A validation study of the CirCom comorbidity score in an English cirrhosis population using the Clinical Practice Research Datalink

Purpose: The CirCom score has been developed from Danish data as a specific measure of comorbidity for cirrhosis to predict all-cause mortality. We compared its performance with the Charlson Comorbidity Index (CCI) in an English cirrhosis population. Patients and methods: We used comorbidity scores in a survival model to predict mortality in a cirrhosis cohort in the Clinical Practice Research Datalink. The discrimination of each score was compared by age, gender, socioeconomic status, cirrhosis etiology, cirrhosis stage, and year after cirrhosis diagnosis. We also measured their ability to predict liver-related versus non-liver-related death. Results: There was a small improvement in the C statistic from the model using the CirCom score (C=0.63) compared to the CCI (C=0.62), and there was an overall improvement in the net reclassification index of 1.5%. The improvement was more notable in younger patients, those with an alcohol etiology, and those with compensated cirrhosis. Both scores performed better (C statistic >0.7) for non-liver-related deaths than liver-related deaths (C statistic <0.6), as comorbidity was only weakly predictive of liver-related death. Conclusion: The CirCom score provided a small improvement in performance over the CCI in the prediction of all-cause and non-liver mortality, but not liver-related mortality. Therefore, it is important to include a measure of comorbidity in studies of cirrhosis survival, alongside a measure of cirrhosis severity

The epidemiology of upper gastrointestinal bleeding

Background There have been many conflicting changes in the prevalence of the risk factors for upper gastrointestinal bleeding and therefore it is not clear what the current trends in mortality or incidence are, nor which factors are important in driving these trends. As populations in many countries are ageing with an increasing burden of co-morbidity, this thesis investigates whether the relationship between non gastrointestinal co-morbidity and upper gastrointestinal bleeding might be an explanation for current trends. I hypothesised that non gastrointestinal co-morbidity was responsible for a large proportion of bleeds in the population and the deaths that occur following a bleed. Methodology Large scale routine population based data records were used to assess the current incidence and mortality trends of upper gastrointestinal bleeding in England, as well as more in depth studies of predictors of its occurrence and subsequent mortality. The databases were examined and compared to external sources to assess their representativeness, and methods for defining cases in linked primary and secondary care were developed. The specific questions addressed in the studies were: 1. What are the current trends and variations in occurrence of upper gastrointestinal bleeding? Incidence rates and adjusted incidence rate ratios were calculated by quintiles of socioeconomic status, age group, sex, region, and calendar year. 2. Has there been an improvement in 30 day mortality following upper gastrointestinal bleeding? A nested case control study using Hospital Episodes Statistics from England 1999-2007 examined mortality trends by age, sex, co-morbidity and type of bleed. 3. Does non gastrointestinal co-morbidity predict upper gastrointestinal bleeding? A matched nested case control study used the linked Hospital Episodes Statistics and General Practice Research Database to examine non gastrointestinal co-morbidity as a risk factor adjusted for other known risk factors for bleeding. Sequential population attributable fractions were calculated to estimate what each risk factor contributed to the disease burden. 4. What are the excess causes of death following upper gastrointestinal bleeding? Causes of death by ICD 10 category were extracted following a bleed from the linked Office for National Statistics death register. Crude mortality rates and excess cumulative incidence functions were calculated; the latter adjusted for the competing risks between different causes of death. Results 1. A higher incidence of upper gastrointestinal bleeding was observed in the north of England, but this variation was dwarfed by the variation associated with deprivation. Areas of greater deprivation had 2-3 fold higher rates of hospitalisation for upper gastrointestinal bleeding than areas of less deprivation suggesting that strong modifiable risk factors exist. 2. Over the last decade there was a 20% improvement in 28 day mortality following upper gastrointestinal bleeding, and those admitted with bleeding were increasingly older and had more co-morbidity. 3. A combined measure of non gastrointestinal co-morbidity was a significant independent predictor of upper gastrointestinal bleeding and explained a greater proportion of the burden of bleeding (19%) than any other risk factor in the population, including medications such as aspirin and NSAIDs. 4. More than half the absolute excess risk of death was due to co-morbidity not related to the upper gastrointestinal tract. Conclusions Non gastrointestinal co-morbidity both strongly predicts an event of upper gastrointestinal bleeding, and is responsible for a large proportion of the subsequent long term mortality. The magnitude of the association in the population explains both why its incidence had not decreased, and why the improvements in mortality were observed irrespective of endoscopic management or bleed type. Furthermore a bleed can be an indicator for a re-assessment of the severity of co-existing non gastrointestinal morbidity

