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1.  The value of signs, symptoms and plasma heart-type fatty acid-binding protein (H-FABP) in evaluating patients presenting with symptoms possibly matching acute coronary syndrome: background and methods of a diagnostic study in primary care 
BMC Family Practice  2014;15(1):203.
Chest complaints presented to a general practitioner (GP) are frequently caused by diseases which have advantageous outcomes. However, in some cases, acute coronary syndrome (ACS) is present (1.5-22% of cases). The patient’s signs, symptoms and electrocardiography results are insufficient diagnostic tools to distinguish mild disease from ACS. Therefore, most patients presenting chest complaints are referred to secondary care facilities where ACS is then ruled out in a majority of patients (78%). Recently, a point of care test for heart-type fatty acid-binding protein (H-FABP) using a low cut-off value between positive and negative of 4 ng/ml has become available. We aim to study the role of this point of care device in triage of patients presenting chest complaints possibly due to ACS, in primary care. Our research protocol is presented in this article. Results are expected in 2015.
Participating GPs will register signs and symptoms in all patients presenting chest complaints possibly due to ACS. Point of care H-FABP testing will also be performed. Our study will be a derivation study to identify signs and symptoms that, combined with point of care H-FABP testing, can be part of an algorithm to either confirm or rule out ACS. The diagnostic value for ACS of this algorithm in general practice will be determined.
A safe diagnostic elimination of ACS by application of the algorithm can be of significant clinical relevance. Improved triage and thus reduction of the number of patients with chest complaints without underlying ACS, that are referred to secondary care facilities, could lead to a substantial cost reduction.
Trial registration, NCT01826994, accepted April 8th 2013.
PMCID: PMC4272772
Acute coronary syndrome (ACS); Acute myocardial infarction (AMI); Diagnostic study; Heart-type fatty acid-binding protein (H-FABP); Point of care test (PoCT); Primary care
2.  Diagnosing serious infections in acutely ill children in ambulatory care (ERNIE 2 study protocol, part A): diagnostic accuracy of a clinical decision tree and added value of a point-of-care C-reactive protein test and oxygen saturation 
BMC Pediatrics  2014;14(1):207.
Acute illness is the most common presentation of children to ambulatory care. In contrast, serious infections are rare and often present at an early stage. To avoid complications or death, early recognition and adequate referral are essential. In a recent large study children were included prospectively to construct a symptom-based decision tree with a sensitivity and negative predictive value of nearly 100%. To reduce the number of false positives, point-of-care tests might be useful, providing an immediate result at bedside. The most probable candidate is C-reactive protein, as well as a pulse oximetry.
This is a diagnostic accuracy study of signs, symptoms and point-of-care tests for serious infections. Acutely ill children presenting to a family physician or paediatrician will be included consecutively in Flanders, Belgium. Children testing positive on the decision tree will get a point-of-care C-reactive protein test. Children testing negative will randomly either receive a point-of-care C-reactive protein test or usual care. The outcome of interest is hospital admission more than 24 hours with a serious infection within 10 days. Aiming to include over 6500 children, we will report the diagnostic accuracy of the decision tree (+/− the point-of-care C-reactive protein test or pulse oximetry) in sensitivity, specificity, positive and negative likelihood ratios, and positive and negative predictive values. New diagnostic algorithms will be constructed through classification and regression tree and multiple logistic regression analysis.
We aim to improve detection of serious infections, and present a practical tool for diagnostic triage of acutely ill children in primary care. We also aim to reduce the number of investigations and admissions in children with non-serious infections.
Trial Registration Identifier: NCT02024282
PMCID: PMC4287386  PMID: 25277457
Child; Serious infections; Infant; Acute illness; C-reactive protein/analysis; Diagnostic accuracy; Safety netting; Point-of-care systems
3.  Optimizing antibiotic prescribing for acutely ill children in primary care (ERNIE2 study protocol, part B): a cluster randomized, factorial controlled trial evaluating the effect of a point-of-care C-reactive protein test and a brief intervention combined with written safety net advice 
BMC Pediatrics  2014;14(1):246.
Despite huge public campaigns, there is still overconsumption of antibiotics in children with self-limiting diseases. Possible explanations may be the physicians’ and parents’ uncertainty about the gravity of the disease and inadequate communication between physicians and parents leading to lack of reassurance for the parents. In this paper we describe the design and methods of a trial aiming to rationalize antibiotic prescribing by decreasing this uncertainty and parental anxiety.
Acutely ill children without suspected serious disease consulting their family physician will be consecutively included in a four-armed cluster randomized factorial controlled trial. The intervention will consist a Point-of-Care C-reactive protein test and/or a brief intervention with safety net advice. The control group will receive usual care. We intend to include 2560 patients in 88 family practices. Patients will be followed up until cure. The primary outcome measure is the immediate antibiotic prescribing rate. Secondary outcomes are: comparison between groups of speed of clinical recovery, parental concern, parental perception of the quality of the communication, parental satisfaction, use of medication, use of diagnostic tests and medical services during the illness episode, and cost-effectiveness of the interventions. Besides this, we will observationally analyse data of the children included in the large ERNIE2-trial, but excluded in the cluster randomized trial, namely children suspected of serious disease presenting in primary care and children who initially present at the out-patient paediatric clinic or emergency department. We will search for predictors of antibiotic prescribing, speed of clinical recovery, parental concern, parental perception of communication, parental satisfaction, use of medication, diagnostic tests and medical services.
