DIAGNOSIS, CLINICAL ASSESSMENT AND PROGNOSIS IN

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1 DIAGNOSIS, CLINICAL ASSESSMENT AND PROGNOSIS IN PATIENTS WITH NON SPECIFIC SERIOUS SYMPTOMS PhD dissertation Esben Næser Faculty of Health Aarhus University 2017

2 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms PhD student: Esben Næser, MD, Research Unit for General Practice, Aarhus University, Denmark, and Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Denmark Supervisors: Professor Peter Vedsted, MD, PhD, Department of Public Health & Research Unit for General Practice, Aarhus University, Bartholins Allé 2, 8000 Aarhus C, Denmark, e mail: p.vedsted@alm.au.dk (main supervisor) Professor and medical director Ulrich Fredberg, PhD, Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Falkevej 1 3, 8600 Silkeborg, Denmark, e mail: ulrifred@rm.dk Professor Henrik Møller, DMSc, Cancer Epidemiology and Population Health, King s College London, United Kingdom, e mail: henrik.moller@kcl.ac.uk Assessment committee: Associate professor Søren Gregersen, MD, PhD, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark (chairman) Professor emeritus Roger Jones, MD, Primary Care and Public Health Science, King s College London, United Kingdom Associate professor Peter Nørregaard, MD, PhD, Abdominal Centre, Diagnostic Unit, Bispebjerg Hospital, Denmark Financial support: The project was supported by the Health Research Fund of the Central Denmark Region (Region Midtjyllands Sundhedsvidenskabelige Forskningsfond), ML Jørgensen & Gunnar Hansen s Foundation, the Danish General Practice Fund (Fonden for Almen Praksis), and Rosa & Asta Jensen s Foundation. 2

3 Acknowledgements ACKNOWLEDGEMENTS The dissertation was carried out in a cooperation between the Diagnostic Centre at Silkeborg Regional Hospital and the Research Unit for General Practice, Aarhus University. First and foremost, I would like to express my gratitude to my main supervisor, Peter Vedsted, who has supported me throughout my thesis journey with his engagement and knowledge while entrusting me to form this project in my own way. I hope to be able to continue our collaboration in the future. Furthermore, I would like to sincerely thank my co supervisor Henrik Møller for the constructive criticism and scientific inspiration that he has provided me with throughout this thesis. Thanks to my co supervisor Ulrich Fredberg: Your motivational behaviour and clinical inputs have been priceless for my project. I would also like to thank Lone Niedziella for great help with linguistic assistance, Hanne Pedersen for her work with retrieving the data from LABKA, Kaare Rud Flarup for his assistance with the data retrieval from the Danish national registries and statistician Anders Helles Carlsen for his assistance on the statistical analyses. Special thanks go to Jan Frystyk for his constructive feedback and cooperation, which considerably helped improve the analysis of paper I in this thesis. Thanks to all my colleges at the Research Unit for General Practice, especially to my loyal office mate, Jakob Søgaard Juul, for good laughs throughout the last three years. My appreciations also go to the doctors and clinical coordinators at the Diagnostic Centre at Silkeborg Regional Hospital for contributing by reporting to the database despite their busy schedule. I would especially like to thank consultant Vera Haahr for her unconditional support. Finally, I wish to thank my family who have continued to support and encourage me throughout this project, Most importantly, I wish to acknowledge my loving and supportive spouse, Anne Sofie, and my three wonderful sons, August, Villum and Aksel, who are my greatest achievements. I thank them for the joy and inspiration they provide to me every day. 3

4 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms 4

5 Contents CONTENTS Preface... 9 Motivation Outline of the thesis The three papers of the thesis List of abbreviations Chapter 1: Introduction Epidemiology of cancer in Denmark Diagnosing cancer in Primary care Organization of the Danish health care system Challenges of diagnosing cancer in primary care Symptomatic presentation of cancer patients The Danish three legged strategy for cancer diagnosis The urgent referral pathway for non specific, serious symptoms The diagnostic centre Prognosis of patients examined at the diagnostic centre Introduction at a glance Aims of thesis Chapter 2: Data and methods Organisation of pathway Data sources The Danish Civil Registration System The Danish National Patient Register The Danish Cancer Register Statistics Denmark The laboratory information system

6 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms The clinical database at Silkeborg Regional Hospital Methods study I Study design Study population Inclusion period Exposure Outcome Statistical analysis Sub analysis of post test probability for specific cancer types Sub analysis of tumour stage at diagnosis for solid cancer Methods study II Study design Study participants Inclusion period Exposure Outcome Statistical analysis Methods study III Study design Study participants Inclusion period Follow up period Exposure Covariates Outcome Statistical analysis Sub analysis of tumour stage at diagnosis for solid cancer Ethics and approvals Chapter 3: Summary of Results Study I

