The NCS-LSD cohort study: a description of the methods and analyses used to assess the long-term effectiveness of enzyme replacement therapy and substrate reduction therapy in patients with lysosomal storage disorders.

Lysosomal storage disorders (LSDs) comprise more than 50 extremely rare, inherited metabolic diseases resulting from a deficiency of specific lysosomal enzymes required for normal macromolecular metabolism. The National Collaborative Study for Lysosomal Storage Disorders (NCS-LSD), was a longitudinal cohort study which collected prospective and retrospective clinical data, and patient-reported data from adults and children with a confirmed diagnosis of Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann Pick disease type C (NPC) in the UK. The study aimed to determine the natural history of these conditions and estimate the effectiveness and cost of therapies. Clinical outcomes were chosen to reflect disease progression. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment while untreated patients contributed natural history data. A total of 711 adults and children were recruited to this study from the seven LSD treatment centres in England. Data was collected from 2008 to 2011. This paper describes the methods used to collect and analyse clinical data for this study. The clinical findings are reported separately in a series of condition-specific articles in this issue.

Risk factors for time to diagnosis of feline upper respiratory tract disease in UK animal adoption shelters.

Feline upper respiratory tract disease (URTD), mainly caused by feline calicivirus (FCV) and feline herpesvirus, is a major cause of disease outbreaks in feline accommodation such as animal shelters, catteries and multi-cat households. We conducted a longitudinal, yearlong study in five UK feline animal shelters to identify risk factors for the time to diagnosis of URTD. We were especially interested in risk factors that could be identified at the time the cat entered the shelter. Shelter staff recorded data for 1,434 cats during 2002-2003. Most of the cats were domestic shorthair cats and were from private households, or were stray or abandoned. Sixty cats without clinical signs of URTD at entry had URTD diagnosed (typically within the first month at the centre). We used two multivariable models: one was a Cox proportional-hazards model, and the other a regression analyses with complementary log-log model. The hazard varied substantially between shelters and was considerably lower for the shelter that had a purpose-built admissions unit with its own isolation facilities. The hazard was greater for purebred cats (HR 4.3-5.0) and for neutered cats (HR 2.0). The hazard was also typically greater if the centre had a greater proportion of cats present with URTD. The analyses suggested that the centre-level risk factors were more important in determining hazard than cat-level risk factors.

A comparison of survival models for assessing risk of racehorse fatality.

Survival analysis was used to assess risk factors for fatal injuries on UK race courses. This allowed assessment of variation due to temporal horse-level effects, including previous racing intensity and historical distribution of race types, as well as race-level factors. Comparisons were made between measuring survival time as number of days and as number of races to injury from the first race. Two related models were presented for time as number of races to injury: a Cox regression model fitted using partial likelihood, with the Efron approximation to handling ties, and a discrete-time logit model fitted using maximum likelihood. The latter approach had the advantages of being computationally more efficient and enabling the testing of different functional forms for the dependence of hazard on time. Retrospective data were available from all race starts on the 59 courses in Britain from 1990 to the end of 1999, as analysed by . The analysis was conducted on the data for the 47,424 horses that had started racing in the UK: 538,895 starts with 1,228 fatal injuries. Horses starting racing abroad were excluded, but some included horses would have raced abroad at some stage during their racing career. The results for the selected models were broadly consistent with each other and with previously published studies. Steeplechase and hurdle races had a higher risk of fatal injury than flat races (relative hazards 1.5 and 1.7, respectively). Risk increased with the firmness of surface, age and race distance (reaching a plateau at 20 furlongs) and decreased with previous racing intensity (reaching a plateau after seven races run in the last 12 months). Horses running their first race of a new type were also found to be at higher risk (relative hazard 1.5). The main difference between the models for time as number of days and number of races concerned the role of age: age at race was identified as the more important factor in the latter model, whereas, age at first race was more significant in the former model.

Vitamin D and Dementia.

Emerging evidence suggests that low vitamin D concentrations are potentially involved in the pathogenesis of dementia. This is of particular interest when considering the high prevalence of vitamin D deficiency in elderly adults and the urgent need to identify modifiable risk factors for dementia. Studies have found that vitamin D is implicated in procognitive and neuroprotective functions, including the reduction of Alzheimer's disease hallmarks such as amyloid beta and phosphorylated tau. Cross-sectional studies have consistently found that vitamin D concentrations are significantly lower in individuals with Alzheimer's disease and cognitive impairment compared to healthy controls. Longitudinal studies support an association between low vitamin D concentrations and an increased risk of dementia and cognitive decline. Neuroimaging studies are beginning to uncover the potential neurodegenerative and cerebrovascular mechanisms that underlie these associations such as white matter hyperintensities and enlarged ventricular volume, although there is currently a lack of longitudinal studies. In contrast to observational studies, findings from interventional studies have produced mixed results on the benefits of vitamin D supplementation on dementia and cognitive outcomes. Interpretation of the findings from these studies is hampered by several major methodological limitations, such as small sample sizes, inadequate doses and inclusion of participants unlikely to benefit from vitamin D supplementation. There is a need for large double-blind randomised-control trials investigating whether vitamin D supplementation can halt or delay the risk of dementia-related outcomes in individuals with low vitamin D concentrations.