This is a unique multifaceted intervention, in that it targets both physicians and parents by aiming specifically at their uncertainty and concerns during the consultation. Both interventions are easy to implement without special training. When proven effective, they could offer a feasible way to decrease inappropriate antibiotic prescribing for children in family practice and thus avoid emergence of bacterial resistance, side effects and unnecessary healthcare costs. Moreover, the observational part of the study will increase our insight in the course, management and parent’s concern of acute illness in children.
Trial registration Identifier: NCT02024282.
PMCID: PMC4287591  PMID: 25277543
Child; Infant; Acute disease; Anti-bacterial agents/economics/; Anti-bacterial agents/therapeutic use; C-reactive protein/analysis; Cluster analysis; Communication; Parent satisfaction; Physician's practice patterns; Point-of-care systems
4.  Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA 
BMJ Open  2014;4(8):e005611.
Despite the growing number of point-of-care (POC) tests available, little research has assessed primary care clinician need for such tests. We therefore aimed to determine which POC tests they actually use or would like to use (if not currently available in their practice).
Cross-sectional survey.
Primary care in Australia, Belgium (Flanders region only), the Netherlands, the UK and the USA.
Primary care doctors (general practitioners, family physicians).
Main measures
We asked respondents to (1) identify conditions for which a POC test could help inform diagnosis, (2) from a list of tests provided: evaluate which POC tests they currently use (and how frequently) and (3) determine which tests (from that same list) they would like to use in the future (and how frequently).
2770 primary care clinicians across five countries responded. Respondents in all countries wanted POC tests to help them diagnose acute conditions (infections, acute cardiac disease, pulmonary embolism/deep vein thrombosis), and some chronic conditions (diabetes, anaemia). Based on the list of POC tests provided, the most common tests currently used were: urine pregnancy, urine leucocytes or nitrite and blood glucose. The most commonly reported tests respondents expressed a wish to use in the future were: D-dimer, troponin and chlamydia. The UK and the USA reported a higher actual and desired use for POC tests than Australia, Belgium and the Netherlands. Our limited data suggest (but do not confirm) representativeness.
Primary care clinicians in all five countries expressed a desire for POC tests to help them diagnose a range of acute and chronic conditions. Rates of current reported use and desired future use were generally high for a small selection of POC tests, but varied across countries. Future research is warranted to explore how specific POC tests might improve primary care.
PMCID: PMC4127935  PMID: 25107438
Epidemiology; Chemical Pathology; General Medicine (see Internal Medicine)
5.  The Intego database: background, methods and basic results of a Flemish general practice-based continuous morbidity registration project 
Intego is the only operational computerized morbidity registration network in Belgium based on general practice data. Intego collects data from over 90 general practitioners. All the information is routinely collected in the electronic health record during daily practice.
In this article we describe the design and methods used within the Intego network together with some of its basic results. The collected data, the quality control procedures, the ethical-legal aspects and the statistical procedures are discussed.
Intego contains longitudinal information on 285 357 different patients, corresponding to over 2.3% of the Flemish population representative in terms of age and sex. More than 3 million diagnoses, 12 million drug prescriptions and 29 million laboratory tests have been recorded.
Intego enables us to present and compare data on health parameters, incidence and prevalence rates, laboratory results, and prescribed drugs for all relevant subgroups on a routine basis and is unique in Belgium.
PMCID: PMC4067630  PMID: 24906941
Morbidity registration network; General practice; Methodology; Quality assessment
6.  Cancer in the Elderly 
Journal of Cancer Epidemiology  2014;2014:872029.
PMCID: PMC4021674  PMID: 24876840
7.  Influence of chronic comorbidity and medication on the efficacy of treatment in patients with diabetes in general practice 
The British Journal of General Practice  2013;63(609):e267-e273.
Evidence on the influence of comorbidity and comedication on clinical outcomes in patients with type 2 diabetes mellitus is scarce.
To ascertain the effect of five chronic diseases (joint disorder, respiratory disease, anaemia, malignancy, depression) and three chronically used drugs (non-steroid anti-inflammatory drugs [NSAIDs], corticosteroids, antidepressants) on treatment for hypoglycaemia in patients with type 2 diabetes.
Design and setting
Retrospective cohort study in a variety of practices across Flanders, Belgium.
A retrospective cohort study was conducted, based on data from Intego, a general practice-based continuous morbidity registry. Multiple logistic regression analysis was used to predict the change in glycosylated haemoglobin (HbA1c) levels related to comorbidity, comedication, and a combination of both in 3416 patients with type 2 diabetes. Adjustments were made for age, sex, and diabetes-treatment group (diet, oral antidiabetic drugs, combination treatment, insulin).
