes, namely, complacency towards breast awareness behaviours following low-risk results, an absence of reassurance following average-risk results and anxiety for high-risk results. Women's information requirements highlights women's desire to be fully informed at invite including understanding why the service is needed. In addition, women wanted risk feedback to focus on plans for management. CONCLUSION: The idea of breast cancer risk assessment was received favourably among this age group, providing that a risk management plan and support from healthcare professionals is available. Determinants of acceptability of a new service included minimising effort required to engage with service, co-development of invitation and risk feedback materials and the importance of educational campaigning about the potential benefits of participation in risk assessment.

Family involvement, patient safety and suicide prevention in mental healthcare: ethnographic study.

BACKGROUND: Family involvement has been identified as a key aspect of clinical practice that may help to prevent suicide. AIMS: To investigate how families can be effectively involved in supporting a patient accessing crisis mental health services. METHOD: A multi-site ethnographic investigation was undertaken with two crisis resolution home treatment teams in England. Data included 27 observations of clinical practice and interviews with 6 patients, 4 family members, and 13 healthcare professionals. Data were analysed using framework analysis. RESULTS: Three overarching themes described how families and carers are involved in mental healthcare. Families played a key role in keeping patients safe by reducing access to means of self-harm. They also provided useful contextual information to healthcare professionals delivering the service. However, delivering a home-based service can be challenging in the absence of a supportive family environment or because of practical problems such as the lack of suitable private spaces within the home. At an organisational level, service design and delivery can be adjusted to promote family involvement. CONCLUSIONS: Findings from this study indicate that better communication and dissemination of safety and care plans, shared learning, signposting to carer groups and support for carers may facilitate better family involvement. Organisationally, offering flexible appointment times and alternative spaces for appointments may help improve services for patients.

Liaison psychiatry practitioners' views on accessing aftercare and psychological therapies for patients who present to hospital following self-harm: multi-site interview study.

BACKGROUND: Timely provision of aftercare following self-harm may reduce risks of repetition and premature death, but existing services are frequently reported as being inadequate. AIMS: To explore barriers and facilitators to accessing aftercare and psychological therapies for patients presenting to hospital following self-harm, from the perspective of liaison psychiatry practitioners. METHOD: Between March 2019 and December 2020, we interviewed 51 staff members across 32 liaison psychiatry services in England. We used thematic analyses to interpret the interview data. RESULTS: Barriers to accessing services may heighten risk of further self-harm for patients and burnout for staff. Barriers included: perceived risk, exclusionary thresholds, long waiting times, siloed working and bureaucracy. Strategies to increase access to aftercare included: (a) improving assessments and care plans via input from skilled staff working in multidisciplinary teams (e.g. including social workers and clinical psychologists); (b) supporting staff to focus on assessments as therapeutic intervention; (c) probing boundaries and involving senior staff to negotiate risk and advocate for patients; and (d) building relationships and integration across services. CONCLUSIONS: Our findings highlight practitioners' views on barriers to accessing aftercare and strategies to circumvent some of these impediments. Provision of aftercare and psychological therapies as part of the liaison psychiatry service were deemed as an essential mechanism for optimising patient safety and experience and staff well-being. To close treatment gaps and reduce inequalities, it is important to work closely with staff and patients, learn from experiences of good practice and implement change more widely across services.

The co-development of personalised 10-year breast cancer risk communications: a 'think-aloud' study.

BACKGROUND: Risk stratified breast cancer screening is being considered as a means of improving the balance of benefits and harms of mammography. Stratified screening requires the communication of risk estimates. We aimed to co-develop personalised 10-year breast cancer risk communications for women attending routine mammography. METHODS: We conducted think-aloud interviews on prototype breast cancer risk letters and accompanying information leaflets with women receiving breast screening through the UK National Breast Screening Programme. Risk information was redesigned following feedback from 55 women in three iterations. A deductive thematic analysis of participants' speech is presented. RESULTS: Overall, participants appreciated receiving their breast cancer risk. Their comments focused on positive framing and presentation of the risk estimate, a desire for detail on the contribution of individual risk factors to overall risk and effective risk management strategies, and clearly signposted support pathways. CONCLUSION: Provision of breast cancer risk information should strive to be personal, understandable and meaningful. Risk information should be continually refined to reflect developments in risk management. Receipt of risk via letter is welcomed but concerns remain around the acceptability of informing women at higher risk in this way, highlighting a need for co-development of risk dissemination and support pathways.

Challenges and adaptations to public involvement with marginalised groups during the COVID-19 pandemic: commentary with illustrative case studies in the context of patient safety research.

