The value of blood-based measures of liver function and urate in lung cancer risk prediction: A cohort study and health economic analysis.

BACKGROUND: Several studies have reported associations between low-cost blood-based measurements and lung cancer but their role in risk prediction is unclear. We examined the value of expanding lung cancer risk models for targeting low-dose computed tomography (LDCT), including blood measurements of liver function and urate. METHODS: We analysed a cohort of 388,199 UK Biobank participants with 1873 events and calculated the c-index and fraction of new information (FNI) for models expanded to include combinations of blood measurements, lung function (forced expiratory volume in 1 s - FEV1), alcohol status and waist circumference. We calculated the hypothetical cost per lung cancer case detected by LDCT for different scenarios using a threshold of ≥ 1.51 % risk at 6 years. RESULTS: The c-index was 0.805 (95 %CI:0.794-0.816) for the model containing conventional predictors. Expanding to include blood measurements increased the c-index to 0.815 (95 %CI: 0.804-0.826;p < 0.0001;FNI:0.06). Expanding to include FEV1, alcohol status, and waist circumference increased the c-index to 0.811 (95 %CI: 0.800-0.822;p < 0.0001;FNI: 0.04). The c-index for the fully expanded model containing all variables was 0.819 (95 %CI:0.808-0.830;p < 0.0001;FNI:0.09). Model expansion had a greater impact on the c-index and FNI for people with a history of smoking cigarettes relative to the full cohort. Compared with the conventional risk model, the expanded models reduced the number of participants meeting the criteria for LDCT screening by 15-21 %, and lung cancer cases detected by 7-8 %. The additional cost per lung cancer case detected relative to the conventional model was £ 1018 for adding blood tests and £ 9775 for the fully expanded model. CONCLUSION: Blood measurements of liver function and urate made a modest improvement to lung cancer risk prediction compared with a model containing conventional risk factors. There was no evidence that model expansion would improve the cost per lung cancer case detected in UK healthcare settings.

Serum urate and lung cancer: a cohort study and Mendelian randomization using UK Biobank.

BACKGROUND: Serum urate is the most abundant small molecule with antioxidant properties found in blood and the epithelial lining fluid of the respiratory system. Moderately raised serum urate is associated with lower rates of lung cancer and COPD in smokers but whether these relationships reflect antioxidant properties or residual confounding is unknown. METHODS: We investigated the observational and potentially causal associations of serum urate with lung cancer incidence and FEV1 using one-sample Mendelian randomization (MR) and the UK Biobank resource. Incident lung cancer events were identified from national cancer registries as FEV1 was measured at baseline. Observational and genetically instrumented incidence rate ratios (IRRs) and risk differences per 10,000 person-years (PYs) by smoking status were estimated. RESULTS: The analysis included 359,192 participants and 1,924 lung cancer events. The associations between measured urate levels and lung cancer were broadly U-shaped but varied by sex at birth with the strongest associations in current smoking men. After adjustment for confounding variables, current smoking men with low serum urate (100 µmol/L) had the highest predicted lung cancer incidence at 125/10,000 PY (95%CI 56-170/10,000 PY) compared with 45/10,000 PY (95%CI 38-47/10,000 PY) for those with the median level (300 µmol/L). Raised measured urate was associated with a lower baseline FEV1. The MR results did not support a causal relationship between serum urate and lung cancer or FEV1. CONCLUSIONS: We found no evidence that serum urate is a modifiable risk factor for respiratory health or lung cancer.

Vitamin D prescribing in children in UK primary care practices: a population-based cohort study.

OBJECTIVE: To examine temporal changes in the incidence and patterns of vitamin D supplementation prescribing by general practitioners (GPs) between 2008 and 2016. DESIGN: Population-based cohort study. SETTING: UK general practice health records from The Health Improvement Network. PARTICIPANTS: Children aged 0 to 17 years who were registered with their general practices for at least 3 months. OUTCOME MEASURES: Annual incidence rates of vitamin D prescriptions were calculated, and rate ratios were estimated using multivariable Poisson regression to explore differences by sociodemographic factors. Data on the type of supplementation, dose, dosing schedule, linked 25-hydroxyvitamin D (25(OH)D) laboratory test results and clinical symptoms suggestive of vitamin D deficiency were analysed. RESULTS: Among 2 million children, the crude annual incidence of vitamin D prescribing increased by 26-fold between 2008 and 2016 rising from 10.8 (95% CI: 8.9 to 13.1) to 276.8 (95% CI: 264.3 to 289.9) per 100 000 person-years. Older children, non-white ethnicity and general practices in England (compared with Wales/Scotland/Northern Ireland) were independently associated with higher rates of prescribing. Analyses of incident prescriptions showed inconsistent supplementation regimens with an absence of pre-supplementation 25(OH)D concentrations in 28.7% to 56.4% of prescriptions annually. There was an increasing trend in prescribing at pharmacological doses irrespective of 25(OH)D concentrations, deviating in part from UK recommendations. Prescribing at pharmacological doses for children with deficient status increased from 3.8% to 79.4%, but the rise was also observed in children for whom guidelines recommended prevention doses (0% to 53%). Vitamin D supplementation at pharmacological doses was also prescribed in at least 40% of children with no pre-supplementation 25(OH)D concentrations annually. CONCLUSIONS: There has been a marked and sustained increase in vitamin D supplementation prescribing in children in UK primary care. Our data suggests that national guidelines on vitamin D supplementation for children are not consistently followed by GPs.

Elevated Vitamin B12 Levels and Cancer Risk in UK Primary Care: A THIN Database Cohort Study.