Concomitant joint and respiratory disorders, as well as the chronic use of NSAIDs and corticosteroids, either separately or in combination, were significantly associated with the worsening of HbA1c levels. Anaemia, depression, malignancy, and antidepressants had no statistically significant influence on the efficacy of treatment for hypoglycaemia.
The presence of some comorbid diseases or drug use can impede the efficacy of treatment for type 2 diabetes. This finding supports the need to develop treatment recommendations, taking into account the presence of both chronic comorbidity and comedication. Further research must be undertaken to ascertain the effect other combinations of chronic diseases have on the efficacy of treatment of this and other diseases.
PMCID: PMC3609474  PMID: 23540483
co-medication; comorbidity; HbA1c; logistic regression; type 2 diabetes
8.  Four screening instruments for frailty in older patients with and without cancer: a diagnostic study 
BMC Geriatrics  2014;14:26.
Frailty in older patients might influence treatment decisions. Frailty can be determined using a Comprehensive Geriatric Assessment (CGA), but this is time-consuming and expensive. Therefore we assessed the diagnostic value of four shorter screening instruments.
We tested the abbreviated CGA (aCGA), the Vulnerable Elders Survey-13 (VES-13), the Groningen Frailty Indicator (GFI) and the Geriatric 8 (G8). A full CGA including functional status, cognitive status, depression, nutrition and comorbidity was used as reference. A minimum of 85% for both sensitivity and specificity was predefined as acceptable. Data were collected through personal interviews by trained interviewers. We assessed people aged ≥ 70 years: 108 patients with recently diagnosed cancer recruited in hospitals and 290 without cancer recruited by general practitioners in the Netherlands and Belgium.
Frailty was defined as having impairment in at least two domains of the full CGA. We used original cut-offs for the screening instruments and calculated sensitivity, specificity, positive and negative diagnostic values and the percentage classified as frail.
Sensitivity of aCGA was 79% and 87% for patients with and without cancer; specificity was 59% and 64%. Sensitivity of VES-13 was 67% and 82% for patients with and without cancer; specificity was 70% and 79%. Sensitivity for GFI was 76% (in both groups) and specificity 73% (in both groups). Sensitivity for G8 was 87% and 75% for patients with and without cancer; specificity was 68% (in both groups).
No screening instrument was acceptable according to our predefined minimum of 85% for both sensitivity and specificity. The diagnostic value of the investigated instruments is rather poor and one could wonder about their additional value to clinical judgment.
PMCID: PMC3938903  PMID: 24571290
Frailty; Screening; Geriatric assessment; Cancer
9.  Long-term evolution of renal function in patients with type 2 diabetes mellitus: a registry-based retrospective cohort study 
BMJ Open  2013;3(12):e004029.
To picture the 10-year evolution of renal function in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) and to describe the risk factors for severe decline.
Primary registration network with 97 general practitioners working in 55 practices sending routinely collected patient data.
From the database, we selected all patients aged 40 years or older with T2DM and at least two creatinine measurements in two different years with an interval of at least 3 months. Based on the last available value of estimated glomerular filtration rate calculated by the modification of diet in renal disease (MDRD) equation, patients were divided into grades of CKD. Severe decline (decline of >4 mL/min/year) and ‘certain drop’ (CD, year-to-year decline >10 mL/min) were determined in patients with CKD. Determinants of severe decline and CD were investigated with logistic regression and longitudinal logistic regression analysis, respectively.
Primary outcome measure
Kidney function (MDRD).
4041 patients, 1980 women, were included. The mean age was 71 years, mean diabetes duration was 7.7 years; 1514 (38%) suffered from CKD, 231 (15%) presented with severe decline and 18% of the patients with CKD presented with two or more CDs. Younger age, male gender, mean glycated haemoglobin and a higher number of CDs were significantly associated with the presence of severe decline (p<0.05); statins and higher diastolic blood pressure were significantly associated with the absence of severe decline (p<0.001). ACE inhibitors, other antihypertensive drugs and antidiabetic drugs including insulin therapy were specific determinants of CD.
CKD is highly prevalent in patients with T2DM; a minority of patients evolve into severe decline that is associated with younger age, male gender, ‘CD’ and manageable factors such as blood pressure, blood glucose, associated drugs prescriptions and statin therapy. Further prospective observational and experimental research is needed to clarify the nature of those associations.
PMCID: PMC3884754  PMID: 24381258
Primary Care
11.  How well do clinical prediction rules perform in identifying serious infections in acutely ill children across an international network of ambulatory care datasets? 
BMC Medicine  2013;11:10.
Diagnosing serious infections in children is challenging, because of the low incidence of such infections and their non-specific presentation early in the course of illness. Prediction rules are promoted as a means to improve recognition of serious infections. A recent systematic review identified seven clinical prediction rules, of which only one had been prospectively validated, calling into question their appropriateness for clinical practice. We aimed to examine the diagnostic accuracy of these rules in multiple ambulatory care populations in Europe.