Patient and public involvement (PPI) is integral to research on patient safety in the NIHR Greater Manchester Patient Safety Translational Research Centre (NIHR GMPSTRC), and is central to our patient safety research within our theme focusing on people in marginalised groups. Due to the impact of COVID-19, researchers had to adapt how they do PPI. For marginalised groups, remote working and digital adaptations (the key adaptations made in accessing and utilising health services in the United Kingdom during COVID-19) can potentially lead to further marginalisation of people already marginalised and provide new barriers to others. This editorial showcases three case examples of PPI with marginalised groups during COVID-19, these are with: (1) adults with vision impairments, (2) adults and carers with lived experience of self-harm and/ or suicide and (3) adults with lived experience of homelessness. In these case examples, we focus on challenges relating to key aspects of PPI during the pandemic. First, setting up a PPI advisory group and secondly maintaining relationships and effective PPI with a pre-existing advisory group. We contrast these examples using more traditional ways of 'doing PPI' i.e. involving public contributors in various stages of the research cycle, with a more fully 'co-produced' approach to research when developing a new patient safety intervention. Important considerations for PPI with marginalised groups during COVID-19 include: how to avoid exacerbating the digital divide when using video conferencing for PPI, the need for enhanced awareness around flexibility and resources, and the value of working closely with specialist charities to enable adaptations that are sensitive to the changed circumstances and needs of PPI contributors.

The National Institute of Health Research (NIHR) Greater Manchester Patient Safety Translational research Centre (GMPSTRC) carries out research to improve patient safety. We work in partnership with patients and members of the public to plan, manage, design, and carry out the research. This is labelled as patient and public involvement. A key area of GMPSTRC research focuses on people who may be marginalised from healthcare and potentially suffer increased patient safety risks relative to the general population. COVID-19 impacted on research in multiple ways, notably how researchers work with members of the public. Remote working via the use of internet enabled technology has now become more commonplace, although this raises concerns about digital exclusion and how to address barriers when face-to-face PPI is not possible. This article showcases three examples of how researchers and public contributors with lived experience have adapted to working together during the COVID-19 pandemic. These case examples are: (1) setting up a public involvement group for developing an intervention to reduce medication errors for adults with vision impairments; (2) working with a pre-existing group of public contributors who are adults and carers with lived experience of self-harm and/or suicide; and (3) working with a charity called Groundswell who train and support researchers with lived experience of homelessness. Challenges during COVID-19 have been making video conferencing meetings accessible to members who have a range of different needs, and addressing the digital divide by allowing members flexibility in how they contribute to research. The article provides examples of how these challenges were addressed.

The perspectives of survivors of Hodgkin lymphoma on lung cancer screening: A qualitative study.

BACKGROUND: Hodgkin lymphoma survivors (HLS) are at excess risk of lung cancer as a consequence of HL treatment. HLS without a heavy smoking history are currently unable to access lung cancer screening (LCS) programmes aimed at ever smokers, and there is an unmet need to develop a targeted LCS programme. In this study we prospectively explored HLS perspectives on a future LCS programme, including motivating factors and potential barriers to participation, with the aim of identifying ways to optimise uptake in a future programme. METHODS: Semistructured telephone interviews were conducted with HLS, aged 18-80 and lymphoma-free for ≥5 years, selected from a clinical database (ADAPT). Participants provided informed consent. Data were analysed using inductive thematic analysis. RESULTS: Despite awareness of other late effects, most participants were unaware of their excess risk of lung cancer. Most were willing to participate in a future LCS programme, citing the potential curability of early-stage lung cancer and reassurance as motivating factors, whilst prior experience of healthcare was a facilitator. Whilst the screening test (a low dose CT scan) was considered acceptable, radiation risk was a concern for some and travel and time off work were potential barriers to participation. CONCLUSIONS: Our results suggest that most HLS would participate in a future LCS programme, motivated by perceived benefits. Their feedback identified a need to develop educational materials addressing lung cancer risk and concerns about screening, including radiation risk. Such materials could be provided upon an invitation to LCS. Uptake in a future programme may be further optimized by offering flexible screening appointments close to home.

'Wasn't offered one, too poorly to ask for one' - Reasons why some patients do not receive a psychosocial assessment following self-harm: Qualitative patient and carer survey.

