Laura Horsfall

Prediagnostic presentations of Parkinson's disease in primary care: a case-control study

BACKGROUND Parkinsons disease has an insidious onset and is diagnosed when typical motor features occur. Several motor and non-motor features can occur before diagnosis, early in the disease process. We aimed to assess the association between first presentation of several prediagnostic features in primary care and a subsequent diagnosis of Parkinsons disease, and to chart the timeline of these first presentations before diagnosis. METHODS We identified individuals with a first diagnosis of Parkinsons disease and those without Parkinsons disease from Jan 1, 1996, to Dec 31, 2012, from The Health Improvement Network UK primary care database. Codes were extracted for a range of possible prediagnostic or early symptoms, comprising motor features (tremor, rigidity, balance impairments, neck pain or stiffness, and shoulder pain or stiffness), autonomic features (constipation, hypotension, erectile dysfunction, urinary dysfunction, and dizziness), neuropsychiatric disturbances (memory problems, late-onset anxiety or depression, cognitive decline, and apathy), and additional features (fatigue, insomnia, anosmia, hypersalivation and rapid-eye-movement sleep behaviour disorder) in the years before diagnosis. We report the incidence of symptoms recorded in more than 1% of cases per 1000 person-years and incidence risk ratios (RRs) for individuals with and without Parkinsons disease at 2, 5, and 10 years before diagnosis. FINDINGS 8166 individuals with and 46,755 individuals without Parkinsons disease were included in the study. Apathy, REM sleep behaviour disorder, anosmia, hypersalivation, and cognitive decline were all reported in less than 1% of people per 1000 person-years and were excluded from further analyses. At 2 years before Parkinsons disease diagnosis, the incidence of all studied prediagnostic features except neck pain or stiffness was higher in patients who went on to develop Parkinsons disease (n=7232) than in controls (n=40,541). At 5 years before diagnosis, compared with controls (n=25,544), patients who went on to develop Parkinsons disease (n=4769) had a higher incidence of tremor (RR 13·70, 95% CI 7·82-24·31), balance impairments (2·19, 1·09-4·16), constipation (2·24, 2·04-2·46), hypotension (3·23, 1·85-5·52), erectile dysfunction (1·30, 1·11-1·51), urinary dysfunction (1·96, 1·34-2·80), dizziness (1·99, 1·67-2·37), fatigue (1·56, 1·27-1·91), depression (1·76, 1·41-2·17), and anxiety (1·41, 1·09-1·79). At 10 years before diagnosis of Parkinsons disease, the incidence of tremor (RR 7·59, 95% CI 1·11-44·83) and constipation (2·01, 1·62-2·49) was higher in those who went on to develop Parkinsons disease (n=1680) than in controls (n=8305). INTERPRETATION A range of prediagnostic features can be detected several years before diagnosis of Parkinsons disease in primary care. These data can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease for inclusion in future trials and to help understand progression in the earliest phase of Parkinsons disease. FUNDING Parkinsons UK.

Serum Bilirubin and Risk of Respiratory Disease and Death

CONTEXT Serum total bilirubin levels in healthy patients reflect genetic and environmental factors that could influence the risk of developing respiratory disease. OBJECTIVE To examine the relationship between bilirubin levels and respiratory disease. DESIGN, SETTING, AND PARTICIPANTS Cohort study among 504,206 adults from a UK primary care research database (the Health Improvement Network) with serum bilirubin levels recorded but no evidence of hepatobiliary or hemolytic disease. Data were recorded between January 1988 and December 2008. MAIN OUTCOME MEASURES Incidence of chronic obstructive pulmonary disease (COPD), lung cancer, and all-cause mortality. RESULTS Median bilirubin levels were 0.64 mg/dL (interquartile range, 0.47-0.88 mg/dL) in men and 0.53 mg/dL (interquartile range, 0.41-0.70 mg/dL) in women. There were 1341 cases of lung cancer, 5863 cases of COPD, and 23,103 deaths, with incidence rates of 2.5, 11.9, and 42.5 per 10,000 person-years, respectively. The incidence of lung cancer per 10,000 person-years in men was 5.0 (95% confidence interval [CI], 4.2-6.0) in the first decile category of bilirubin compared with 3.0 (95% CI, 2.3-3.8) in the fifth decile. The corresponding incidences for COPD in men were 19.5 (95% CI,17.7-21.4) and 14.4 (95% CI, 12.7-16.2). The mortality rates per 10,000 person-years in men were 51.3 (95% CI, 48.5-54.2) in the first decile category compared with 38.1 (95% CI, 35.5-40.8) in the fifth decile. The associations were similar for women. After adjusting for other important health indicators, regression estimates for incidence rate of lung cancer per 0.1-mg/dL increase in bilirubin level were an 8% decrease (95% CI, 5%-11%) for men and an 11% decrease (95% CI, 7%-14%) for women. The regression estimate for COPD in men per 0.1-mg/dL increase in bilirubin level was a 6% decrease (95% CI, 5%-7%) and for mortality in men was a 3% decrease (95% CI, 2%-3%) after accounting for other health indicators. The results for COPD and mortality in women were very similar. CONCLUSION Among patients with normal-range bilirubin levels in primary care practices, relatively higher levels of bilirubin were associated with a lower risk of respiratory disease and all-cause mortality.