Training-related factors associated with dorsometacarpal disease in young Thoroughbred racehorses in the UK.

REASONS FOR PERFORMING STUDY: Dorsometacarpal disease (DMD) is common in young Thoroughbred (TB) racehorses, often interfering with their training programme. No reports exist on incidence rate or associated risk factors in the UK. OBJECTIVES: To estimate the incidence rate of DMD in TB horses in training for flat racing in the UK and identify associated risk factors, particularly in relation to training regimens. METHODS: Data were drawn from a large prospective study in which TB horses in 13 training yards were monitored for a period of up to 2 years, recording daily training information and details of musculoskeletal injury, including DMD. The incidence of DMD was calculated and survival analysis performed to determine features of the training regimen related to the risk of disease. RESULTS: A total of 335 horses provided 4235 months at risk of DMD. Seventy-nine first episodes were recorded, resulting in an incidence rate of 1.87/100 horse months (95% confidence interval 1.50-2.33). Increasing exercise distances at canter and high speed in short periods (up to 1 month) were associated with an increasing risk of DMD. However, increasing cumulative exercise distances since entering training were associated with a decreasing risk of the disease. CONCLUSIONS: The risk of DMD in young TBs decreases with accumulation of distances exercised at canter and high speed; this reflects the adaptive response of the third metacarpal bone to the loads placed upon it. However, increasing exercise distances in short periods (up to 1 month) increases the risk of DMD, probably as a consequence of microdamage and its associated remodelling response, and should therefore be avoided. POTENTIAL RELEVANCE: Training regimens for young TBs can be adjusted to prevent the occurrence of DMD. Early but gradual introduction of small amounts of high-speed exercise may be beneficial. Canter exercise should be kept minimal on high-speed work days and large amounts of both cantering and high-speed work per week, 2 weeks or per month should be avoided, particularly during the early stages of training, in order to minimise the risk of DMD.

Patient characteristics predicting failure to receive indicated care for type 2 diabetes.

AIMS: To determine which patient characteristics were associated with failure to receive indicated care for diabetes over time. METHODS: English Longitudinal Study of Ageing participants aged 50 or older with diabetes reported receipt of care described by four diabetes quality indicators (QIs) in 2008-9 and 2010-11. Annual checks for glycated haemoglobin (HbA1c), proteinuria and foot examination were assessed as a care bundle (n=907). A further QI (n=759) assessed whether participants with cardiac risk factors were offered ACE inhibitors or angiotensin II receptor blockers (ARBs). Logistic regression modelled associations between failure to receive indicated care in 2010-11 and participants' socio-demographic, lifestyle and health characteristics, diabetes self-management knowledge, health literacy, and previous QI achievement in 2008-9. RESULTS: A third of participants (2008-9=32.8%; 2010-11=32.2%) did not receive all annual checks in the care bundle. Nearly half of those eligible were not offered ACE inhibitors/ARBs (2008-9=44.6%; 2010-11=44.5%). Failure to receive a complete care bundle was associated with lower diabetes self-management knowledge (odds ratio (OR) 2.05), poorer cognitive performance (1.78), or having previously received incomplete care (3.32). Participants who were single (OR=2.16), had low health literacy (1.50) or had received incomplete care previously (6.94) were more likely to not be offered ACE inhibitors/ARBs. Increasing age (OR=0.76) or body mass index (OR=0.70) was associated with lower odds of failing to receive this aspect of care. CONCLUSIONS: Quality improvement initiatives for diabetes might usefully target patients with previous receipt of incomplete care, poor knowledge of annual diabetes care processes, and poorer cognition and health literacy.

Comparison of the effectiveness of non-nucleoside reverse transcriptase inhibitor-containing and protease inhibitor-containing regimens using observational databases.

OBJECTIVES: To compare the effectiveness of first protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: Data were analysed from three large HIV patient databases: Apache HIV Insight (APACHE), Target Management Services (TMS) and Clinical Partners (CP). The effectiveness of therapy was the time taken for HIV-1 RNA to fall below detectable levels on first highly active antiretroviral therapy regimen (PI- or NNRTI-containing) and the subsequent time to failure (two consecutive detectable measurements). Comparisons were made using proportional hazards models, adjusting for differences in age, sex, previous reverse transcriptase inhibitor use, calendar year and baseline viral load and CD4 T-cell count. RESULTS: The type of regimen was not associated with time to undetectable viral load in any of the three databases, all of which had high power to detect a difference. PI-containing regimens were significantly less likely to fail after reaching undetectable viral loads for APACHE and CP patients (relative hazard, 1.7; 95% confidence interval, 1.3--2.1 and relative hazard, 1.6; 95% confidence interval, 1.0--2.5 respectively). These results remained significant after allowing for an unmeasured confounder with moderate effect on risk. No significant association between time to failure and regimen was found for TMS patients, possibly due to low power (67% to detect a relative hazard of 1.5). No difference was found between regimens in the time taken for an increase of > 100 x 10(9)cells/l in CD4 T-cell count. In the APACHE database, those on NNRTI-containing regimens were more likely to have a failing CD4 T-cell response. CONCLUSIONS: PI-containing regimens have a lower risk of treatment failure than NNRTI-containing regimens.

