A method for acquiring random range uncertainty probability distributions in proton therapy.

In treatment planning we depend upon accurate knowledge of geometric and range uncertainties. If the uncertainty model is inaccurate then the plan will produce under-dosing of the target and/or overdosing of OAR. We aim to provide a method for which centre and site-specific population range uncertainty due to inter-fraction motion can be quantified to improve the uncertainty model in proton treatment planning. Daily volumetric MVCT data from previously treated radiotherapy patients has been used to investigate inter-fraction changes to water equivalent path-length (WEPL). Daily image-guidance scans were carried out for each patient and corrected for changes in CTV position (using rigid transformations). An effective depth algorithm was used to determine residual range changes, after corrections had been applied, throughout the treatment by comparing WEPL within the CTV at each fraction for several beam angles. As a proof of principle this method was used to quantify uncertainties for inter-fraction range changes for a sample of head and neck patients of [Formula: see text] mm, [Formula: see text] mm and overall [Formula: see text] mm. For prostate [Formula: see text] mm, [Formula: see text] mm and overall [Formula: see text] mm. The choice of beam angle for head and neck did not affect the inter-fraction range error significantly; however this was not the same for prostate. Greater range changes were seen using a lateral beam compared to an anterior beam for prostate due to relative motion of the prostate and femoral heads. A method has been developed to quantify population range changes due to inter-fraction motion that can be adapted for the clinic. The results of this work highlight the importance of robust planning and analysis in proton therapy. Such information could be used in robust optimisation algorithms or treatment plan robustness analysis. Such knowledge will aid in establishing beam start conditions at planning and for establishing adaptive planning protocols.

Paediatric referral and attendance rates for the clinical genetics service in south-east Scotland--a comparison of a regional clinic with satellite clinics.

BACKGROUND AND AIMS: In some studies the establishment of specialist satellite clinics nearer to the homes of patients has resulted in increased referral and attendance rates, particularly amongst populations in lower socio-economic groups. We investigated the effect on these rates of establishing satellite genetic counselling clinics for families with paediatric conditions in South East Scotland. METHODS AND RESULTS: Families offered appointments at a clinic at the regional paediatric hospital were compared with those offered appointments at a satellite clinic at a local district general hospital. Both groups of families were more socially deprived than the general population (regional clinic p < 0.001, satellite clinics p < 0.05), and in both groups attendance rate at first appointment was 88% and inversely related to social deprivation. There was no evidence of greater attendance amongst more deprived patients at the satellite clinics compared to the regional clinic. CONCLUSION: Our study found no evidence that the establishment of satellite clinics for genetic counselling in South East Scotland increases attendance by families with paediatric conditions in lower socio-economic groups. This suggests that factors other than clinic location determine referral and attendance rates, and these may include understanding of the reason for referral and the advantage of attendance.

Life expectancy and death from cardiomyopathy amongst carriers of Duchenne and Becker muscular dystrophy in Scotland.

OBJECTIVES: To assess life expectancy and cardiovascular mortality in carriers of Duchenne and Becker muscular dystrophy. DESIGN: Family pedigrees of individuals affected with these conditions, held by the four genetics centres in Scotland, were examined to identify a cohort of definite carriers. Electronic death registration data, held by the General Register Office for Scotland, were used to identify death certificates of carriers who had died, to obtain age at death and cause of death. Survival and mortality data were obtained for the general population for comparison. PATIENTS: 397 definite carriers in 202 pedigrees were identified from which 94 deaths were identified by record linkage to death certificates. MAIN OUTCOME MEASURES: Observed numbers surviving to certain ages and numbers dying of cardiac causes were compared with expected numbers calculated from general population data. RESULTS: There were no significant differences between observed and expected numbers surviving to ages 40-90. The standardised mortality ratio for the 371 carriers alive in 1974 was 0.53 (95% confidence interval 0.32 to 0.82). CONCLUSIONS: Whereas female carriers may have clinical features of cardiomyopathy, this study does not suggest that this is associated with reduced life expectancy or increased risk of cardiac death. Routine cardiac surveillance of obligate carriers is therefore probably unnecessary.

Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1.