Four clinical prediction rules and two national guidelines, based on signs and symptoms, were validated retrospectively in seven individual patient datasets from primary care and emergency departments, comprising 11,023 children from the UK, the Netherlands, and Belgium. The accuracy of each rule was tested, with pre-test and post-test probabilities displayed using dumbbell plots, with serious infection settings stratified as low prevalence (LP; <5%), intermediate prevalence (IP; 5 to 20%), and high prevalence (HP; >20%) . In LP and IP settings, sensitivity should be >90% for effective ruling out infection.
In LP settings, a five-stage decision tree and a pneumonia rule had sensitivities of >90% (at a negative likelihood ratio (NLR) of < 0.2) for ruling out serious infections, whereas the sensitivities of a meningitis rule and the Yale Observation Scale (YOS) varied widely, between 33 and 100%. In IP settings, the five-stage decision tree, the pneumonia rule, and YOS had sensitivities between 22 and 88%, with NLR ranging from 0.3 to 0.8. In an HP setting, the five-stage decision tree provided a sensitivity of 23%. In LP or IP settings, the sensitivities of the National Institute for Clinical Excellence guideline for feverish illness and the Dutch College of General Practitioners alarm symptoms ranged from 81 to 100%.
None of the clinical prediction rules examined in this study provided perfect diagnostic accuracy. In LP or IP settings, prediction rules and evidence-based guidelines had high sensitivity, providing promising rule-out value for serious infections in these datasets, although all had a percentage of residual uncertainty. Additional clinical assessment or testing such as point-of-care laboratory tests may be needed to increase clinical certainty. None of the prediction rules identified seemed to be valuable for HP settings such as emergency departments.
PMCID: PMC3566974  PMID: 23320738
clinical prediction rules; serious infection in children; external validation; NICE guidelines feverish illness; Yale Observation Scale; diagnostic accuracy
12.  Diabetes and intermediate hyperglycaemia in Kisantu, DR Congo: a cross-sectional prevalence study 
BMJ Open  2012;2(6):e001911.
To study the prevalence and risk markers of diabetes mellitus and intermediate hyperglycaemia (IH) in Kisantu, a semirural town in Bas-Congo province, The Democratic Republic of Congo.
A cross-sectional population-based survey.
A modified WHO STEPwise strategy was used. Capillary glycaemia was measured for fasting plasma glucose and 2-h-postload glucose. Both WHO/IDF (International Diabetes Federation) 2006 and American Diabetes Association (ADA) 2003 diagnostic criteria for diabetes and IH were used.
1898 subjects aged ⩾ 20 years.
Response rate was 93.7%. Complete data were available for 1759 subjects (86.9%). Crude and standardised (for Doll and UN population) prevalence of diabetes were 4.8% and 4.0–4.2%. Crude IH prevalence was 5.8% (WHO/IDF) and 14.2% (ADA). Independent risk markers for diabetes (p<0.01) were male (OR 2.5), age 50–69 years (OR 2.6), family history (OR 3.5), waist (OR 4.1) and alcohol consumption (OR 0.36). In receiver operating characteristic (ROC) analysis, prediction of diabetes was slightly better by waist than body mass index (BMI). IH defined according to WHO/IDF was associated with BMI (OR 2.6, p<0.001). IH defined according to ADA was associated (p<0.05) with waist (OR 1.4), education level (OR 1.6), BMI (OR 2.4) and physical activity (OR 0.7).
Current prevalence of diabetes in DR Congo exceeds IDF projections for 2030. The lower glucose threshold used by ADA almost triples impaired fasting glucose prevalence compared to WHO/IDF criteria. The high proportion of disorders of glycaemia made up by IH suggests the early stages of a diabetes epidemic.
PMCID: PMC3533060  PMID: 23161091
Intermediate Hyperglycaemia; Prevalence; Population Based Survey; Sub-Saharan Africa, Dr Congo
13.  European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene 
Rafnar, Thorunn | Vermeulen, Sita H. | Sulem, Patrick | Thorleifsson, Gudmar | Aben, Katja K. | Witjes, J. Alfred | Grotenhuis, Anne J. | Verhaegh, Gerald W. | Hulsbergen-van de Kaa, Christina A. | Besenbacher, Soren | Gudbjartsson, Daniel | Stacey, Simon N. | Gudmundsson, Julius | Johannsdottir, Hrefna | Bjarnason, Hjordis | Zanon, Carlo | Helgadottir, Hafdis | Jonasson, Jon Gunnlaugur | Tryggvadottir, Laufey | Jonsson, Eirikur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Bishop, D. Timothy | Chung-Sak, Sei | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H. | Knowles, Margaret A. | de Verdier, Petra J. | Ryk, Charlotta | Lindblom, Annika | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Panadero, Angeles | Sanz-Velez, José I. | Sanchez, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D. | Hengstler, Jan G. | Selinski, Silvia | Gerullis, Holger | Ovsiannikov, Daniel | Khezri, Abdolaziz | Aminsharifi, Alireza | Malekzadeh, Mahyar | van den Berg, Leonard H. | Ophoff, Roel A. | Veldink, Jan H. | Zeegers, Maurice P. | Kellen, Eliane | Fostinelli, Jacopo | Andreoli, Daniele | Arici, Cecilia | Porru, Stefano | Buntinx, Frank | Ghaderi, Abbas | Golka, Klaus | Mayordomo, José I. | Matullo, Giuseppe | Kumar, Rajiv | Steineck, Gunnar | Kiltie, Anne E. | Kong, Augustine | Thorsteinsdottir, Unnur | Stefansson, Kari | Kiemeney, Lambertus A.