7 Contents Study population and probability of cancer Abnormal blood tests and post test probability of cancer Sub analysis of post test probability for specific cancer types Study II Study population and risk of serious disease Clinical characteristics and risk of serious disease Study III Study population Mortality among patients examined at the diagnostic centre Comparison of mortality in cancer patients examined at the diagnostic centre and reference group Sub analysis of tumour stage at diagnosis for solid cancer Chapter 4: Discussion of methods Design Internal Validity Selection bias Information bias Effect measure modification and confounding Statistical methods External validity Chapter 5: Discussion of results Study I Study II Study III Chapter 6: Main conclusions Study I Study II Study III

8 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms Chapter 7: Future aspects References English summary Dansk resume Paper I Paper II Paper III Appendix I: Clinical database Appendix II Serious diagnoses includes in study II

9 Preface PREFACE 9

10 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms Motivation I was introduced to the diagnostic workup of patients with non specific serious symptoms when I started working at the Diagnostic Centre at Silkeborg Regional Hospital in During the two years that I worked at the Diagnostic Centre, I realized that the diagnostic workup of this patient group was a complex and challenging task. It was interesting and important work, and it gave me great satisfaction that I was able to offer my patients timely multidisciplinary diagnostic workup in close collaboration with colleagues. Therefore, it was a welcome opportunity for me to be able to further explore this complex group of patients through a PhD project. The research questions developed for this PhD thesis originated from a desire to improve the diagnostic strategies for patients with non specific symptoms and signs of serious disease and to evaluate the efficiency of the new diagnostic pathway for these patients. I sincerely hope that the scientific contribution from this thesis will benefit the patients presenting with non specific symptoms of serious disease in the future. 10

11 Preface OUTLINE OF THE THESIS Chapter 1 of the thesis introduces the research area, including the urgent referral pathway for non specific, serious symptoms. The aims of the thesis are presented at the end of this chapter. Chapter 2 describes the setting, the data sources and the study methodology. Chapter 3 summarises the results of the three studies. Chapter 4 contains a critical evaluation of the methodology and a discussion of the generalisability of the results. In Chapter 5, the results are discussed in relation to existing literature. Chapter 6 presents the conclusions of the three studies, and Chapter 7 outlines aspects of relevance for future research. References are listed at the end. The reference list is followed by an English summary and a Danish summary, the three scientific papers and appendices. 11

12 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms THE THREE PAPERS OF THE THESIS Paper I: Naeser E, Møller H, Fredberg U, Frystyk J, Vedsted P. Routine blood tests and probability of cancer in patients referred with non specific serious symptoms: a cohort study. BMC Cancer. 2017;17(1):817 Paper II: Naeser E, Fredberg U, Møller H, Vedsted P. Clinical characteristics and risk of serious disease in patients referred to a diagnostic centre: a cohort study. Cancer Epidemiology 2017;50(Pt A): Paper III: Naeser E, Møller H, Fredberg U, Vedsted P. Mortality in patients examined at a diagnostic centre in Denmark: a matched cohort study. Manuscript completed. 12

13 Preface LIST OF ABBREVIATIONS CA 125: Cancer antigen 125 CI: Confidence interval CCI: Charlson Comorbidity Index CDR: Central Denmark Region CRS: Civil Registration System CT TAP: Computed tomography of thorax, abdomen and pelvis DCR: Danish Cancer Register GP: General practitioner ICD 10: International Classification of Diseases, 10 th revision hcg: Human chorionic gonadotropin HR: Hazard ratio LABKA: Clinical laboratory information system LR: Likelihood ratio NPR: National Patient Register NPU: Nomenclature, properties and units PPV: Positive predictive value TNM: Tumour, node, metastasis (cancer staging system) 13

14 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms 14

15 Introduction CHAPTER 1: INTRODUCTION 15

16 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms EPIDEMIOLOGY OF CANCER IN DENMARK Cancer is a common disease in Denmark, accounting for 36,640 new cases in 2014 (excluding non melanoma skin cancer) 1. The age standardized incidence of cancer is higher in men (504 in 100,000) than women (447 in 100,000) 1. The incidence rate increases with age for most cancer type, and breast, prostate, lung and bowel cancers together represent nearly half (47%) of the new cancers in Denmark 1. Cancer accounted for 31% of all deaths in 2014 and has been the leading cause of death in Denmark since The overall five year relative survival is 58% for men and 61% for women, but it varies depending on cancer type, tumour morphology and disease stage at diagnosis 1,3. The relative survival of cancer has improved over the last years in many countries, including Denmark 4 7. Nevertheless, several studies have also demonstrated survival differences between countries with similar health care systems (Figure 1.1) 1,5,6,8,9. Some studies have shown that Danish cancer patients have lower survival rates than patients in many other countries in Western Europe 1,5,6,9. 16

17 Introduction 5 year age standardized relative survival in women 5 year age standardized relative survival in men Figure 1.1. The 5 year age standardised relative cancer survival in Nordic countries from 1965 to 2014 for patients aged 0 89 at diagnosis, stratified by sex, for all cancer types (excluding nonmelanoma skin cancer) 1. 17