Cardiovascular Events as a Function of Serum Bilirubin Levels in a Large, Statin-Treated Cohort

Background— Serum bilirubin is an endogenous antioxidant that is routinely measured before a statin is prescribed primarily to assess liver function, but the association with cardiovascular disease (CVD) in this population has not been explored. Method and Results— We identified patients from a United Kingdom primary care database (The Health Improvement Network) with measurements of serum total bilirubin levels recorded 3 months before the first statin treatment between January 1, 2000, and December 31, 2010, and no history of liver disease or CVD. In total, 130 052 patients met the inclusion criteria, and after a median follow-up of 43 months, there were 7850 CVD events. In men, the incidence of CVD in the lowest decile category of bilirubin (1–6 &mgr;mol/L [0.06–0.35 mg/dL]) was 215 per 10 000 person-years compared with 163 per 10 000 person-years in the highest decile (19–40 &mgr;mol/L [1.1–2.3 mg/dL]). Similar differences were seen for women. After conventional CVD risk factors were accounted for, the associations with bilirubin were nonlinear (L shaped), and the models predicted that, compared with patients with a bilirubin level of 10 &mgr;mol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 &mgr;mol/L (0.3 mg/dL) had an 18% (95% confidence interval, 9–27) higher risk of any CVD event, a 34% (95% confidence interval, 13–56) higher risk of myocardial infarction, and a 33% (95% confidence interval, 21–46) higher risk of death resulting from any cause. Conclusions— Serum bilirubin level measured before a statin prescription to assess liver function is an independent risk factor for CVD and death in both men and women.

Mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability: UK population based cohort study.

Objectives To describe the incidence of recorded mental illness and challenging behaviour in people with intellectual disability in UK primary care and to explore the prescription of psychotropic drugs in this group. Design Cohort study. Setting 571 general practices contributing data to The Health Improvement Network clinical database. Participants 33 016 adults (58% male) with intellectual disability who contributed 211 793 person years’ data. Main outcome measures Existing and new records of mental illness, challenging behaviour, and psychotropic drug prescription. Results 21% (7065) of the cohort had a record of mental illness at study entry, 25% (8300) had a record of challenging behaviour, and 49% (16 242) had a record of prescription of psychotropic drugs. During follow-up, the rate of new cases of mental illness in people without a history at cohort entry was 262 (95% confidence interval 254 to 271) per 10 000 person years and the rate of challenging behaviour was 239 (231 to 247) per 10 000 person years. The rate of new psychotropic drug prescription in those without a previous history of psychotropic drug treatment was 518 (503 to 533) per 10 000 person years. Rates of new recording of severe mental illness declined by 5% (95% confidence interval 3% to 7%) per year (P<0.001), and new prescriptions of antipsychotics declined by 4% (3% to 5%) per year P<0.001) between 1999 and 2013. New prescriptions of mood stabilisers also decreased significantly. The rate of new antipsychotic prescribing was significantly higher in people with challenging behaviour (incidence rate ratio 2.08, 95% confidence interval 1.90 to 2.27; P<0.001), autism (1.79, 1.56 to 2.04; P<0.001), and dementia (1.42, 1.12 to 1.81; P<0.003) and in those of older age, after control for other sociodemographic factors and comorbidity. Conclusions The proportion of people with intellectual disability who have been treated with psychotropic drugs far exceeds the proportion with recorded mental illness. Antipsychotics are often prescribed to people without recorded severe mental illness but who have a record of challenging behaviour. The findings suggest that changes are needed in the prescribing of psychotropics for people with intellectual disability. More evidence is needed of the efficacy and safety of psychotropic drugs in this group, particularly when they are used for challenging behaviour.

Identifying periods of acceptable computer usage in primary care research databases.

To examine the effect of applying different data quality filters on the incidence of disease and prescribing trends over time in a primary care research database and validate a new method for defining periods of adequate computer usage.

Gilbert's syndrome and the risk of death: a population-based cohort study

Gilberts syndrome is a common familial hyperbilirubinemia that may reduce the risk of various age‐related diseases because of the antioxidant properties of bilirubin. We conducted a large cohort study using The Health Improvement Network primary care database and compared all‐cause mortality rates in those with and without Gilberts syndrome.

Prevalence of Clinically Relevant UGT1A Alleles and Haplotypes in African Populations

Variation of a short (TA)n repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP‐glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilberts syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low‐activity (risk) alleles ((TA)7 and (TA)8)) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low‐activity (TA)n alleles frequencies were highest in equatorial Africa, (TA)7, being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)n. Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)n on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.