Human Molecular Genetics  2011;20(21):4268-4281.
Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC.
PMCID: PMC3188988  PMID: 21750109
14.  Neuropsychiatric Inventory data in a Belgian sample of elderly persons with and without dementia 
This study assesses and compares prevalence of psychological and behavioral symptoms in a Belgian sample of people with and without dementia.
A total of 228 persons older than 65 years with dementia and a group of 64 non-demented persons were assessed using the Neuropsychiatric Inventory (NPI) in 2004.
Within the group without dementia, the most frequent symptoms were depression, agitation, and irritability. Within the group with dementia, the most common symptoms were depression, irritability, apathy, and agitation. Prevalence of delusions (P < 0.05), hallucinations (P < 0.05), anxiety (P < 0.05), agitation (P < 0.05), apathy (P < 0.01), aberrant motor behavior (P < 0.01), and eating disorders (P < 0.05) were significantly higher in the group with dementia.
Depression, elation, irritability, disinhibition, and sleeping disorders are not specific to dementia. Agitation, apathy, anxiety, and delusions are more frequent in dementia but were not specific to the dementia group because their prevalence rates were close to 10% in the group without dementia. Hallucinations, aberrant motor behavior, and eating disorders are specific to dementia. The distinction between specific and nonspecific symptoms may be useful for etiological research on biological, psychological, and environmental factors.
PMCID: PMC3479895  PMID: 23109804
behavior; behavior disorders; epidemiology; dementia; psychiatric symptoms; neuropsychiatry
15.  Chronic Diseases among Older Cancer Survivors 
Journal of Cancer Epidemiology  2012;2012:206414.
Objective. To compare the occurrence of pre-existing and subsequent comorbidity among older cancer patients (≥60 years) with older non-cancer patients. Material and Methods. Each cancer patient (n = 3835, mean age 72) was matched with four non-cancer patients in terms of age, sex, and practice. The occurrence of chronic diseases was assessed cross-sectionally (lifetime prevalence at time of diagnosis) and longitudinally (incidence after diagnosis) for all cancer patients and for breast, prostate, and colorectal cancer patients separately. Cancer and non-cancer patients were compared using logistic and Cox regression analysis. Results. The occurrence of the most common pre-existing and incident chronic diseases was largely similar in cancer and non-cancer patients, except for pre-existing COPD (OR 1.21, 95% CI 1.06–1.37) and subsequent venous thrombosis in the first two years after cancer diagnosis (HR 4.20, 95% CI 2.74–6.44), which were significantly more frequent (P < 0.01) among older cancer compared to non-cancer patients. Conclusion. The frequency of multimorbidity in older cancer patients is high. However, apart from COPD and venous thrombosis, the incidence of chronic diseases in older cancer patients is similar compared to non-cancer patients of the same age, sex, and practice.
PMCID: PMC3432539  PMID: 22956953
16.  Coronary heart disease in primary care: accuracy of medical history and physical findings in patients with chest pain – a study protocol for a systematic review with individual patient data 
BMC Family Practice  2012;13:81.
Chest pain is a common complaint in primary care, with coronary heart disease (CHD) being the most concerning of many potential causes. Systematic reviews on the sensitivity and specificity of symptoms and signs summarize the evidence about which of them are most useful in making a diagnosis. Previous meta-analyses are dominated by studies of patients referred to specialists. Moreover, as the analysis is typically based on study-level data, the statistical analyses in these reviews are limited while meta-analyses based on individual patient data can provide additional information. Our patient-level meta-analysis has three unique aims. First, we strive to determine the diagnostic accuracy of symptoms and signs for myocardial ischemia in primary care. Second, we investigate associations between study- or patient-level characteristics and measures of diagnostic accuracy. Third, we aim to validate existing clinical prediction rules for diagnosing myocardial ischemia in primary care. This article describes the methods of our study and six prospective studies of primary care patients with chest pain. Later articles will describe the main results.
We will conduct a systematic review and IPD meta-analysis of studies evaluating the diagnostic accuracy of symptoms and signs for diagnosing coronary heart disease in primary care. We will perform bivariate analyses to determine the sensitivity, specificity and likelihood ratios of individual symptoms and signs and multivariate analyses to explore the diagnostic value of an optimal combination of all symptoms and signs based on all data of all studies. We will validate existing clinical prediction rules from each of the included studies by calculating measures of diagnostic accuracy separately by study.