Sexual dimorphisms in the dermal denticles of thelesser-spotted catshark, Scyliorhinus canicula (Linnaeus, 1758)

The dermal layers of several elasmobranch species have been shown to be sexually dimorphic. Generally, when this occurs the females have thicker dermal layers compared to those of males. This sexual dimorphism has been suggested to occur as a response to male biting during mating. Although male biting as a copulatory behaviour in Scyliorhinus canicula has been widely speculated to occur, only relatively recently has this behaviour been observed. Male S. canicula use their mouths to bite the female's pectoral and caudal fins as part of their pre-copulatory behaviour and to grasp females during copulation. Previous work has shown that female S. canicula have a thicker epidermis compared to that of males. The structure of the dermal denticles in females may also differ from that of males in order to protect against male biting or to provide a greater degree of friction in order to allow the male more purchase. This study reveals that the length, width and density of the dermal denticles of mature male and female S. canicula are sexually dimorphic across the integument in areas where males have been observed to bite and wrap themselves around females (pectoral fin, area posterior to the pectoral fin, caudal fin, and pelvic girdle). No significant differences in the dermal denticle dimensions were found in other body areas examined (head, dorsal skin and caudal peduncle). Sexually dimorphic dermal denticles in mature S. canicula could be a response to male biting/wrapping as part of the copulatory process

A comparison of the recording of comorbidity in primary and secondary care by using the Charlson Index to predict short-term and long-term survival in a routine linked data cohort

OBJECTIVE: Hospital admission records provide snapshots of clinical histories for a subset of the population admitted to hospital. In contrast, primary care records provide continuous clinical histories for complete populations, but might lack detail about inpatient stays. Therefore, combining primary and secondary care records should improve the ability of comorbidity scores to predict survival in population-based studies, and provide better adjustment for case-mix differences when assessing mortality outcomes. DESIGN: Cohort study. SETTING: English primary and secondary care 1 January 2005 to 1 January 2010. PARTICIPANTS: All patients 20 years and older registered to a primary care practice contributing to the linked Clinical Practice Research Datalink from England. OUTCOME: The performance of the Charlson index with mortality was compared when derived from either primary or secondary care data or both. This was assessed in relation to short-term and long-term survival, age, consultation rate, and specific acute and chronic diseases. RESULTS: 657,264 people were followed up from 1 January 2005. Although primary care recorded more comorbidity than secondary care, the resulting C statistics for the Charlson index remained similar: 0.86 and 0.87, respectively. Higher consultation rates and restricted age bands reduced the performance of the Charlson index, but the index's excellent performance persisted over longer follow-up; the C statistic was 0.87 over 1 year, and 0.85 over all 5 years of follow-up. The Charlson index derived from secondary care comorbidity had a greater effect than primary care comorbidity in reducing the association of upper gastrointestinal bleeding with mortality. However, they had a similar effect in reducing the association of diabetes with mortality. CONCLUSIONS: These findings support the use of the Charlson index from linked data and show that secondary care comorbidity coding performed at least as well as that derived from primary care in predicting survival

Community acquired pneumonia incidence before and after proton pump inhibitor prescription: population based study