18 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms DIAGNOSING CANCER IN PRIMARY CARE Organization of the Danish health care system The Danish health care system is tax financed, and all Danish residents have free access to diagnosis and treatment in general practice and hospitals 10. Almost all Danish residents (98%) are registered with a general practitioner (GP) 11, whom they must consult for medical advice and treatment. The average GP has 1,600 patients 12. Being first line health care providers, GPs are gate keepers to diagnostic investigations and the secondary health care system. Almost all GPs have direct access to x ray, ultrasound and laboratory investigations for cancer diagnosis 13. Challenges of diagnosing cancer in primary care The majority of cancer patients are diagnosed on the basis of symptomatic presentation, and the GP is involved in the diagnostic process in approximately 75 85% of all cancer patients Diagnosing cancer may be challenging for the GP for several reasons. First, potential warning signs of cancer are frequently seen in general practice. In a Norwegian survey, GPs registered potential warnings signs of cancer in 12.4% of all consultations, but only 1.7% of these were later diagnosed with a malignant disease 17. Second, epidemiological studies from the UK have shown that 20% of the patients who are subsequently diagnosed with cancer consult their GP 3 5 times for cancer related symptoms before referral to a hospital 18. This suggests opportunity to diagnose cancer earlier in some patients 19. Symptomatic presentation of cancer patients Several epidemiological studies have investigated the risk of cancer for symptomatic patients in primary care 20. The best known are the risk assessment tools developed from case control studies in primary care by Hamilton 21 and the QCancer studies developed from cohorts from primary care electronic health 18

19 Introduction records 22,23. The studies may guide further investigation and referral 20 and have been widely adapted in the United Kingdom. The main limitation in the studies is the reliance on the GP s carefulness to report all symptoms, also in the patients who did not develop cancer 24. Some cancer patients present with specific alarm symptoms, e.g. rectal bleeding, dysphagia and breast lump, which will indicate the affected organ system 21, A review showed that only eight alarm symptoms had a positive predictive value (PPV) of cancer above 5% in primary care patients 26. Most other symptoms (including other alarm symptoms) in primary care have a low PPV of cancer, ranging between 1% and 5% 21,25,26. Therefore, alarm symptoms are most often attributable to benign conditions 31. Other cancer patients present with non specific symptoms, e.g. weight loss, fatigue and general malaise, without an obvious link to a specific cancer site 17,27. As such symptoms are seen for both non malignant disease and several cancer types 21 23,27,28,32 38, it may be difficult for the GP to recognize symptoms of cancer in these patients at the first visit 39,40 and to identify the most appropriate referral pathway 41,42. Patients with non specific symptoms may thus risk to experience multiple referrals to different medical specialties before a diagnosis is reached

20 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms THE DANISH THREE LEGGED STRATEGY FOR CANCER DIAGNOSIS Cancer strategies have been implemented in many health care system to ensure a timely diagnosis of cancer This strategy is supported by epidemiological studies suggesting that expedited diagnosis of symptomatic cancer patients is likely to benefit the patients in terms of improved survival Delays during the time period from the first experienced symptoms to initiated treatment of cancer may be attributed to the patient, the GP and/or the secondary health care system 53,54. Delayed referrals from primary care and delayed cancer diagnoses may explain some of the variation in the survival between countries 29,55,56. In 2000, a two week wait (2WW) referral pathway was implemented in the United Kingdom, which enabled the GPs to refer patients suspected of cancer for a fasttrack diagnostic pathway in the secondary sector 45,57,58. To ensure earlier diagnosis of cancer, The National Institute for Health and Care Excellence (NICE) have recently updated their recommendation for referral to the two week wait (2WW). Based on epidemiological evidence from primary care 20 23, the updated guidelines have now changed the risk threshold for referral from a 5% to 3% for adult cancers 59. The lowered risk threshold was based on a pragmatic decision balancing different views: in a large scaled vignette study patients preferred a 1% risk threshold 60. At the same time, the recommendation had to take into account the economic and clinical costs of investigating large numbers of people at low risk of cancer 24,59. Urgent referral pathways for specific cancer types were introduced in Denmark in ,61. This initiative was inspired by the two week wait (2WW) referral pathways from the United Kingdom, but the Danish initiative does not contain a specific cancer risk threshold for referral. The purpose of the national implementation was to expedite cancer diagnosis, improve cancer survival and ultimately increase patient satisfaction. The Danish urgent referral pathways consist of guidelines for diagnostic procedures, treatments and standard time 20