A recent study, looking at the lifetime risk of developing malignant peripheral nerve sheath tumour (MPNST) in patients with neurofibromatosis type 1 (NF1), estimated the risk to be 8-13%. Prior to this, longitudinal studies had shown that patients with NF1 had a risk of 4-5% of developing MPNST, and cross-sectional studies had found that only 1-2% of patients with NF1 had MPNST. The aim of this study was to estimate the lifetime risk of MPNST in patients with NF1 in southern Scotland, using patient records obtained from the Edinburgh and Glasgow Genetic Units and Scottish Cancer Register. In the period 1993-2002, 14 patients with NF1 were diagnosed with MPNST in a population of 3.5 million. The lifetime risk of MPNST in the Scottish patients with NF1 was calculated to be 5.9-10.3%. This provides further evidence that patients with NF1 are at greater risk of developing MPNST than was previously estimated, and emphasises the importance of educating patients about suspicious symptoms, which may need an urgent medical opinion. The mean age at diagnosis of MPNST (p<0.05) and 5-year survival (p<0.01) were significantly lower in patients with NF1 than in unaffected individuals. This may be due to patients with NF1 presenting later, because the tumour is mistaken for a neurofibroma, or due to MPNST having a more aggressive course in NF1.

Characterization of fimN, a new Bordetella bronchiseptica major fimbrial subunit gene.

Fimbrial proteins play an important role in the binding of Bordetella bronchiseptica to mammalian cells, an event that is key to the pathogenesis of this organism. The fimbrial phenotype of B. bronchiseptica isolates is usually defined serologically by Fim2 and Fim3 antigens. In this study, a previously unidentified fimbrial gene, fimN, was cloned and sequenced. The identity of fimN is based on several observations. The predicted FimN protein has 59.4 and 52. 2% homology with B. bronchiseptica Fim2 and Fim3, respectively, and is similar in size to these fimbriae. fimN, expressed as a recombinant protein, is recognized by mAb prepared against Fim2 from Bordetella pertussis. The fimN promoter region contains a stretch of cytosine residues similar in length to those of other fimbrial genes expressed by Bordetella species. It also has an activator binding region, upstream from the C-stretch, that closely resembles a corresponding bvg regulated region in fim2, fim3, and fimX. The fimN gene was isolated from a cosmid prepared with B. bronchiseptica genomic DNA that restored normal properties of cellular adhesion to an adhesion deficient strain of B. bronchiseptica. As such, FimN may be a previously overlooked fimbrial antigen and may play an important role in the pathogenicity of B. bronchiseptica.

Presymptomatic testing for Huntington's disease by linkage and by direct mutation analysis: comparison of uptake of testing and characteristics of test applicants.

In Edinburgh, we have compared presymptomatic testing by linkage and by direct mutation analysis by investigating the demand for testing and characteristics of test applicants. Annual new requests for the direct test (DT) are now double the peak with the linkage test (LT) but only 6% individuals have requested re-testing. DT applicants were older with a smaller proportion having lived with an affected relative that LT applicants. This was because many were relatives of newly diagnosed first known cases in their family. This may also explain why DT applicants were less likely to expect a negative result and more likely to be uncertain about their risk. A greater proportion of DT applicants first heard about the test from relatives or their GP than LT applicants who were more likely to hear from Genetic Centre. The demand for follow-up by the Geneticist/Genetic Nurse was much less for DT than for LT applicants largely due to the support offered by the HD Advisors.

Coefficients of relationship by isonymy among Scottish males with multiple primary cancers.

Patients with heritable cancer syndromes often develop multiple primary cancers (mpc) affecting one or more organs or tissues. However, it is less clear whether the presence of mpc in a patient implies that genetic factors have an important role in aetiology. We have investigated this by comparing the surname distributions of 11205 males with mpc on the Scottish Cancer Register, with corresponding distributions in male controls and in males with individual cancers, by calculating coefficients of relationship by isonymy. Our results suggest that although genetic factors may have a role in the aetiology of mpc, particularly if the cancers affect different tissues or organs, their effect is small compared with that of environmental factors.

Clinical heterogeneity of familial motor neuron disease: report of 11 pedigrees from a population based study in Scotland. The Scottish Motor Neuron Disease Research Group.

Five percent of incident patients with MND in Scotland 1989-1990 had a family history of this disease. This paper assesses the demographic and clinical features of this group.