Our study will face several methodological challenges. First, the number of studies will be limited. Second, the investigators of original studies defined some outcomes and predictors differently. Third, the studies did not collect the same standard clinical data set. Fourth, missing data, varying from partly missing to fully missing, will have to be dealt with.
Despite these limitations, we aim to summarize the available evidence regarding the diagnostic accuracy of symptoms and signs for diagnosing CHD in patients presenting with chest pain in primary care.
Review registration
Centre for Reviews and Dissemination (University of York): CRD42011001170
PMCID: PMC3545850  PMID: 22877212
MeSH; Chest pain; Myocardial ischemia; Medical history taking; Sensitivity and specificity; Primary health care
17.  Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer 
Nature Genetics  2009;41(9):991-995.
We conducted a genome-wide association study on 969 bladder cancer cases and 957 controls from Texas. For fast-track validation, we evaluated 60 SNPs in three additional US populations and validated the top SNP in nine European populations. A missense variant (rs2294008) in the PSCA gene showed consistent association with bladder cancer in US and European populations. Combining all subjects (6,667 cases, 39,590 controls), the overall P-value was 2.14 × 10−10 and the allelic odds ratio was 1.15 (95% confidence interval 1.10–1.20). rs2294008 alters the start codon and is predicted to cause truncation of nine amino acids from the N-terminal signal sequence of the primary PSCA translation product. In vitro reporter gene assay showed that the variant allele significantly reduced promoter activity. Resequencing of the PSCA genomic region showed that rs2294008 is the only common missense SNP in PSCA. Our data identify rs2294008 as a new bladder cancer susceptibility locus.
PMCID: PMC3313685  PMID: 19648920
18.  Designing the selenium and bladder cancer trial (SELEBLAT), a phase lll randomized chemoprevention study with selenium on recurrence of bladder cancer in Belgium 
BMC Urology  2012;12:8.
In Belgium, bladder cancer is the fifth most common cancer in males (5.2%) and the sixth most frequent cause of death from cancer in males (3.8%). Previous epidemiological studies have consistently reported that selenium concentrations were inversely associated with the risk of bladder cancer. This suggests that selenium may also be suitable for chemoprevention of recurrence.
The SELEBLAT study opened in September 2009 and is still recruiting all patients with non-invasive transitional cell carcinoma of the bladder on TURB operation in 15 Belgian hospitals. Recruitment progress can be monitored live at Patients are randomly assigned to selenium yeast (200 μg/day) supplementation for 3 years or matching placebo, in addition to standard care. The objective is to determine the effect of selenium on the recurrence of bladder cancer. Randomization is stratified by treatment centre. A computerized algorithm randomly assigns the patients to a treatment arm. All study personnel and participants are blinded to treatment assignment for the duration of the study.
The SELEnium and BLAdder cancer Trial (SELEBLAT) is a phase III randomized, placebo-controlled, academic, double-blind superior trial.
This is the first report on a selenium randomized trial in bladder cancer patients.
Trial registration identifier: NCT00729287
PMCID: PMC3352119  PMID: 22436453
Selenium; Bladder cancer; Transitional Cell Carcinoma; Chemoprevention; Randomized clinical trial; Urology
19.  Dealing with low-incidence serious diseases in general practice 
Cost-effective health care depends on high-quality triage. The most challenging aspect of triage, which GPs confront on a regular basis, is diagnosing rare but serious disease. Failure to shoulder any risk in this situation overloads the health system and subjects patients to unnecessary investigation. Adopting too high a risk threshold leads to missed cases, late diagnosis, and sometimes avoidable death. It also undermines the credibility of primary care practitioners. Quantification of diagnostic risk suggests there is a potential risk gap between the maximum certainty with which GPs can assess the risk of serious disease at presentation and the minimum certainty required by many health systems for further investigation or hospital referral. Physician gut-feeling and diagnostic safety netting are often employed to fill the gap. Neither strategy is well defined or well supported by evidence. It should be possible to reduce the diagnostic risk gap cost-effectively by adopting more explicit diagnostic algorithms and providing better GP access to new diagnostic technologies. It is also essential, given the decreasing experience of triage clinicians employed in a number of countries, that a teachable evidence base is constructed for gut feeling and diagnostic safety netting. However, this construction of an evidence base requires very large-scale studies, and the global primary care research community remains small. The challenge therefore needs to be met by urgent and effective international collaboration.
PMCID: PMC3020049  PMID: 21401991
diagnoses and examinations; diagnostic techniques and procedures; gut feeling; low-incidence diseases; safety netting
20.  Incident somatic comorbidity after psychosis: results from a retrospective cohort study based on Flemish general practice data 
BMC Family Practice  2011;12:132.