21 Introduction frames for all phases of the pathway. For each cancer type, the urgent referral pathway contains a description of selected alarm symptoms and signs that may raise suspicion of cancer and qualify for further referral 44. The diagnostic interval has decreased for cancer patients after the implementation of the urgent referral pathways However, only 37 43% of cancer patients (depending on cancer type) are primarily referred to an urgent referral pathway by the GP 15,65. Cancer patients referred through urgent referral pathways have shorter diagnostic intervals than patients referred through other routes 62,66. A high proportion of cancer patients have thus not benefitted from these pathways. A Danish study has shown that only half of all cancer patients presented symptoms interpreted as alarm symptoms by the GP at the first visit 15. The remaining half presented either symptoms interpreted as vague (30%) or nonspecific, serious symptoms (20%). Patients who did not present alarm symptoms were less likely to be referred to an organ specific urgent referral pathway and had longer diagnostic interval than patients presenting with alarm symptoms. Furthermore, symptoms in primary care present along a continuum from certainly not serious to definitely serious 67. Between these extremes, are the so called low risk but not no risk symptoms 68, where the symptom is most probably not a sign of cancer, although cancer cannot be excluded 67. The GP must be able to identify cancer along the whole continuum of symptoms and refer timely. This implies that the existing urgent referral pathways may favour patients presenting with alarm symptoms rather than embrace the entire spectrum of symptoms presented by cancer patients 15,57,67. To expedite cancer diagnosis for a broader population of symptomatic patients with possible cancer, new referral pathways from primary care have been developed as part of the Danish three legged cancer strategy (Figure 1.2) 67. This strategy is based on the idea that the GP may identify symptoms as alarm symptoms, non specific symptoms or vague symptoms. 21

22 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms Figure 1.2. Organisation of the Danish three legged cancer strategy. Adapted from A differentiated approach to referrals from general practice to support early cancer diagnosis the Danish threelegged strategy, by P. Vedsted and F. Olesen, 2015, British Journal of Cancer, 112, p The Danish three legged cancer strategy has involved the development of two new diagnostic pathways from primary care: the urgent referral pathway for nonspecific serious symptoms and the no yes clinics. The no yes clinics primarily target patients presenting with vague symptoms of specific cancer types ( lowrisk but not no risk symptoms ) and give the GP direct access to expedited investigations without double gate keeping in the secondary sector 67. Referral to the urgent referral pathway for non specific serious symptoms may be based on one or more unexplained non specific symptoms or findings 69. Guidance on which symptoms and signs that may cause the GP to suspect serious disease and refer to the pathway are described in the national guidelines (Table 1.1) 69. However, unlike the urgent referral pathways for specific cancer types, less definitive referral criteria in relation to symptoms or signs exist for the urgent referral pathway for non specific serious symptoms 69,70. Based on the clinical context, the individual GP decides when to refer to the urgent referral pathway for non specific serious symptoms. 22

23 Introduction Symptom interpretation and patient management may vary between GPs 65,71, i.e. some symptoms (as abdominal pain or bone pain) may present as both an alarm symptom, a non specific symptom or a vague symptom. The Danish three legged cancer strategy provides the GP with diagnostic routes that takes into account the variability of symptoms presented in primary care. This thesis focuses on the urgent referral pathway for non specific serious symptoms. Table 1.1 Referral criteria for the urgent referral pathway for non specific, serious symptoms (adapted from the national guideline for the urgent referral pathway for non specific, serious symptoms 69 ). Possible referral criteria GP s suspicion of serious disease a Examples of symptoms or findings that may lead to referral Unexplained non specific symptoms Unexplained abnormal laboratory findings Sudden increase in number of contacts to the health care services or sudden increase in medication use General malaise, unintended weight loss, extreme fatigue, fever of unknown origin, diffuse abdominal pain or bone pain. Anaemia, high alkaline phosphatase or high calcium a Patients presenting with symptoms or findings suggestive of a specific cancer type and fulfilling the referral criteria for an organ specific pathway should be referred to this specific pathway. 23

24 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms THE URGENT REFERRAL PATHWAY FOR NON SPECIFIC, SERIOUS SYMPTOMS Silkeborg Regional Hospital was the first to develop and implement a diagnostic pathway for patients with non specific serious symptoms 72. Subsequently, a working group under the Danish Health Authority developed the urgent referral pathway for non specific serious symptoms based on the experiences from Silkeborg Regional Hospital. The pathway was implemented nationally in and enabled the GP to refer patients with non specific symptoms suggestive of serious illness to a coordinated diagnostic trajectory 69. The urgent referral pathway for non specific serious symptoms gives the GP access to both rapid diagnostic investigations and a fast track pathway for clinical assessment at the diagnostic centres. All patients in this pathway are initially referred from the GP to a triage function 73. The purpose of the triage function is to guide the GP in the initial diagnostic workup of serious disease (cancer or serious non malignant disease). The triage function consists of imaging (combined abdominal ultrasound and chest X ray or computed tomography of thorax, abdomen and pelvis (CT TAP)) and a number of standardized blood tests. The diagnostic investigations in the triage function may differ between the diagnostic centres 69,74,75. A national working group chose the blood test panel based on best practice 69, but these blood tests have never been examined among patients referred with non specific, serious symptoms. Patients referred to this blood test panel have a different diagnostic spectrum and a higher prevalence of cancer compared to a usual primary care setting; this indicates that the clinical performance of these blood tests may vary substantially 76,77. The diagnostic centre The urgent referral pathway for non specific serious symptoms enables the GP to refer patients to a diagnostic centre after the initial GP initiated triage function. Referral to the diagnostic centre is warranted if no obvious explanation for the 24