Objective To examine the risk of community acquired pneumonia before and after prescription of proton pump inhibitor (PPI) and assess whether unmeasured confounding explains this association. Design Cohort study and self controlled case series. Setting Clinical Practice Research Datalink (1990 to 2013) in UK. Participants Adult patients with a new prescription for a PPI individually matched with controls. Main outcome measures Association of community acquired pneumonia with PPI prescription estimated by three methods: a multivariable Cox model comparing risk in PPI exposed patients with controls, corrected for potential confounders; a self controlled case series; and a prior event rate ratio (PERR) analysis over the 12 month periods before and after the first PPI prescription. Results 160 000 new PPI users were examined. The adjusted Cox regression showed a risk of community acquired pneumonia 1.67 (95% confidence interval 1.55 to 1.79) times higher for patients exposed to PPI than for controls. In the self controlled case series, among 48 451 PPI exposed patients with a record of community acquired pneumonia, the incidence rate ratio was 1.19 (95% confidence interval 1.14 to 1.25) in the 30 days after PPI prescription but was higher in the 30 days before a PPI prescription (1.92, 1.84 to 2.00). The Cox regressions for prior event rate ratio similarly showed a greater increase in community acquired pneumonia in the year before than the year after PPI prescription, such that the analysis showed a reduced relative risk of pneumonia associated with PPI use (prior event rate ratio 0.91, 95% confidence interval 0.83 to 0.99). Conclusion The association between the use of PPIs and risk of community acquired pneumonia is likely to be due entirely to confounding factors

The risk of Clostridium difficile infection in patients with pernicious anaemia: a retrospective cohort study using primary care database.

Background: Studies have found an association between proton pump inhibitor (PPI) use and Clostridium difficile infection. The purpose of this study was to determine whether the mechanism by which PPIs induce an increased risk of C. difficile infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia. Methods: Using a database of anonymised primary care records between 1990 and 2013, we selected exposed patients with a diagnosis of pernicious anaemia treated with vitamin B12 therapy. Each exposed patient was matched by age, gender and general practice to up to 10 controls. Cox regression analysis was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for C. difficile infection with pernicious anaemia, adjusted for potential confounders. Results: We identified 45,467 exposed patients matched to 449,635 controls. The crude incidence rate of C. difficile infection was 1.85/1000 person-years for the exposed cohort and 1.09/1000 person-years for controls. Patients with pernicious anaemia had a greater risk of C. difficile infection than the controls (adjusted HR 1.57, 95% CI 1.40–1.76). Conclusions: Pernicious anaemia patients have an increased risk of C. difficile infection. This supports the theory that severe achlorhydria is the mechanism that increases the risk of C. difficile infection in long-term PPI users

The epidemiology of upper gastrointestinal bleeding

Background There have been many conflicting changes in the prevalence of the risk factors for upper gastrointestinal bleeding and therefore it is not clear what the current trends in mortality or incidence are, nor which factors are important in driving these trends. As populations in many countries are ageing with an increasing burden of co-morbidity, this thesis investigates whether the relationship between non gastrointestinal co-morbidity and upper gastrointestinal bleeding might be an explanation for current trends. I hypothesised that non gastrointestinal co-morbidity was responsible for a large proportion of bleeds in the population and the deaths that occur following a bleed. Methodology Large scale routine population based data records were used to assess the current incidence and mortality trends of upper gastrointestinal bleeding in England, as well as more in depth studies of predictors of its occurrence and subsequent mortality. The databases were examined and compared to external sources to assess their representativeness, and methods for defining cases in linked primary and secondary care were developed. The specific questions addressed in the studies were: 1. What are the current trends and variations in occurrence of upper gastrointestinal bleeding? Incidence rates and adjusted incidence rate ratios were calculated by quintiles of socioeconomic status, age group, sex, region, and calendar year. 2. Has there been an improvement in 30 day mortality following upper gastrointestinal bleeding? A nested case control study using Hospital Episodes Statistics from England 1999-2007 examined mortality trends by age, sex, co-morbidity and type of bleed. 3. Does non gastrointestinal co-morbidity predict upper gastrointestinal bleeding? A matched nested case control study used the linked Hospital Episodes Statistics and General Practice Research Database to examine non gastrointestinal co-morbidity as a risk factor adjusted for other known risk factors for bleeding. Sequential population attributable fractions were calculated to estimate what each risk factor contributed to the disease burden. 4. What are the excess causes of death following upper gastrointestinal bleeding? Causes of death by ICD 10 category were extracted following a bleed from the linked Office for National Statistics death register. Crude mortality rates and excess cumulative incidence functions were calculated; the latter adjusted for the competing risks between different causes of death. Results 1. A higher incidence of upper gastrointestinal bleeding was observed in the north of England, but this variation was dwarfed by the variation associated with deprivation. Areas of greater deprivation had 2-3 fold higher rates of hospitalisation for upper gastrointestinal bleeding than areas of less deprivation suggesting that strong modifiable risk factors exist. 2. Over the last decade there was a 20% improvement in 28 day mortality following upper gastrointestinal bleeding, and those admitted with bleeding were increasingly older and had more co-morbidity. 3. A combined measure of non gastrointestinal co-morbidity was a significant independent predictor of upper gastrointestinal bleeding and explained a greater proportion of the burden of bleeding (19%) than any other risk factor in the population, including medications such as aspirin and NSAIDs. 4. More than half the absolute excess risk of death was due to co-morbidity not related to the upper gastrointestinal tract. Conclusions Non gastrointestinal co-morbidity both strongly predicts an event of upper gastrointestinal bleeding, and is responsible for a large proportion of the subsequent long term mortality. The magnitude of the association in the population explains both why its incidence had not decreased, and why the improvements in mortality were observed irrespective of endoscopic management or bleed type. Furthermore a bleed can be an indicator for a re-assessment of the severity of co-existing non gastrointestinal morbidity