The prognosis of adult-onset motor neuron disease: a prospective study based on the Scottish Motor Neuron Disease Register.

The Scottish Motor Neuron Disease Register (SMNDR) is a prospective, collaborative, population-based project which has been collecting data on incident patients since 1989. In this report we present the clinical features of 229 patients with motor neuron disease (218 sporadic and 11 familial) diagnosed in 1989 and 1990 and compare their prognosis with previous studies of survival. The overall 50% survival from symptom onset was 2.5 years (95% CI, 2.2-3.0) and 5-year survival 28% (95% CI, 20-36%). The presence of progressive bulbar palsy (PBP), either at presentation or developing during the course of the illness, significantly reduced survival and was the most important prognostic indicator. Patients who survived longer than 5 years from symptom onset did not have PBP as part of their presenting illness. The prognosis was worse for women, and this was in part related to the higher frequency of PBP in older women, but age was also an independent adverse risk factor. Differences in survival between this and previous series can probably be explained on the basis of variation in case definition and ascertainment methods.

Coefficients of relationship by isonymy among oral cancer registrations in Scottish males.

The role of inherited susceptibility to oral cancers was studied by comparing groups of cancer patients and controls in terms of the coefficient of relationship by isonymy (Ri), both within and between Regions of mainland Scotland. Surname distributions for 3658 male cancer cases were derived from the Scottish Cancer Register for the years 1959-85. Control distributions were derived from a total of 32,468 male deaths in Scotland for 1976. For cancer of the floor of mouth, there was no evidence for increased isonymy in patients compared to controls and therefore no indication that familial factors contribute to cancer at this site. For cancer of the tongue there was a suggestion of increased isonymy within but not between Regions, perhaps reflecting environmental risk factors common to members of the same family. For cancers of the lip and salivary gland there was evidence of increased isonymy both within and to a lesser extent between Regions, suggesting a genetic contribution. There is corroborative evidence from other sources for a heritable component in salivary gland cancer but the reasons for the similar pattern of results in cancer of the lip are less clear.

Coefficients of relationship by isonymy among registrations for five common cancers in Scottish males.

STUDY OBJECTIVE: The aim was to assess the relative importance of genetic factors in carcinoma of the stomach, colon, rectum, prostate, and bladder in Scottish males. DESIGN: Cancer cases and controls were compared in terms of the coefficient of relationship by isonymy (Ri). SETTING: Surname distributions for cancer cases were derived from the Scottish Cancer Register for the years 1959-85. Control distributions were derived from all births, marriages and deaths in Scotland for 1976. SUBJECTS: Analysis was carried out on a total of 60,933 cancer registrations and 101,836 births, marriages, and deaths over the 12 local government regions of Scotland. MAIN RESULTS: Comparisons of Ri within and between regions indicated that inherited susceptibility was of greatest importance in carcinoma of the prostate and colon, of intermediate importance in carcinoma of the rectum and stomach, and of minimal importance in carcinoma of the bladder. Familial aggregation of cancers was most pronounced in Highland, Tayside, and Borders Regions. For Highland, this appeared to be the result of region-specific familial influences, while Tayside and the Borders shared genetic factors contributing to cancer aetiology with neighbouring regions in south east Scotland. CONCLUSIONS: Surname analysis is a simple but useful tool for studying population genetic structure and its relationship to disease incidence.

Coefficients of relationship by isonymy among Scottish males with early and late onset cancers.

Studies of certain cancers suggest that early onset cases tend to have a more pronounced hereditary component than late onset cases. We have analysed data from 60,924 Scottish males with cancer of the stomach, colon, rectum, prostate or bladder, using the coefficient of relationship by isonymy to compare patients whose age at registration was below the median with those whose age at registration was equal to or above the median. There was no evidence for greater isonymy in younger patients suggesting that, although known genetically determined cancers may have earlier onset than other cancers at the same site, early age at onset is not widely associated with a familial predisposition to malignancy.

Coefficients of relationship by isonymy among the parents of Scottish twins: a test of familial aggregation.