OBJECTIVE: Psychosocial assessment following self-harm presentations to hospital is an important aspect of care. However, many people attending hospital following self-harm do not receive an assessment. We sought to explore reasons why some patients do not receive a psychosocial assessment following self-harm from the perspective of patients and carers. METHODS: Between March and November 2019, we recruited 88 patients and 14 carers aged ⩾18 years from 16 mental health trusts and community organisations in the United Kingdom, via social media, to a co-designed qualitative survey. Thematic analyses were used to interpret the data. RESULTS: Patients' reasons for refusing an assessment included long waiting times, previous problematic interactions with staff and feeling unsafe when in the emergency department. Two people refused an assessment because they wanted to harm themselves again. Participants reported organisational reasons for non-assessment, including clinicians not offering assessments and exclusion due to alcohol intoxication. Other patients felt they did not reach clinically determined thresholds because of misconceptions over perceived heightened fatality risk with certain self-harm methods (e.g. self-poisoning vs self-cutting). CONCLUSION: Our results provide important insights into some of the reasons why some people may not receive a psychosocial assessment following self-harm. Parallel assessments, compassionate care and specialist alcohol services in acute hospitals may help reduce the number of people who leave before an assessment. Education may help address erroneous beliefs that self-injury and self-harm repetition are not associated with greatly raised suicide risk.

Breast Cancer Risk Assessment and Primary Prevention Advice in Primary Care: A Systematic Review of Provider Attitudes and Routine Behaviours.

Implementing risk-stratified breast cancer screening is being considered internationally. It has been suggested that primary care will need to take a role in delivering this service, including risk assessment and provision of primary prevention advice. This systematic review aimed to assess the acceptability of these tasks to primary care providers. Five databases were searched up to July-August 2020, yielding 29 eligible studies, of which 27 were narratively synthesised. The review was pre-registered (PROSPERO: CRD42020197676). Primary care providers report frequently collecting breast cancer family history information, but rarely using quantitative tools integrating additional risk factors. Primary care providers reported high levels of discomfort and low confidence with respect to risk-reducing medications although very few reported doubts about the evidence base underpinning their use. Insufficient education/training and perceived discomfort conducting both tasks were notable barriers. Primary care providers are more likely to accept an increased role in breast cancer risk assessment than advising on risk-reducing medications. To realise the benefits of risk-based screening and prevention at a population level, primary care will need to proactively assess breast cancer risk and advise on risk-reducing medications. To facilitate this, adaptations to infrastructure such as integrated tools are necessary in addition to provision of education.

'Relieved to be seen'-patient and carer experiences of psychosocial assessment in the emergency department following self-harm: qualitative analysis of 102 free-text survey responses.

OBJECTIVES: We sought to explore patient and carer experiences of psychosocial assessments following presentations to hospital after self-harm. DESIGN: Thematic analysis of free-text responses to an open-ended online survey. SETTING: Between March and November 2019, we recruited 88 patients (82% women) and 14 carers aged ≥18 years from 16 English mental health trusts, community organisations, and via social media. RESULTS: Psychosocial assessments were experienced as helpful on some occasions but harmful on others. Participants felt better, less suicidal and less likely to repeat self-harm after good-quality compassionate and supportive assessments. However, negative experiences during the assessment pathway were common and, in some cases, contributed to greater distress, less engagement and further self-harm. Participants reported receiving negative and stigmatising comments about their injuries. Others reported that they were refused medical care or an anaesthetic. Stigmatising attitudes among some mental health staff centred on preconceived ideas over self-harm as a 'behavioural issue', inappropriate use of services and psychiatric diagnosis. CONCLUSION: Our findings highlight important patient experiences that can inform service provision and they demonstrate the value of involving patients/carers throughout the research process. Psychosocial assessments can be beneficial when empathetic and collaborative but less helpful when overly standardised, lacking in compassion and waiting times are unduly long. Patient views are essential to inform practice, particularly given the rapidly changing service context during and after the COVID-19 emergency.

What are the benefits and harms of risk stratified screening as part of the NHS breast screening Programme? Study protocol for a multi-site non-randomised comparison of BC-predict versus usual screening (NCT04359420).