Psychotic conditions and especially schizophrenia, have been associated with increased morbidity and mortality. Many studies are performed in specialized settings with a strong focus on schizophrenia. Somatic comorbidity after psychosis is studied, using a general practice comorbidity registration network.
Hazard ratios are presented resulting from frailty models to assess the risk of subsequent somatic disease after a diagnosis of psychosis compared to people without psychosis matched on practice, age and gender. Diseases studied are cancer, physical trauma, diabetes mellitus, gastrointestinal disorders, joint disorders, irritable bowel syndrome, general infections, metabolic disorders other than diabetes, hearing and vision problems, anemia, cardiovascular disease, alcohol abuse, lung disorders, mouth and teeth problems, sexually transmitted diseases.
Significant higher risks after a diagnosis of psychosis were found for the emergence of diabetes, physical trauma, gastrointestinal disorders, alcohol abuse, chronic lung disease and teeth and mouth problems. With regard to diabetes, by including the type of antipsychotic medication it is clear that the significant overall effect was largely due to the use of atypical antipsychotic medication. No significant higher risk was seen for cancer, joint conditions, irritable bowel syndrome, general infections, other metabolic conditions, hearing/vision problems, anaemia, cardiovascular disease or diabetes, in case no atypical antipsychotic medication was used.
Significantly higher morbidity rates for some somatic conditions in patients with psychosis are apparent. People with a diagnosis of psychosis benefit from regular assessments for the emergence of somatic disorders and risk factors, including diabetes in case of atypical antipsychotic medication.
PMCID: PMC3248871  PMID: 22126584
21.  Study protocol of KLIMOP: a cohort study on the wellbeing of older cancer patients in Belgium and the Netherlands 
BMC Public Health  2011;11:825.
Cancer is mainly a disease of older patients. In older cancer patients, additional endpoints such as quality of survival and daily functioning might be considered equally relevant as overall or disease free survival. However, these factors have been understudied using prospective designs focussing on older cancer patients. Therefore, this study will focus on the impact of cancer, ageing, and their interaction on the long-term wellbeing of older cancer patients.
This study is an observational cohort study. We aim to recruit 720 cancer patients above 70 years with a new diagnosis of breast, prostate, lung or gastrointestinal cancer and two control groups: one control group of 720 patients above 70 years without a previous diagnosis of cancer and one control group of 720 cancer patients between 50 - 69 years newly diagnosed with breast, prostate, lung or gastrointestinal cancer. Data collection will take place at inclusion, after six months, after one year and every subsequent year until death or end of the study. Data will be collected through personal interviews (consisting of socio-demographic information, general health information, a comprehensive geriatric assessment, quality of life, health locus of control and a loneliness scale), a handgrip test, assessment of medical records, two buccal swabs and a blood sample from cancer patients (at baseline). As an annex study, caregivers of the participants will be recruited as well. Data collection for caregivers will consist of a self-administered questionnaire examining depression, coping, and burden.
This extensive data collection will increase insight on how wellbeing of older cancer patients is affected by cancer (diagnosis and treatment), ageing, and their interaction. Results may provide new insights, which might contribute to the improvement of care for older cancer patients.
PMCID: PMC3215168  PMID: 22026575
22.  Incidence and outcome of first syncope in primary care: A retrospective cohort study 
BMC Family Practice  2011;12:102.
Assessment of risk for serious cardiovascular outcome after syncope is difficult.
To determine the incidence of first syncope in primary care. To investigate the relation between syncope and serious cardiovascular (CV) outcome and serious injury.
Retrospective cohort study using data from the Intego general practice-based registration network, collecting data from 55 general practices (90 GP's). All patients with a first syncope from 1994 to 2008 were included; five participants without syncope were matched for age and gender for every patient with syncope. The main outcome measures were incidence of first syncope by age and gender and one year risk of serious CV outcome or injury after syncope.
2785 patients with syncope and 13909 matched patients without syncope were included. The overall incidence of a first syncope was 1.91 per 1000 person-years (95% CI 1.83-1.98). The incidence was higher in females (2.42 (95% CI 2.32-2.55) per 1000 person-years) compared to males (1.4 (95% CI 1.32-1.49) per 1000 person-years) and follows a biphasic pattern according to age: a first peak at the age of 15-24 years is followed by a sharp rise above the age of 45. One year serious outcome after syncope was recorded in 12.3% of patients. Increasing age (HR 1.04 (1.03-1.04)), CV comorbidity (HR 3.48 (95% CI 2.48-4.90) and CV risk factors (HR 1.65 (95% CI 1.24-2.18) are associated with serious outcome. Cox regression, adjusting for age, gender, CV comorbidity and risk factors, showed that syncope was an independent risk factor for serious CV outcome or injury (HR 3.99 (95% CI 3.44-4.63)). The other independent risk factors were CV comorbidity (HR 1.81 (95% CI 1.51-2.17)) and age (HR 1.03 (95% CI 1.03-1.04)).