25 Introduction patient s symptoms are present after the triage function (Table 1.1). The proportion of patients referred to a diagnostic centre after the triage function varies between 18% and 59% 74. In this thesis, the Diagnostic Centre at Silkeborg Regional Hospital is used as representative example of this type of centre. At the diagnostic centre, the patient undergoes multidisciplinary diagnostic work based on symptoms and findings. However, as non specific symptoms may have several causes, it may be challenging for the clinicians to distinguish between patients with serious disease and less serious self limiting disease. Previous studies have mainly focused on the risk of cancer among patients examined at a diagnostic centre and have not considered the entire spectrum of serious disease (cancer and serious non malignant disease) 78,79. Only one small scale study has examined the diagnostic value of clinical characteristics in cancer diagnosis, but this study included only few clinical characteristics and did not examine the role of these characteristics in the diagnosis of serious non malignant disease 79. Prognosis of patients examined at the diagnostic centre Urgent referral pathways should ideally lead to improved prognosis by a more timely cancer diagnosis 44,80. However, the diagnostic workup in patients with nonspecific serious symptoms may be difficult, and these patients may have a longer diagnostic pathway 40,73, which may influence the prognosis negatively. The few studies on the prognosis of cancer patients examined at a diagnostic centre have reported high mortality or high tumour stage, which suggests diagnosis at a late stage of disease progression 42,79,81. However, these studies were small and did not include a comparison group of cancer patients examined through other routes. In conclusion, our knowledge is sparse on the mortality of patients examined through a diagnostic centre. 25

26 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms INTRODUCTION AT A GLANCE The urgent referral pathway for non specific, serious symptoms was implemented in Denmark in as one of several initiatives to expedite cancer diagnosis. This new diagnostic pathway gives the GPs access to both rapid diagnostic investigations and a fast track pathway to refute or confirm the suspicion of serious disease in patients with non specific symptoms. Knowledge about the diagnostic spectrum and the diagnostic value of specific clinical characteristics can help clinicians and policymakers optimise this pathway. Furthermore, improving the prognosis of cancer patients was an important reason for implementing the urgent referral pathway for non specific, serious symptoms. This knowledge is also important for evaluating the pathway. 26

27 Introduction AIMS OF THESIS The overall aim of this thesis was to gain insight into the diagnosis, the clinical assessment and the prognosis of patients referred by the GP through the urgent referral pathway for non specific serious symptoms. This aim was explored in three separate studies with the following specific aims: 1. To calculate the probability of cancer for abnormal blood test results in the blood test panel performed as part of the urgent referral pathway for non specific serious symptoms at Silkeborg Regional Hospital. 2. To estimate the distribution of serious disease, i.e. cancer and serious non malignant disease, and to describe and quantify the diagnostic value of selected clinical characteristics for the diagnosis of serious disease in patients examined at the Diagnostic Centre at Silkeborg Regional Hospital. 3. To assess the mortality in patients examined at the Diagnostic Centre at Silkeborg Regional Hospital stratified by diagnostic outcome and to compare the mortality of cancer patients examined at the Diagnostic Centre with a cancer reference group diagnosed through other routes. 27

28 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms 28

29 Data and methods CHAPTER 2: DATA AND METHODS 29

30 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms The study population in this thesis consists of two cohorts of patients referred by their GP to the urgent referral pathway for non specific serious symptoms at Silkeborg Regional Hospital. In study I, the cohort consisted of patients referred to the standardized blood test panel in the triage function. In study II and study III, the cohort consisted of patients examined at the Diagnostic Centre. In the following, the organisation of the urgent referral pathway for non specific, serious symptoms at Silkeborg Regional Hospital will be outlined. The subsequent paragraphs describe the data sources for the three studies and the methods used in each study. Table 2.1 gives a schematic overview of the study designs, study populations, data sources and outcomes used in the three studies. 30

31 Data and methods Table 2.1 Overview of study designs, study populations, data sources and outcomes Study Study design Study population Data sources Outcomes I Delayed type cross sectional study Patients ( 18 years) referred from GP to the triage function blood test panel at Silkeborg Regional Hospital between 1 February 2011 and 31 December 2013 LABKA, DCR Abnormal blood tests in the triage function Diagnosis of cancer II Delayed type cross sectional study Patients ( 18 years) referred from GP to the Diagnostic Centre at Silkeborg Regional Hospital between 1 July 2012 and 30 September 2014 Clinical database at Silkeborg Regional Hospital, DCR, NPR and LABKA Symptoms, clinical findings, abnormal blood tests and imaging Diagnosis of cancer and serious non malignant disease III 1. Cohort study 1. Patients ( 18 years) referred from GP to the Diagnostic Centre at Silkeborg Regional Hospital between 1 July 2012 and 30 September 2014 Clinical database at Silkeborg Regional Hospital and Statistics Denmark All cause mortality 2. Matchedcohort study 2. Cancer patients examined at the Diagnostic Centre at Silkeborg Regional Hospital and a matched group of cancer patients examined through other routes. DCR: Danish Cancer Register; LABKA: Laboratory information system; NPR: National Patient Register. 31

