Epidemiology of severe hypoglycaemia in children and adolescents with type 1 diabetes FG Mahesh (Max) K. Bulsara BSc (Hons) Mathematics MSc Statistics FG This thesis is submitted for the degree of Doctor of Philosophy at The University of Western Australia School of Population Health Telethon Institute for Child Health Research Faculty of Medicine, Dentistry and Health Science 2008 JK i STATEMENT OF CONTRIBUTION The author of this thesis, under the guidance of the candidate’s co- ordinating supervisor Professor D’Arcy Holman and co-supervisor Clinical Associate Professor Tim Jones, undertook the planning, structuring of the data, data checking, statistical analysis, literature reviews, interpretation of the results, discussions and conclusions included in this thesis. The candidate was responsible for 100% of the drafting of this thesis and for 90% of all peer-reviewed publications associated with it (the bibliographic details of all the published manuscripts are listed in section 1.3; page 4 of this thesis). The author of this thesis was not directly involved in the collection of all the clinical data. This was carried out by the Diabetes Research Team at Princess Margaret Hospital. Professor Holman and Assoc Professor Jones provided feedback on various drafts of the thesis and manuscripts. Due to the multi-disciplinary nature of this project, most of the manuscripts have collaborators listed as co-authors and hence permission was sought and granted by all collaborators to include the publications in this thesis. Signed: ------------------------------------------------------ M.K. BULSARA (Candidate) ------------------------------------------------------ Professor C.D.J. HOLMAN (Co-ordinating supervisor) i ABSTRACT Type 1 Diabetes is emerging as a significant public health problem faced by nearly every country in the world. It has major economic and social implications with considerable burden of illness. Approximately 140,000 Australians have been diagnosed with T1DM with an annual increase in incidence rate of 3% per year, comparable to the overall global increase. The management of T1DM requires insulin therapy which places considerable burden on the patient and their carers. Coping with daily insulin injections, dietary changes, modification of physical activity and vigilant monitoring of blood glucose levels, will impact on patient’s quality of life. The optimum goal for the treatment of type 1 diabetes is to safely achieve near-normal glycaemia and failure to maintain this goal accelerates the progression of the devastating long term complications of diabetes. Unfortunately attempts to achieve near normal glycaemia are limited by the risk of excessive lowering of blood glucose levels and hypoglycaemia remains a major barrier to strict glucose control of diabetes. In general this thesis focuses on two fundamental issues related to the epidemiology of severe hypoglycaemia. Namely, methodological consideration when analysing prospective observational data and application of the most robust methodology. A prospective open cohort study of the Princess Margaret Hospital diabetes clinic established in 1992, with 99% case ascertainment was used. This hospital is the only paediatric referral centre for type 1 diabetes and every child diagnosed in the state of Western Australia is treated at this centre. The purpose of this thesis was to utilize the longitudinal data to examine the most robust statistical models available to investigate changes in incidence rates of severe hypoglycaemia, identify risk factors associated with severe hypoglycaemia and the impact of the changes over time of these risk ii factors. Investigate genetic risk factors and identify factors that predispose some type 1 diabetics to recurrent episodes of severe hypoglycaemia. Two studies (chapter 3 and 5) investigate the use of regression models in assessing risk factors for severe hypoglycaemia and scrutinize the impact of model misspecification and its clinical implications. The number of severe hypoglycaemic episodes for an individual is a non-negative (0,1,2,3,4 etc) count and is traditionally analysed using the Poisson regression model. However, in the presence of excess zero counts (over 70%), alternative models are considered. The over dispersion and likelihood ratio statistics were calculated for each analytical method, namely, the Poisson regression, negative binomial, zero-inflated Poisson (ZIP) and zero-inflated negative binomial (ZINB) models, and were compared. Poisson regression models may lead to biased parameter estimates and the use of either the negative binomial or zero-inflated models is recommended. The study of seasonal patterns in epidemiological studies is important. There are numerous ways to examine this and chapter 4 investigates four methods of measuring seasonality that are commonly used in epidemiological investigations. Results of two commonly used methods are compared to two regression based methods and highlight the advantages using the latter approach. The study to investigate the impact of changing treatment on the incidence rate of severe hypoglycaemia after a decade of follow-up is presented in chapter 6. The results of this study showed that severe hypoglycaemia remains a major problem and recent approaches to therapy may be allowing a degree of improved control without the expected increased risk of severe hypoglycaemia. The study in chapter 7 investigates genetic risk factors related to severe hypoglycaemia. A significant relationship where the presence of the iii deletion (D) allele of the angiotensin-converting enzyme (ACE) increases risk of severe hypoglycaemia has been reported. This study concludes that the presence of D allele of the ACE gene does not predict a significantly higher risk of severe hypoglycaemia. In an attempt to optimize glycemic control, patients may suffer multiple episodes of severe hypoglycaemia which can adversely affect quality of life as well as educational and intellectual disadvantage. The study in chapter 8 investigates the factors related to recurrent severe hypoglycaemia. A rigorous and informative time-to-event approach is used to account for within child correlation, staggered enrolment and time- varying covariates. This allows important risk factors to change over time. Preschool children have an increased risk of experiencing recurrent severe hypoglycaemia. The findings of this thesis highlights the importance of selecting appropriate analytical methodology to identify risk factors associated with severe hypoglycaemia and also to dismiss factors that had previously been thought to be important. This will help in formulating management plans in order to limit the impact of severe hypoglycaemia. iv CONTENTS STATEMENT OF CONTRIBUTION .........................................................................I CONTENTS ......................................................................................................... V APPENDICIES..................................................................................................... XI FIGURES ........................................................................................................... XII TABLES ..........................................................................................................XIVV ABBREVIATIONS ............................................................................................XVII ACKNOWLEDGEMENT..................................................................................XVIIII CHAPTER 1. INTRODUCTION..............................................................................2 1.1. RESEARCH AIM:......................................................................................................... 3 1.2. OUTLINE OF THESIS:.................................................................................................. 3 1.3. JOURNAL ARTICLES RELATED TO THIS THESIS:............................................................. 4 1.4. AWARDS AND RECOGNITION:.................................................................................. 6 1.5. ABSTRACTS OF CONFERENCE PRESENTATIONS RELATED TO THIS THESIS:..................... 6 1.6. OTHER DIABETES RELATED JOURNAL ARTICLES: .......................................................... 8 CHAPTER 2. BACKGROUND .............................................................................11 2.1. THE EPIDEMIOLOGY OF TYPE 1 DIABETES MELLITUS.................................................11 2.1.1. Global Incidence of T1DM:...........................................................................11 2.1.2. Incidence of T1DM in Australia:...................................................................15 2.2. COMMENTS ON THE RISING INCIDENCE OF T1DM .................................................17 2.2.1. “Hygiene” and the “Spring Harvest” Hypothesis:......................................17 2.3. MANAGEMENT OF T1DM: .....................................................................................19 2.4. COMPLICATIONS OF T1DM ...................................................................................21 2.4.1. Introduction:....................................................................................................21 2.4.2. Hypoglycaemia and its Causes: ...................................................................26 2.4.3. Definitions and symptoms of hypoglycaemia:............................................30 2.4.4. Nocturnal Hypoglycaemia: ...........................................................................33