BACKGROUND: Elevated vitamin B12 levels (B12) are associated with increased short-term cancer risk. However, the implications for early cancer detection in primary care have not been assessed. METHODS: Individuals with plasma B12 measurements were sampled from The Health Improvement Network primary care database, UK. Persons with low B12 levels were excluded together with persons with cancer or B12 treatment before date of B12 measurement. Incident cancer was the outcome of interest and was identified through Read codes. Individuals were disaggregated according to plasma B12 levels (unit: pmol/L): 150-600 (reference range values), 601-800, 801-1,000, and >1,000. RESULTS: Among the 757,185 persons who met the inclusion criteria, we identified 33,367 incident cancers during 2,874,059 years of follow-up. We found a higher 1-year cancer risk among the 25,783 (3.4%) persons with elevated B12 levels compared with those with normal B12 levels. After multivariable adjustment for lifestyle factors and social deprivation, persons with B12 >1,000 pmol/L had a 1-year incidence rate ratio of 4.72 (95% confidence interval: 3.99-5.58). The association showed a nonlinear dose-response pattern, and it remained robust in stratified analyses, including when reducing the risk of confounding by indication in subanalyses. The risks were particularly elevated for liver cancer, pancreas cancer, and myeloid malignancies among persons with elevated B12 levels. CONCLUSIONS: Elevated plasma B12 levels were associated with a higher 1-year cancer risk than normal B12 levels among persons seen in UK primary care, suggesting that some cancers may affect B12 metabolism. IMPACT: Elevated B12 may mark occult cancer.

Sociodemographic trends in the incidence of pancreatic and biliary tract cancer in UK primary care.

BACKGROUND: The UK incidence of pancreatic ductal adenocarcinoma (PDAC) is approximately 9/100,000 population compared with 1-2/100,000 for biliary tract cancer (BTC). This study explores the incidence of these cancers over time and the influence of socio-demographic and geographic factors in a UK primary care cohort. METHODS: This study uses data from a large UK primary care database, The Health Improvement Network (THIN). All adult patients contributing data to THIN between January 2000 and December 2010 were included. Annual incidence rates were calculated, adjusted for age, gender, time period, deprivation score (Townsend quintile) and strategic health authority. RESULTS: From 2000-2010, the annual incidence of PDAC increased by an average of 3% per year (95% CI 1.00-4.00%) and BTC by 4% (95% CI 2.00-6.00%). Incidence of both cancers increased steeply with age and was higher in men. BTC was associated with increasing deprivation (most deprived versus least deprived quintile (OR: 1.45 [95% CI: 1.17, 1.79.]). CONCLUSIONS: The overall incidence of both cancers is low but increasing. Variations in incidence may reflect changes in coding practice or increased exposure to associated risk factors.

Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert's syndrome) and respiratory health in the 1946 British birth cohort.

BACKGROUND & AIMS: Bilirubin has potent antioxidant properties in vitro and raised serum levels have been associated with lower rates of respiratory disease. The enzyme uridine diphosphate glucuronosyltransferase polypeptide 1A1 (UGT1A1) is solely responsible for clearing bilirubin from the blood and homozygosity for seven thymine-adenine (TA) repeats in the TATA box regulatory element of the UGT1A1 gene underlies a mild hereditary unconjugated hyperbilirubinaemia (Gilbert's syndrome). Our aim was to investigate whether this genetic variation is associated with differences in respiratory health. METHODS: The relationship between the promoter genotype underlying Gilbert's syndrome (UGT1A1 rs8175347 [TA]7/7) and respiratory outcomes assessed at ages 43, 53, and 60-64 were examined in 2190 members of the 1946 British birth cohort. RESULTS: The (TA)7/7 genotype, present in 9% of the cohort, was associated with higher forced expiratory volume (FEV1) and forced vital capacity (FVC). The relationship was strongest for heavy smokers (⩾20 cigarettes per day) at age 53 with mean FEV1 409 ml higher (191 to 627; p<0.001) and mean FVC 530 ml higher (95% CI 262-798; p<0.001) for UGT1A1 (TA)7/7 Gilbert's syndrome participants than for all others, indicating a protection from the pulmonary consequences of heavy smoking. The odds of respiratory disease (chronic obstructive pulmonary disease, self-reported asthma, or prescription of respiratory drugs) were half in those with Gilbert's syndrome genotype (odds ratio 0.49 [95% CI 0.39-0.74]; p<0.001) compared to those without this genotype. CONCLUSIONS: Genetically raised unconjugated serum bilirubin is associated with higher adult respiratory function and protection from respiratory disease.

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.

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

BACKGROUND AND AIMS: Gilbert's 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 Gilbert's syndrome. METHODS: Mortality rates in patients with a diagnosis of Gilbert's syndrome and raised bilirubin level (n = 4266) were compared with those of patients with similar characteristics but with normal bilirubin levels (n = 21 968). Multivariate Poisson regression was also used to estimate adjusted mortality rate ratios. RESULTS: During the 350 000 PYs of follow up across the Gilbert's and comparison cohorts, there were 1174 deaths. Mortality rates were 24/10 000 PYs in the Gilbert's cohort versus 50/10 000 PYs in the comparison cohort. Mortality rates were around half in patients with Gilbert's syndrome after accounting for sociodemographics and general health indicators (adjusted mortality rate ratio: 0.5 [95% confidence interval; 0.4-0.7; P < 0.001]). CONCLUSIONS: Mortality rates observed for people with Gilbert's syndrome in the general population are almost half those of people without evidence of Gilbert's syndrome.

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 µmol/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 µmol/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 µmol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 µmol/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.

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.

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 (Gilbert's 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.