Changes in testing for and incidence of celiac disease in the UK: a population-based cohort study

The diagnosis rates of coeliac disease differ substantially between countries. Intriguingly, there has been recent evidence from Olmstead County, USA and Finland that in the last 5-10 years incidence has plateaued or even declined. In most populations the prevalence also varies widely, serological prevalence from 0% to 1.87% and clinical prevalence from 0.9 to 12.9 per 100000. Understanding of why this variation exists is minimal, yet one of the key aspects governing incidence rates of any disease are “health system drivers”, such as the availability and use of diagnostic tests. We previously reported rising incidence rates of coeliac disease from 1990 to 2011with inequality by deprivation in the UK. Although national guidance on recognition and diagnosis of coeliac disease published in 2009 suggested widening the patient groups that should be tested for coeliac disease, NHS financial constraints could have hindered implementation of these guidelines. Indeed in the USA it has been observed that over the period 2000-2010 there was a marked decrease in treated prevalence of many diseases alongside a sustained period of reduced spending on health care

Incidence and prevalence of celiac disease and dermatitis herpetiformis in the UK over two decades: population-based study

OBJECTIVES: Few studies have quantified the incidence and prevalence of celiac disease (CD) and dermatitis herpetiformis (DH) nationally and regionally by time and age groups. Understanding this epidemiology is crucial for hypothesizing about causes and quantifying the burden of disease. METHODS: Patients with CD or DH were identified in the Clinical Practice Research Datalink between 1990 and 2011. Incidence rates and prevalence were calculated by age, sex, year, and region of residence. Incidence rate ratios (IRR) adjusted for age, sex, and region were calculated with Poisson regression. RESULTS: A total of 9,087 incident cases of CD and 809 incident cases of DH were identified. Between 1990 and 2011, the incidence rate of CD increased from 5.2 per 100,000 (95% confidence interval (CI), 3.8-6.8) to 19.1 per 100,000 person-years (95% CI, 17.8-20.5; IRR, 3.6; 95% CI, 2.7-4.8). The incidence of DH decreased over the same time period from 1.8 per 100,000 to 0.8 per 100,000 person-years (average annual IRR, 0.96; 95% CI, 0.94-0.97). The absolute incidence of CD per 100,000 person-years ranged from 22.3 in Northern Ireland to 10 in London. There were large regional variations in prevalence for CD but not DH. CONCLUSIONS: We found a fourfold increase in the incidence of CD in the United Kingdom over 22 years, with large regional variations in prevalence. This contrasted with a 4% annual decrease in the incidence of DH, with minimal regional variations in prevalence. These contrasts could reflect differences in diagnosis between CD (serological diagnosis and case finding) and DH (symptomatic presentation) or the possibility that diagnosing and treating CD prevents the development of DH