Translation, validity and reliability of the British Sign Language (BSL) version of the EQ-5D-5L.

PURPOSE: To translate the health questionnaire EuroQol EQ-5D-5L into British Sign Language (BSL), to test its reliability with the signing Deaf population of BSL users in the UK and to validate its psychometric properties. METHODS: The EQ-5D-5L BSL was developed following the international standard for translation required by EuroQol, with additional agreed features appropriate to a visual language. Data collection used an online platform to view the signed (BSL) version of the tests. The psychometric testing included content validity, assessed by interviewing a small sample of Deaf people. Reliability was tested by internal consistency of the items and test-retest, and convergent validity was assessed by determining how well EQ-5D-5L BSL correlates with CORE-10 BSL and CORE-6D BSL. RESULTS: The psychometric properties of the EQ-5D-5L BSL are good, indicating that it can be used to measure health status in the Deaf signing population in the UK. Convergent validity between EQ-5D-5L BSL and CORE-10 BSL and CORE-6D BSL is consistent, demonstrating that the BSL version of EQ-5D-5L is a good measure of the health status of an individual. The test-retest reliability of EQ-5D-5L BSL, for each dimension of health, was shown to have Cohen's kappa values of 0.47-0.61; these were in the range of moderate to good and were therefore acceptable. CONCLUSIONS: This is the first time EQ-5D-5L has been translated into a signed language for use with Deaf people and is a significant step forward towards conducting studies of health status and cost-effectiveness in this population.

The theoretical and practical determination of clinical cut-offs for the British Sign Language versions of PHQ-9 and GAD-7.

BACKGROUND: The PHQ-9 and the GAD-7 assess depression and anxiety respectively. There are standardised, reliability-tested versions in BSL (British Sign Language) that are used with Deaf users of the IAPT service. The aim of this study is to determine their appropriate clinical cut-offs when used with Deaf people who sign and to examine the operating characteristics for PHQ-9 BSL and GAD-7 BSL with a clinical Deaf population. METHODS: Two datasets were compared: (i) dataset (n = 502) from a specialist IAPT service for Deaf people; and (ii) dataset (n = 85) from our existing study of Deaf people who self-reported having no mental health difficulties. Parameter estimates, with the precision of AUC value, sensitivity, specificity, positive predicted value (ppv) and negative predicted value (npv), were carried out to provide the details of the clinical cut-offs. Three statistical choices were included: Maximising (Youden: maximising sensitivity + specificity), Equalising (Sensitivity = Specificity) and Prioritising treatment (False Negative twice as bad as False Positive). Standard measures (as defined by IAPT) were applied to examine caseness, recovery, reliable change and reliable recovery for the first dataset. RESULTS: The clinical cut-offs for PHQ-9 BSL and GAD-7 BSL are 8 and 6 respectively. This compares with the original English version cut-offs in the hearing population of 10 and 8 respectively. The three different statistical choices for calculating clinical cut-offs all showed a lower clinical cut-off for the Deaf population with respect to the PHQ-9 BSL and GAD-7 BSL with the exception of the Maximising criteria when used with the PHQ-9 BSL. Applying the new clinical cut-offs, the percentage of Deaf BSL IAPT service users showing reliable recovery is 54.0 % compared to 63.7 % using the cut-off scores used for English speaking hearing people. These compare favourably with national IAPT data for the general population. CONCLUSIONS: The correct clinical cut-offs for the PHQ-9 BSL and GAD-7 BSL enable meaningful measures of clinical effectiveness and facilitate appropriate access to treatment when required.

Interventions to improve patient access to and utilisation of genetic and genomic counselling services.

This is the protocol for a review and there is no abstract. The objectives are as follows. PRIMARY OBJECTIVE: The primary objective is to assess the effectiveness of interventions to improve patient identification, access to and utilisation of genetic and genomic counselling services when compared to: No intervention;Usual or current practice; andOther active intervention. SECONDARY OBJECTIVE: The secondary objective is to explore the resource use and costs associated with interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. We will report on factors that may explain variation in the effectiveness of interventions aimed at improving patient identification, access to and utilisation of genetic and genomic counselling services from studies meeting the eligibility criteria. Another secondary objective is to explore how interventions which target improved patient identification, access to and utilisation of genetic and genomic counselling services affect the subsequent appropriate use of health services for the prevention or early detection of disease. It is also possible that the genetic counselling interaction itself will contribute to the possible use of preventative services.

Better life expectancy in women with BRCA2 compared with BRCA1 mutations is attributable to lower frequency and later onset of ovarian cancer.

PURPOSE: No formal assessment of life expectancy in women with BRCA1 and BRCA2 mutations in these genes has been reported previously. We have evaluated life expectancy using actuarial analysis and assessed the effect of breast and ovarian cancers on premature death in >1,000 BRCA1/2 carriers. METHODS: Families with pathogenic mutations in BRCA1 and BRCA2 have been ascertained in a 10-million population region of United Kingdom since 1996. Mutation carriers and their first-degree relatives were used in an analysis of breast and ovarian cancer incidence and mortality as well as to derive and compare an actuarial assessment of life expectancy. RESULTS: Six hundred twelve BRCA1 and 482 BRCA2 female mutation carriers were identified from 482 families. Life expectancy was significantly reduced for BRCA1 carriers compared with BRCA2 (P = 0.0002). This effect was attributable to an increased death rate from ovarian cancer (P = 0.04). Kaplan-Meier analysis revealed a better long-term survival from early-stage ovarian cancer in BRCA2 carriers but no significant differences in deaths from breast cancer or from women presenting with late-stage ovarian cancer. There was no other major contributing cause to death other than breast/ovarian cancer in BRCA1/2 female carriers. CONCLUSION: Interventions to reduce ovarian cancer incidence are likely to have a greater effect on life expectancy in BRCA1 compared with BRCA2 carriers.