The ability of the coefficient of relationship by isonymy Ri to detect familial aggregation of conditions suspected of being under a degree of genetic control was tested on groups of fathers and mothers of like-sex twins, fathers and mothers of unlike-sex twins, and fathers and mothers of singleton controls born from 1977 to 1981 in Scotland. No statistically significant difference of within-group or between-group Ri was found, either for all surnames or for rare surnames only. However, the overall pattern of results for rare surnames showed a measure of agreement with what is already known of the genetics of twinning. The relatively high within-group Ri for mothers of unlike-sex twins is consistent with a maternal genetic influence on dizygous twinning, whereas the relatively high between-group Ri for fathers with mothers of unlike-sex twins suggests that paternal as well as maternal genes may be involved. Values of Ri for the parents of like-sex twins raise the possibility of a paternal but not a maternal genetic contribution to monozygous twinning.

Attitudes of general practitioners to presymptomatic testing for Huntington's disease.

A postal questionnaire was sent to all 797 general practitioners (GPs) in the Lothians, Borders, and Fife (Scotland), enquiring about attitudes to presymptomatic testing for Huntington's disease. The response rate was 74%. Eighty-two percent were in favour of the principle of predictive testing for Huntington's disease. A majority of those not in favour were prepared to refer their patients for testing. However, three-quarters of GPs were unfamiliar with the details of DNA based linkage analysis. Half of the respondents felt that disclosure of the test result and subsequent counselling and support were the responsibility of the genetic clinic. A third of respondents considered that the genetic clinic should disclose the test result while the GP should give post-test counselling and support. These findings suggest that delivering presymptomatic testing to persons at risk of Huntington's disease would be facilitated by a closer involvement of local GPs.

Coefficients of relationship by isonymy within and between the regions of Scotland.

The distribution of surnames for births, marriages and deaths in 1976 among residents of the 12 Local Government Regions of Scotland was analyzed in terms of the coefficient of relationship by isonymy, Ri. Differences between sexes and events for Ri within Regions were consistent with greater inter-Region mobility among males compared with females and among young adults compared with the elderly. There were near zero correlations of geographical distance with Ri between Regions based on all surnames or common surnames. With Ri based on rare surnames, there was a small though statistically nonsignificant negative correlation. The best-fitting two dimensional relationship derived from Ri values based on rare surnames showed a fair correspondence with the map of Scotland, indicating a degree of genetic isolation between the Regions.

Motor neurone disease in the Lothian Region of Scotland 1961-81.

One hundred and sixty one patients with motor neurone disease (MND), from the Lothian Region of Scotland, were studied in an attempt to identify factors important in disease aetiology. Onset of the disease was between 1961 and 1981 and the incidence was highest between 1968 and 1975. The probability of developing MND was greatest between the ages of 65 and 69, and a greater proportion of female patients than of males had onset in the bulbar muscles. Some 5% of patients had a positive family history of MND. There was no evidence that infective agents were important in the aetiology of the disease. There was a suggestion that the patient group contained a greater number of electrical workers, food, drink and tobacco workers, and rubber workers than would have been expected. However, a larger series of patients would be needed to confirm an increased susceptibility to MND in individuals engaged in these occupations.

Heritability estimation from concordant twin pairs alone.

Heritability estimation is possible from concordant twin pairs alone, based on the proportion of like-sexed pairs among all concordant affected pairs. The method is limited to conditions found in both sexes in the prevalence range 0.1% to 10%, and a relatively large population size is required to give an adequate sample of twin pairs. However, the method has the considerable advantage that zygosity determination is not required and that any bias due to incomplete diagnosis/ascertainment is likely to be small. The method is particularly suited to diseases where registration is obligatory and computerised so that the register can be scanned for pairs of individuals with the same date of birth, place of birth and birth surname.

A family study of Paget's disease of bone.

Familial aggregation of Paget's disease of bone occurs occasionally and an exclusively genetic aetiology has been proposed in the past. On the other hand, epidemiological surveys point to an important environmental contribution, and evidence is accumulating to suggest that the disease may be caused by a slow virus infection. Analysis of 407 family history questionnaires completed by patients with Paget's disease confirmed the familial nature of the disease. Overall, the findings were consistent with the hypothesis that Paget's disease is caused by infection with a common and widespread virus superimposed on genetic variation for susceptibility and perhaps severity of the disease.