Incidence rate of first syncope in primary care was 1.91 per 1000 person-years. One year risk of serious outcome after syncope was 12.3%. Increasing age, CV comorbidity and risk factors are associated with serious outcome. Compared to a control group, syncope on itself is an independent risk factor for serious outcome (adjusted for age, gender, CV comorbidity and risk factors).
PMCID: PMC3191330  PMID: 21951825
Syncope; risk assessment; primary health care
23.  Diagnosing dementia: No easy job 
BMC Family Practice  2011;12:60.
From both clinical experience and research we learned that in complex progressive disorders such as dementia, diagnosis includes multiple steps, each with their own clinical and research characteristics.
Diagnosing starts with a trigger phase in which the GP gradually realizes that dementia may be emerging. This is followed by a disease-oriented diagnosis and subsequently a care -oriented diagnosis. In parallel the GP should consider the consequences of this process for the caregiver and the interaction between both. As soon as a comprehensive diagnosis and care plan are available, monitoring follows.
We propose to split the diagnostic process into four diagnostic steps, followed by a monitoring phase. We recommend to include these steps when designing studies on screening, diagnosis and monitoring of patients with dementia and their families.
PMCID: PMC3141512  PMID: 21707988
24.  Dietary intake of micronutrients and the risk of developing bladder cancer: results from the Belgian case–control study on bladder cancer risk 
Cancer Causes & Control  2011;22(3):469-478.
We aimed to investigate the effect of dietary intake of micronutrients that are metabolized and excreted via the urinary tract on bladder cancer risk.
A semi-quantitative 322 item food frequency questionnaire (FFQ) was used to collect dietary data from 200 bladder cancer cases and 386 control subjects participating in the Belgian case–control study on bladder cancer risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression adjusting for age, sex, smoking characteristics, occupational exposures, and energy intake.
We observed a positive association between calcium intake and bladder cancer (OR: 1.77; 95% CI: 1.00–3.15; p-trend = 0.049) and increased odds, although not statistically significant, for highest tertile of phosphorus intake (OR: 1.82; 95% CI: 0.95–3.49; p-trend = 0.06). We identified possible modification of the effects of both calcium and phosphorus by level of magnesium intake. Increased odds of bladder cancer were also observed for participants with highest intake of phosphorus and lowest intake of vitamin D (OR: 4.25; 95% CI: 1.44–12.55) and among older participants with the highest intakes of calcium (OR: 1.90; 95% CI: 1.08–3.36) and phosphorus (OR: 2.02; 95% CI: 1.05–3.92).
The positive associations we observed between bladder cancer and intake of calcium and phosphorus require confirmation by other studies. The balances between inter-related micronutrients also warrant further examination.
PMCID: PMC3042097  PMID: 21203820
Bladder cancer; Micronutrients; Calcium; Vitamin D
25.  A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer 
Kiemeney, Lambertus A | Sulem, Patrick | Besenbacher, Soren | Vermeulen, Sita H | Sigurdsson, Asgeir | Thorleifsson, Gudmar | Gudbjartsson, Daniel F | Stacey, Simon N | Gudmundsson, Julius | Zanon, Carlo | Kostic, Jelena | Masson, Gisli | Bjarnason, Hjordis | Palsson, Stefan T | Skarphedinsson, Oskar B | Gudjonsson, Sigurjon A | Witjes, J Alfred | Grotenhuis, Anne J | Verhaegh, Gerald W | Bishop, D Timothy | Sak, Sei Chung | Choudhury, Ananya | Elliott, Faye | Barrett, Jennifer H | Hurst, Carolyn D | de Verdier, Petra J | Ryk, Charlotta | Rudnai, Peter | Gurzau, Eugene | Koppova, Kvetoslava | Vineis, Paolo | Polidoro, Silvia | Guarrera, Simonetta | Sacerdote, Carlotta | Campagna, Marcello | Placidi, Donatella | Arici, Cecilia | Zeegers, Maurice P | Kellen, Eliane | Gutierrez, Berta Saez | Sanz-Velez, José I | Sanchez-Zalabardo, Manuel | Valdivia, Gabriel | Garcia-Prats, Maria D | Hengstler, Jan G | Blaszkewicz, Meinolf | Dietrich, Holger | Ophoff, Roel A | van den Berg, Leonard H | Alexiusdottir, Kristin | Kristjansson, Kristleifur | Geirsson, Gudmundur | Nikulasson, Sigfus | Petursdottir, Vigdis | Kong, Augustine | Thorgeirsson, Thorgeir | Mungan, N Aydin | Lindblom, Annika | van Es, Michael A | Porru, Stefano | Buntinx, Frank | Golka, Klaus | Mayordomo, José I | Kumar, Rajiv | Matullo, Giuseppe | Steineck, Gunnar | Kiltie, Anne E | Aben, Katja K H | Jonsson, Eirikur | Thorsteinsdottir, Unnur | Knowles, Margaret A | Rafnar, Thorunn | Stefansson, Kari
Nature genetics  2010;42(5):415-419.
Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
PMCID: PMC2923020  PMID: 20348956

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