32 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms ORGANISATION OF PATHWAY Silkeborg Regional Hospital is situated in the Central Denmark Region (CDR) and has a catchment area of approximately 177,700 residents aged 18 years 43. The triage function at Silkeborg Regional Hospital consists of 48 standardized blood tests (please see Paper I, additional file 1) and a combined abdominal ultrasound and chest X ray. The triage function tests are performed on the same day. If the imaging raises suspicion of malignancy, the radiologist routinely performs a CT TAP in continuation of the triage function. If the imaging raises suspicion of cancer, the radiologist refers the patient directly to a relevant urgent referral pathway for a specific cancer type. The GP receives the results of the triage function electronically within three days and decides on the further diagnostic approach. If a specific non malignant disease or a specific cancer type is suspected (e.g. haematological cancer), the diagnostic approach could involve referral to a special medical department or to an urgent pathway for a specific cancer type. If the triage function yields no obvious explanation for the patient s symptoms, the GP is advised to refer the patient to the Diagnostic Centre for further investigation. The first visit to the Diagnostic Centre in Silkeborg is scheduled within 1 3 days after referral 43,72. Based on the medical history and the results of previous investigations, referred patients undergo individual diagnostic programmes that are developed in a close cooperation between relevant experts. All internal medical specialities are represented at Silkeborg Regional Hospital and are available for consultation on daily multidisciplinary conferences. Furthermore, the Diagnostic Centre has made preferential arrangements with several specialists to expedite the diagnostic investigations (e.g. gynaecological examination, gastrointestinal endoscopy, diagnostic imaging and biopsy). The programme may include concurrent diagnostic workup involving different medical specialties, 32

33 Data and methods and these are coordinated in the Diagnostic Centre. The Diagnostic Centre is responsible for the patient during the entire diagnostic workup, which must be completed within 16 calendar days according to local guidelines at Silkeborg Regional Hospital. Depending on the diagnosis, the patient may be referred to a special medical department, an urgent referral pathway for a specific cancer type or back to the GP. 33

34 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms DATA SOURCES The three studies in this thesis are based on information from several Danish national registers, a laboratory information system and a clinical database. These data sources are described in the following. The Danish Civil Registration System The Danish Civil Registration System (CRS) is an nationwide administrative register of personal information on Danish residents 82,83. The register has existed since 1968, and it contains daily updated information on migration, vital status and address for all Danish residents. All Danish residents are assigned a unique ten digit identifier (the civil registration number) at birth or immigration; this number is recorded in the CRS. We used the civil registration number to link information in national registries and in the database, and this data was applied in the three studies. The information on vital status and emigration was also used to calculate the time to death in study III. The Danish National Patient Register The Danish National Patient Register (NPR) is a nationwide administrative register, which holds information on hospital contacts in Denmark 84,85. Since 1978, all inpatient contacts in non psychiatric hospitals have been reported to this register. From 1995, all somatic outpatient, emergency department and psychiatric contacts were also included in the register. The NPR serves as the basis for monitoring the health service utilization for the Danish Health Authority. Since 2002, the register has formed the basis for remuneration of public and private hospitals through the diagnosis related group system 86. Registration is obligatory for all hospitals and must be done for each hospital contact. The NPR holds information about the patient s contact type (inpatient, 34

35 Data and methods outpatient or emergency department), dates of admission and discharge, clinical investigations (radiological procedures and other examinations) and diagnosis 84. The diagnosis associated with each hospital contact is registered as one primary diagnosis ( main reason for the hospital contact ) and a number of secondary diagnoses ( other relevant diseases related to the current hospital contact ) may be noted 87. In study II, we used the NPR to retrieve information on new non malignant diagnoses. In study III, we used the NPR to calculate the Charlson Comorbidity Index (CCI) and to identify patients with a referral code [AFA01A] for a diagnostic centre 69. The CCI predicts the 1 year mortality for patients, depending on the severity of comorbidity 88. The index assigns a weighted score to a range of comorbidities based on the strength of relation to mortality in the subsequent year 89. The index has been adapted for administrative hospital data that records medical conditions using the 10 th International Classification system (ICD 10) 90,91. In study III, we used the CCI as described by Quan 90. We measured the impact of pre existing diseases based on all available primary and secondary diagnoses in the NPR within the last 10 years before referral to the diagnostic centre. The Danish Cancer Register The Danish Cancer Register (DCR) is a population based research register, which holds information about incident cancers in the entire Danish population since The DCR collects information about diagnoses (according to the ICD 10), specifically date of diagnosis, tumour morphology and tumour stage at diagnosis according to the tumour, node, metastasis (TNM) staging system 93. The DCR is generated from the mandatory electronic notifications from hospitals (through the NPR) and GPs and data from the Danish Register of Causes of Death 94 and the Danish Pathology Register