A qualitative exploration of trial-related terminology in a study involving Deaf British Sign Language users.

BACKGROUND: Internationally, few clinical trials have involved Deaf people who use a signed language and none have involved BSL (British Sign Language) users. Appropriate terminology in BSL for key concepts in clinical trials that are relevant to recruitment and participant information materials, to support informed consent, do not exist. Barriers to conceptual understanding of trial participation and sources of misunderstanding relevant to the Deaf community are undocumented. METHODS: A qualitative, community participatory exploration of trial terminology including conceptual understanding of 'randomisation', 'trial', 'informed choice' and 'consent' was facilitated in BSL involving 19 participants in five focus groups. Data were video-recorded and analysed in source language (BSL) using a phenomenological approach. RESULTS AND DISCUSSION: Six necessary conditions for developing trial information to support comprehension were identified. These included: developing appropriate expressions and terminology from a community basis, rather than testing out previously derived translations from a different language; paying attention to language-specific features which support best means of expression (in the case of BSL expectations of specificity, verb directionality, handshape); bilingual influences on comprehension; deliberate orientation of information to avoid misunderstanding not just to promote accessibility; sensitivity to barriers to discussion about intelligibility of information that are cultural and social in origin, rather than linguistic; the importance of using contemporary language-in-use, rather than jargon-free or plain language, to support meaningful understanding. CONCLUSIONS: The study reinforces the ethical imperative to ensure trial participants who are Deaf are provided with optimum resources to understand the implications of participation and to make an informed choice. Results are relevant to the development of trial information in other signed languages as well as in spoken/written languages when participants' language use is different from the dominant language of the country.

BRCA1/2 predictive testing: a study of uptake in two centres.

Differences in reported uptake of genetic testing for mutations in BRCA1 and BRCA2 can largely be accounted for by different methodologies and by studying research vs nonresearch families. In our joint study of 75 nonresearch families from two UK centres in which at least 3 years had elapsed since the initial proband had been informed of the availability of testing, only 45 and 34% of eligible individuals from Manchester and London, respectively, had come forward for counselling. Final uptake rates using a non-proactive approach were 53 and 29% for women and 11-12% for men, but the figure among those attending clinic was 73 and 62%, respectively. Unlike previous studies, we did not find that uptake had stabilised after a year with 25% of those being tested more than 2 years after the family was informed, and several delaying a considerable time between genetics appointments. We believe that the particularly low uptake even of counselling in men may need to be addressed by improving family communication or providing information sheets for family members to disseminate.

Mutation analyses of Uroplakin II in children with renal tract malformations.

BACKGROUND: Uroplakin (UP) proteins cover urothelial apical surfaces. Mice lacking UPIIIa have elevated urothelial permeability and congenital renal tract anomalies, and UPIIIa mutations have been reported in children with kidney and ureter malformations. Mice with null mutation of another UP family member, UPII, are often born with congenital hydronephrosis. We hypothesized that UPII mutations may be present in humans with renal tract malformations. METHODS: Mutations were sought, using direct sequencing of the five UPII exons, in 42 children with diverse renal tract anomalies. RESULTS: No UPII abnormalities were detected in 41 patients, whereas one index case had a heterozygous frameshift change which, if expressed, would generate a truncated protein. This Caucasian child presented with vesicoureteric reflux (VUR), bilateral nephropathy and renal failure. The genetic change was also found in the index case's mother who had normal renal ultrasonography, but it was absent in 150 healthy Caucasian control individuals (96 assessed by direct sequencing and another 54 assessed by restriction digests). UPII was immunolocalized in urothelium of the normal human embryonic renal pelvis in a pattern similar to UPIIIa. CONCLUSION: This study offers no definitive support for UPII mutations causing human renal tract malformations. In rare patients, UPII variants might be implicated in pathogenesis when acting in conjunction with other yet-to-be-defined, genetic or environmental modifying factors.

De novo Uroplakin IIIa heterozygous mutations cause human renal adysplasia leading to severe kidney failure.

Human renal adysplasia usually occurs sporadically, and bilateral disease is the most common cause of childhood end-stage renal failure, a condition that is lethal without intervention using dialysis or transplantation. De novo heterozygous mutations in Uroplakin IIIa (UPIIIa) are reported in four of 17 children with kidney failure caused by renal adysplasia in the absence of an overt urinary tract obstruction. One girl and one boy in unrelated kindreds had a missense mutation at a CpG dinucleotide in the cytoplasmic domain of UPIIIa (Pro273Leu), both of whom had severe vesicoureteric reflux, and the girl had persistent cloaca; two other patients had de novo mutations in the 3' UTR (963 T-->G; 1003 T-->C), and they had renal adysplasia in the absence of any other anomaly. The mutations were absent in all sets of parents and in siblings, none of whom had radiologic evidence of renal adysplasia, and mutations were absent in two panels of 192 ethnically matched control chromosomes. UPIIIa was expressed in nascent urothelia in ureter and renal pelvis of human embryos, and it is suggested that perturbed urothelial differentiation may generate human kidney malformations, perhaps by altering differentiation of adjacent smooth muscle cells such that the metanephros is exposed to a functional obstruction of urine flow. With advances in renal replacement therapy, children with renal failure, who would otherwise have died, are surviving to adulthood. Therefore, although the mechanisms of action of the UPIIIa mutations have yet to be determined, these findings have important implications regarding genetic counseling of affected individuals who reach reproductive age.