Assessment of an incentivised scheme to provide annual health checks in primary care for adults with intellectual disability: a longitudinal cohort study

BACKGROUND People with intellectual disabilities (ID) have many comorbidities but experience inequities in access to health care. National Health Service England uses an opt-in incentive scheme to encourage annual health checks of patients with ID in primary care. We investigated whether the first 3 years of the programme had improved health care of people with ID. METHODS We did a longitudinal cohort study that used data from The Health Improvement Network primary care database. We did multivariate logistic regression to assess associations between various characteristics and whether or not practices had opted in to the incentivised scheme. FINDINGS We assessed data for 8692 patients from 222 incentivised practices and those for 918 patients in 48 non-incentivised practices. More blood tests (eg, total cholesterol, odds ratio [OR] 1·88, 95% CI 1·47-2·41, p<0·0001) general health measurements (eg, smoking status, 6·0, 4·10-8·79, p<0·0001), specific health assessments (eg, hearing, 24·0, 11·5-49·9, p<0·0001), and medication reviews (2·23, 1·68-2·97, p<0·0001) were done in incentivised than in non-incentivised practices, and more health action plans (6·15, 1·41-26·9, p=0·0156) and secondary care referrals (1·47, 1·05-2·05, p=0·0256) were made. Identification rates were higher in incentivised practices for thyroid disorder (OR 2·72, 95% CI 1·09-6·81, p=0·0323), gastrointestinal disorders (1·94, 1·03-3·65, p=0·0390), and obesity (2·49, 1·76-3·53, p<0·0001). INTERPRETATION Targeted annual health checks for people with ID in primary care could reduce health inequities. FUNDING National Institute for Health Research.

Serum uric acid and the risk of respiratory disease: a population-based cohort study

Introduction Uric acid is the most abundant molecule with antioxidant properties found in human blood serum. We examined the relationship between serum uric acid and the incidence of respiratory disease including any effect modification by smoking status. Methods A cohort with serum uric acid measured between 1 January 2000 and 31 December 2012 was extracted from The Health Improvement Network primary care research database. New diagnoses of COPD and lung cancer were ascertained based on diagnostic codes entered into the medical records. Results During 1 002 496 person years (PYs) of follow-up, there were 3901 COPD diagnoses and 1015 cases of lung cancer. After multivariable adjustment, strong interactions with smoking status were detected (p<0.001) for both outcomes with significant negative relationships between serum uric acid and respiratory disease for current smokers but no strong relationships for never-smokers or ex-smokers. The relationships were strongest for lung cancer in heavy smokers (≥20 cigarettes per day) with predicted incidence rates 97 per 10 000 PYs (95% CI 68 to 126) in the lowest serum uric acid quintile (100–250 µmol/L) compared with a predicted 28 per 10 000 PYs (95% CI 14 to 41) in the highest quintile (438–700 µmol/L). Conclusions Low levels of serum uric acid are associated with higher rates of COPD and lung cancer in current smokers after accounting for conventional risk factors.

Access to Cancer Screening in People with Learning Disabilities in the UK: Cohort Study in the Health Improvement Network, a Primary Care Research Database

Objectives To assess whether people with learning disability in the UK have poorer access to cancer screening. Design Four cohort studies comparing people with and without learning disability, within the recommended age ranges for cancer screening in the UK. We used Poisson regression to determine relative incidence rates of cancer screening. Setting The Health Improvement Network, a UK primary care database with over 450 General practices. Participants Individuals with a recorded diagnosis of learning disability including general diagnostic terms, specific syndromes, chromosomal abnormalities and autism in their General Practitioner computerised notes. For each type of cancer screening, a comparison cohort of up to six people without learning disability was selected for each person with a learning disability, using stratified sampling on age within GP practice. Main outcome measures Incidence rate ratios for receiving 1) a cervical smear test, 2) a mammogram, 3) a faecal occult blood test and 4) a prostate specific antigen test. Results Relative rates of screening for all four cancers were significantly lower for people with learning disability. The adjusted incidence rate ratios (95% confidence intervals) were Cervical smears: Number eligible with learning disability = 6,254; IRR = 0.54 (0.52–0.56). Mammograms: Number eligible with learning disability = 2,956; IRR = 0.76 (0.72–0.81); Prostate Specific Antigen: Number eligible = 3,520; IRR = 0.87 (0.80–0.96) and Faecal Occult Blood Number eligible = 6,566; 0.86 (0.78–0.94). Differences in screening rates were less pronounced in more socially deprived areas. Disparities in cervical screening rates narrowed over time, but were 45% lower in 2008/9, those for breast cancer screening appeared to widen and were 35% lower in 2009. Conclusion Despite recent incentives, people with learning disability in the UK are significantly less likely to receive screening tests for cancer that those without learning disability. Other methods for reducing inequalities in access to cancer screening should be considered.