36 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms The date of diagnosis in the DCR is defined as the earliest date of the first hospital contact, where the cancer is registered, or the date where the cancer is first verified in the Danish Pathology Register 95,96. The DCR was used 1) to identify all new cancers (excluding non melanoma skin cancer) in study I and study II, 2) to identify a reference group of cancer patients in study III and 3) to collect information about tumour stage in study I and study III. Statistics Denmark Statistics Denmark is a state institution that collects and delivers statistics on Danish citizens and society. The registers at Statistics Denmark are available for researchers on request. Statistics Denmark delivered information on education, type of household, income and labour market affiliation for study III. Education is defined as the highest completed education for each person by the end of each year 97. Type of household is the number of persons who live at the same address (i.e. cohabiting or living alone) 98. Labour market affiliation is based on each person s most important source of income calculated at the end of November every year 99. Disposable income is based on taxable household income in accordance with the Organisation for Economic Cooperation and Development (OECD) adjusted household income ( OECD modified equivalence scale ), which considers size and age of a household 100,101. Data for the thesis was stored on the servers of Statistics Denmark and anonymised. Data was accessed online through a secure remote access. The laboratory information system The laboratory information system LABKA holds results of all blood tests analysed at clinical laboratories in the CDR 102. The LABKA system records results of every blood sample taken in a hospital or by a GP in the CDR. Exceptions are 36

37 Data and methods results for some rapid point of care devices, e.g. haemoglobin or C reactive protein 102. The LABKA system electronically transmits test results to the requesting hospital department or GP. The system holds information on the date of blood sample analysis, the patient s CPR number and the identification code for the physician or hospital requesting the blood test analysis. Information is recorded in a uniform way according to the international Nomenclature, Properties and Units (NPU) coding system with a unique identification number for each single blood test 103. In study I, we used the LABKA system to identify the study population and the results of the standardized blood test panel. We used a specific identifier that allowed us to identify all patients referred by the GP to the standardized blood test panel. Further, LABKA was used in study II to retrieve information on the results of a number of selected blood tests performed within 14 days preceding the first visit to the Diagnostic Centre. We used the unique NPU code to identify the selected blood tests. The clinical database at Silkeborg Regional Hospital The aim of establishing the database was to improve the clinical knowledge on patients referred to the Diagnostic Centre at Silkeborg Regional Hospital through the urgent referral pathway for non specific serious symptoms. Development of database. The database was developed by a project group at Silkeborg Regional Hospital and implemented at the Diagnostic Centre in July The items of the database were based on clinical knowledge and a questionnaire used in a research project among GPs referring patients to the triage function 73,74. Before the implementation of the database, a pilot test was undertaken to evaluate whether the questions were correctly understood. Based on feedback from 37

38 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms clinicians and coordinators at the Diagnostic Centre, wording of questions were adjusted before the implementation of the database. Data entry. Data was filled out by the involved healthcare personal during the outpatient trajectory using the web based research portal e Trial (Appendix I). Public Health and Quality Improvement in the CDR hosted the database. Items in the database. At the first visit to the Diagnostic Centre, the clinician was asked to register chronic diseases prior to referral, presenting symptoms, performance status and clinical findings on the basis of the systematic physical examination. In the database, 21 symptoms and 11 chronic diseases were listed with the possibility of adding additional items. Additional items were classified by the author according to the ICD 10. Performance status was defined according to the standard by the World Health Organization (WHO) 104. Clinical findings included observations that were found relevant to the referral. Thirteen clinical findings were listed in the database according to the affected organ systems. Available imaging data included results of chest X ray, abdominal ultrasound and CT TAP performed prior to the first visit at the Diagnostic Centre. Based on the radiological description of each imaging modality, the clinicians indicated whether the imaging was characterized as one of the following: 1) no abnormalities, 2) suspicion of malignancy requiring further diagnostic examinations, 3) non malignant findings requiring treatment and 4) nonmalignant findings requiring treatment or further diagnostic examinations. The clinician also registered if the examination of the abdominal ultrasound was inconclusive. In that case, a supplementary CT TAP was performed. Time intervals. The coordinators at the Diagnostic Centre registered the date of referral, the date of first visit and the date of last visit. This information was used 38

39 Data and methods to calculate the waiting time in calendar days from: 1) referral from GP to first visit, 2) from first to last visit and 3) overall waiting time from referral to last visit. Data extract. Public Health and Quality Improvement delivered a complete data extract of all patients registered in the database from 1 July 2012 to 30 September Data cleansing was performed by the author, and this dataset was combined with register data for study II and study III. 39

40 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms METHODS STUDY I Study design We performed a delayed type cross sectional study 105 in the catchment area of Silkeborg Regional Hospital by combining data on results of the standardized blood test panel (obtained from LABKA) with data on registered cancers during a follow up period of three months (obtained from the DCR). Study population We included patients aged 18 years if they met the following inclusion criteria: had been referred to the standardized blood test panel by their GP, had no history of cancer within the preceding 10 years and had 10 or more valid blood tests. Inclusion period The inclusion period was from 1 February 2011 until 31 December Exposure Abnormal blood test results. From the standardized blood test panel, we included 26 abnormal blood test results for women and 27 blood test results for men as the main exposure (see Paper 1, additional file 1). We defined blood test results as abnormal when the results were outside the reference range established by the Department of Clinical Chemistry at Silkeborg Regional Hospital (see Paper 1, table 1). Anaemia subtype. Using measurements of haemoglobin, ferritin and C reactive protein, we defined four subtypes of anaemia on the basis of the diagnostic algorithm for unexplained anaemia suggested by the Danish Society of Gastroenterology and Hepatology 106 : 1) iron deficiency anaemia, 2) anaemia from other causes, 3) combined anaemia and 4) inflammatory anaemia. 40