BACKGROUND: In principle, risk-stratification as a routine part of the NHS Breast Screening Programme (NHSBSP) should produce a better balance of benefits and harms. The main benefit is the offer of NICE-approved more frequent screening and/ or chemoprevention for women who are at increased risk, but are unaware of this. We have developed BC-Predict, to be offered to women when invited to NHSBSP which collects information on risk factors (self-reported information on family history and hormone-related factors via questionnaire; mammographic density; and in a sub-sample, Single Nucleotide Polymorphisms). BC-Predict produces risk feedback letters, inviting women at high risk (≥8% 10-year) or moderate risk (≥5 to < 8% 10-year) to have discussion of prevention and early detection options at Family History, Risk and Prevention Clinics. Despite the promise of systems such as BC-Predict, there are still too many uncertainties for a fully-powered definitive trial to be appropriate or ethical. The present research aims to identify these key uncertainties regarding the feasibility of integrating BC-Predict into the NHSBSP. Key objectives of the present research are to quantify important potential benefits and harms, and identify key drivers of the relative cost-effectiveness of embedding BC-Predict into NHSBSP. METHODS: A non-randomised fully counterbalanced study design will be used, to include approximately equal numbers of women offered NHSBSP (n = 18,700) and BC-Predict (n = 18,700) from selected screening sites (n = 7). In the initial 8-month time period, women eligible for NHSBSP will be offered BC-Predict in four screening sites. Three screening sites will offer women usual NHSBSP. In the following 8-months the study sites offering usual NHSBSP switch to BC-Predict and vice versa. Key potential benefits including uptake of risk consultations, chemoprevention and additional screening will be obtained for both groups. Key potential harms such as increased anxiety will be obtained via self-report questionnaires, with embedded qualitative process analysis. A decision-analytic model-based cost-effectiveness analysis will identify the key uncertainties underpinning the relative cost-effectiveness of embedding BC-Predict into NHSBSP. DISCUSSION: We will assess the feasibility of integrating BC-Predict into the NHSBSP, and identify the main uncertainties for a definitive evaluation of the clinical and cost-effectiveness of BC-Predict. TRIAL REGISTRATION: Retrospectively registered with clinicaltrials.gov (NCT04359420).

Role of hypofractionated stereotactic radiotherapy in treatment of skull base meningiomas.

The objective of this paper is to examine the efficacy and safety of hypofractionated stereotactic radiotherapy (SRT) in the treatment of skull base meningiomas. Thirty-eight patients were treated with a median prescribed dose of 37.5 Gy in 15 fractions to the 80% isodose. Median follow-up was 47 months. Ten males and 28 females of median age 55.5 years were followed. SRT was the primary treatment in 15 patients, adjuvant in 10 and given for recurrence in 14 patients. On clinical follow-up 27 patients are unchanged and in six their symptoms have resolved. One patient had symptomatic deterioration and four patients have developed new symptoms. No patients have radiological evidence of progression. Our data suggest that conventional hypofractionated radiotherapy schemes for benign CNS disease may be useful in conjunction with stereotactic techniques. Such schemes are attractive in terms of resource allocation and where tumour size or cranial nerve tolerance is of concern.

Robust estimation of experimentwise P values applied to a genome scan of multiple asthma traits identifies a new region of significant linkage on chromosome 20q13.

Over 30 genomic regions show linkage to asthma traits. Six asthma genes have been cloned, but the putative loci in many linked regions have not been identified. To search for asthma susceptibility loci, we performed genomewide univariate linkage analyses of seven asthma traits, using 202 Australian families ascertained through a twin proband. House-dust mite sensitivity (Dpter) exceeded the empirical threshold for significant linkage at 102 cM on chromosome 20q13, near marker D20S173 (empirical pointwise P = .00001 and genomewide P = .005, both uncorrected for multiple-trait testing). Atopy, bronchial hyperresponsiveness (BHR), and forced expiratory volume in 1 s (FEV1) were also linked to this region. In addition, 16 regions were linked to at least one trait at the suggestive level, including 12q24, which has consistently shown linkage to asthma traits in other studies. Some regions were expected to be false-positives arising from multiple-trait testing. To address this, we developed a new approach to estimate genomewide significance that accounts for multiple-trait testing and for correlation between traits and that does not require a Bonferroni correction. With this approach, Dpter remained significantly linked to 20q13 (empirical genomewide P = .042), and airway obstruction remained linked to 12q24 at the suggestive level. Finally, we extended this method to show that the linkage of Dpter, atopy, BHR, FEV1, asthma, and airway obstruction to chromosome 20q13 is unlikely to be due to chance and may result from a quantitative trait locus in this region that affects several of these traits.

The validity and heritability of self-report osteoarthritis in an Australian older twin sample.

In order to investigate the genetic and environmental antecedents of osteoarthritis (OA), self-report measures of joint pain, stiffness and swelling were obtained from a population-based sample of 1242 twin pairs over 50 years of age. In order to provide validation for these self-report measures, a subsample of 118 twin pairs were examined according to the American College of Rheumatology clinical and radiographic criteria for the classification of osteoarthritis. A variety of statistical methods were employed to identify the model derived from self-report variables which would provide optimal prediction of these standardised assessments, and structural equation modelling was used to determine the relative influences of genetic and environmental influences on the development of osteoarthritis. Significant genetic effects were found to contribute to osteoarthritis of the hands, hips and knees in women, with heritability estimates ranging from 30-46% depending on the site. In addition, the additive genetic effects contributing to osteoarthritis in various parts of the body were confirmed to be the same. Statistically significant familial aggregation of osteoarthritis in men was also observed, but it was not possible to determine whether this was due to genetic or shared environmental effects.