An epidemiological approach to prevention and control of three common heritable diseases in canine pedigree breeds in the United Kingdom.

This paper reviews recent epidemiological research in the United Kingdom for controlling deafness in Dalmatians, glaucoma in flat coated retrievers and great Danes and hip dysplasia in flat coated retrievers, Newfoundlands, Gordon setters and Labrador retrievers. These studies assessed the prevalence of the disease, identified the factors affecting prevalence, and developed predictive statistical models of offspring/parent relationships. For each disease/breed combination, the research identified those sires and dams that might justifiably be regarded as suitable/unsuitable as potential parents in a selective breeding strategy to control or prevent the disease. Future progress in the control of these diseases is likely to come from greater understanding of their mode of inheritance. Insight, even for these complex diseases, can be derived from further detailed statistical evaluation of datasets such as those described in this paper.

The effect of inspired gas density on pulmonary artery transmural pressure and exercise induced pulmonary haemorrhage.

REASONS FOR PERFORMING STUDY: Pulmonary capillary stress failure, largely as a result of high pulmonary vascular pressures, has been implicated in the aetiology of EIPH. However, the role of the respiratory system in determining the magnitude of EIPH has received little attention. HYPOTHESIS: Horses breathing a gas of greater density than air will exhibit greater transmural pulmonary arterial pressures (TPAP) and more severe EIPH, and horses breathing a gas of lower density than air will exhibit lower TPAP and less severe EIPH, both compared with horses breathing air. METHODS: Following a warm-up, 8 Thoroughbred horses were exercised for 1 min at 10, 11 and 12 m/sec (5 degrees incline) breathing air or 21% oxygen/79% helium or 21% oxygen/79% argon in a randomised order. Heart rate, respiratory rate, pulmonary arterial pressure and oesophageal pressure were measured during exercise. Bronchoalveolar lavage fluid (BALF) was collected from the dorsocaudal regions of the left and right lungs 40 min post exercise and red blood cell (RBC) counts were performed. RESULTS: The exercise tests induced mild EIPH. Maximum changes in oesophageal pressure were lower on helium-oxygen compared to argon-oxygen (P<0.001). TPAP and median RBC counts did not differ between gas mixtures. BALF RBC counts from the left lung correlated with counts from the right lung (P<0.0001). However BALF RBC counts from the left lung were higher than those from the right lung (P = 0.004). CONCLUSION: As alterations in pulmonary arterial and oesophageal pressure caused by changes in inspired gas density were of similar magnitude, TPAP remained unchanged and there was no significant effect on EIPH severity. POTENTIAL RELEVANCE: Manipulations that decrease swings in intrapleural pressure may only decrease the degree of EIPH in horses severely affected by the condition.

Vaccination and ill-health in dogs: a lack of temporal association and evidence of equivalence.

Following concerns raised over the safety of canine vaccines, an epidemiological investigation was conducted to evaluate the evidence for a temporal association between vaccination and ill-health in dogs. The owners of a randomly selected population of dogs were sent 9055 postal questionnaires, 4040 of which were returned. No temporal association was found between vaccination and ill-health in dogs after adjusting for potential confounders, such as age. However, reliable inferences from non-significant test results are limited and so equivalence-testing methods were also used to make informative inferences. Results demonstrated that recent vaccination (< 3 months) does not increase signs of ill-health by more than 0.5% and may actually decrease it by as much as 5%. This general approach should be used in all field studies of vaccine safety.

Breed incidence of lymphoma in a UK population of insured dogs.

Canine lymphoma is one of the commonest forms of spontaneous canine neoplasia. Improved understanding of the genetic and environmental risk factors for canine lymphoma, including breed differences, may have comparative benefits for the study of non-Hodgkin's lymphoma in humans. In this study, data from a pet insurance company were used to estimate the incidences of canine lymphoma for pedigree breeds in the UK. Out of a total of 130,684 insured dogs, 103 had a diagnosis of lymphoma recorded. A significant breed effect was found with the boxer, bulldog and bull mastiff breeds, all having a high incidence of lymphoma. The small number of lymphoma cases recorded may have limited our ability to detect other breeds with an elevated risk. Incidence of lymphoma was found to increase with age, peaking at 10 years of age.