41 Data and methods Combination of two abnormal blood tests. We examined combinations of two abnormal blood test results on the basis of seven predefined blood tests that we hypothesized as frequently abnormal in patients with cancer: high alkaline phosphatase, high C reactive protein, high calcium, high lactate dehydrogenase, high platelet count, high white blood cell count and low haemoglobin. Outcome Cancer. All patients were followed for three months in the DCR for a new cancer diagnosis (excluding non melanoma skin cancer). Statistical analysis We used the chi square test and the Wilcoxon rank sum test to identify differences between patients diagnosed with cancer and patients without cancer. The pre test probability of cancer was calculated as the proportion of patients registered with a new cancer during the three months of follow up. For each abnormal blood test, the likelihood ratio (LR) of cancer was calculated (LR = sensitivity/(1 specificity 107 )). Post test probability of cancer was calculated using Bayes theorem 108. We calculated the post test probability of cancer on the basis of the number of abnormal test results in different intervals (0, 1 2, 3 5, 6 8 and 9 abnormal blood test results). For abnormal blood tests, effect modification of age and gender on the LR of cancer was calculated if: 1) the LR of cancer was more than 1.0 in the study population and 2) there were at least 100 patients with abnormal test results. Statistical significance was set at 0.05 or less, and the 95% confidence intervals (CI) were calculated assuming exact binomial distribution. Data analysis was conducted using Stata statistical software, version 14. The Stata command for summary statistics of diagnostic tests written by Seed was used to calculate LRs of cancer and post test probabilities of cancer

42 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms Sub analysis of post test probability for specific cancer types Using the seven predefined abnormal tests that we hypothesized were frequently abnormal in patients with cancer, we calculated the post test probability for three frequently diagnosed cancer types in the triage function: colorectal cancer, haematological cancer and lung cancer 74. Sub analysis of tumour stage at diagnosis for solid cancer Using TNM staging information in the DCR, solid cancers were categorised as local (no positive lymph nodes or metastasis), regional (positive lymph nodes) or distant (metastatic cancer), or missing (missing TNM components). 42

43 Data and methods METHODS STUDY II Study design This study was designed as a delayed type cross sectional study at the Diagnostic Centre at Silkeborg Regional Hospital using data from a clinical database on clinical characteristics and national registry data on diagnosis. Study participants Patients (aged 18 years) referred by their GP to the Diagnostic Centre at Silkeborg Regional Hospital through the urgent referral for non specific serious symptoms. Inclusion period The inclusion period was from 1 July 2012 until 30 September Exposure Symptoms. Each symptom was dichotomised as present or absent. Additionally, we grouped symptoms into general and focal and made subgroups of focal symptoms based on the presumptively affected organ. Clinical findings: Clinical findings were defined as either present or absent. Abnormal blood tests. We included 14 blood tests that were part of the standardized blood test panel (Paper 2, Table 5). These tests were assumed to be routinely used in the triage function in similar pathways at other Danish hospitals 69. Each blood test was dichotomised into normal or abnormal on the basis of the reference values of the local department of clinical chemistry. Abnormal diagnostic imaging. We included results of chest X ray, abdominal ultrasound and CT TAP. Abnormal diagnostic imaging was defined as: 1) 43

44 Diagnosis, clinical assessment and prognosis in patients with non-specific serious symptoms findings suspicious of malignancy or 2) non malignant findings requiring further treatment or further diagnostic workup. Outcome Serious disease (cancer and serious non malignant disease). All patients were followed up for three months in the national registries for a new serious diagnosis. From the DCR, all cancer diagnoses (excluding non melanoma skin cancer) were included and classified as serious disease. Using the NPR, we retrieved data on all new non malignant diagnoses for patients who had not been registered with cancer in the DCR. Thus, we excluded diagnoses already registered within the ten years preceding the first visit to the Diagnostic Centre. Furthermore, we excluded: 1) diagnoses describing symptoms, signs, abnormal clinical findings and illdefined conditions without classifiable diagnosis (ICD 10: R00 R99) and 2) diagnoses describing acute traumatic conditions (e.g. broken hip). All new diagnoses other than cancer were independently reviewed by three authors and classified as either serious non malignant disease or non serious disease. Disagreements were discussed until consensus was reached. Serious diagnoses were grouped according to disease type (cancer or serious non malignant disease) and relevant medical specialty of diagnosis. The list of the 189 included serious diseases is shown in Appendix II. Statistical analysis Categorical variables were described as frequencies and percentages. The risk of serious disease was calculated as the proportion of patients registered with a new serious diagnosis within the follow up period of three months. We calculated LRs of cancer and LRs of serious non malignant disease for symptoms, clinical findings, abnormal blood tests and abnormal diagnostic imaging. We calculated 95% CIs assuming exact binomial distribution. Data analysis was performed using Stata statistical software, version 14. The Stata command for summary 44