Interpretative reading of the antibiogram:a semi-naïve Bayesian approach

AbstractBackgroundAn antibiogram (ABG) gives the results of in vitro susceptibility tests performed on a pathogen isolated from a culture of a sample taken from blood or other tissues. The institutional cross-ABG consists of the conditional probability of susceptibility for pairs of antimicrobials. This paper explores how interpretative reading of the isolate ABG can be used to replace and improve the prior probabilities stored in the institutional ABG. Probabilities were calculated by both a naïve and semi-naïve Bayesian approaches, both using the ABG for the given isolate and institutional ABGs and cross-ABGs.Methods and MaterialWe assessed an isolate database from an Israeli university hospital with ABGs from 3347 clinically significant blood isolates, where on average 19 antimicrobials were tested for susceptibility, out of 31 antimicrobials in regular use for patient treatment. For each of 14 pathogens or groups of pathogens in the database the average (prior) probability of susceptibility (also called the institutional ABG) and the institutional cross-ABG were calculated. For each isolate, the normalized Brier distance was used as a measure of the distance between susceptibility test results from the isolate ABG and respectively prior probabilities and posteriori probabilities of susceptibility. We used a 5-fold cross-validation to evaluate the performance of different approaches to predict posterior susceptibilities.ResultsThe normalized Brier distance between the prior probabilities and the susceptibility test results for all isolates in the database was reduced from 37.7% to 28.2% by the naïve Bayes method. The smallest normalized Brier distance of 25.3% was obtained with the semi-naïve min2max2 method, which uses the two smallest significant odds ratios and the two largest significant odds ratios expressing respectively cross-resistance and cross-susceptibility, calculated from the cross-ABG.ConclusionA practical method for predicting probability for antimicrobial susceptibility could be developed based on a semi-naïve Bayesian approach using statistical data on cross-susceptibilities and cross-resistances. The reduction in Brier distance from 37.7% to 25.3%, indicates a significant advantage to the proposed min2max2 method (p<10 99)

Geographic variation in diagnostic and treatment interval, cancer stage and mortality among colorectal patients : an international comparison between Denmark and Scotland using data-linked cohorts

FUNDING This project was conducted without external funding and with the support of the Data Safe Haven (DaSH) of the University of Aberdeen and Statistics Denmark. Acknowledgements We wish to acknowledge Dr Vicky Munro and Dr Joanne Lumsden from the Aberdeen Centre of Data Health Science who worked with the authors in preparing the Scottish Data for Transfer to Statistic Denmark. We also acknowledge Statistics Denmark for hosting the combined dataset for analysis and Kaare Rud Flarup for help with data management. We also acknowledge Professor Lesley Anderson and Dr Lisa Iversen for providing comments on the manuscript.Peer reviewedPostprin

Cancer risk in persons with new-onset anaemia:a population-based cohort study in Denmark

Abstract Background The time interval from first symptom and sign until a cancer diagnosis significantly affects the prognosis. Therefore, recognising and acting on signs of cancer, such as anaemia, is essential. Evidence is sparse on the overall risk of cancer and the risk of specific cancer types in persons with new-onset anaemia detected in an unselected general practice population. We aimed to assess the risk of cancer in persons with new-onset anaemia detected in general practice, both overall and for selected cancer types. Methods This observational population-based cohort study used individually linked electronic data from laboratory information systems and nationwide healthcare registries in Denmark. We included persons aged 40–90 years without a prior history of cancer and with new-onset anaemia (no anaemia during the previous 15 months) detected in general practice in 2014–2018. We measured the incidence proportion and standardised incidence ratios of a new cancer diagnosis (all cancers except for non-melanoma skin cancers) during 12 months follow-up. Results A total of 48,925 persons (median [interquartile interval] age, 69 [55–78] years; 55.5% men) were included in the study. In total, 7.9% (95% confidence interval (CI): 7.6 to 8.2) of men and 5.2% (CI: 4.9 to 5.5) of women were diagnosed with cancer during 12 months. Across selected anaemia types, the highest cancer incidence proportion was seen in women with ‘anaemia of inflammation’ (15.3%, CI: 13.1 to 17.5) (ferritin > 100 ng/mL and increased C-reactive protein (CRP)) and in men with ‘combined inflammatory iron deficiency anaemia’ (19.3%, CI: 14.5 to 24.1) (ferritin < 100 ng/mL and increased CRP). For these two anaemia types, the cancer incidence across cancer types was 10- to 30-fold higher compared to the general population. Conclusions Persons with new-onset anaemia detected in general practice have a high cancer risk; and markedly high for ‘combined inflammatory iron deficiency anaemia’ and ‘anaemia of inflammation’. Anaemia is a sign of cancer that calls for increased awareness and action. There is a need for research on how to improve the initial pathway for new-onset anaemia in general practice

Diagnostic workup of cancer in patients with new-onset anaemia:a Danish cohort study in general practice

Background Anaemia is associated with adverse outcomes, including increased morbidity and all-cause mortality. Diagnostic workup of patients with anaemia is essential to detect underlying disease, especially undiagnosed malignancy. Objective To describe the cancer-relevant diagnostic workup in patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and the diagnostic workup. Design Observational population-based cohort study using electronic laboratory and register data. Setting Danish general practice. Subjects Patients aged 40–90 years with new-onset anaemia (no anaemia in the preceding 15 months) detected in general practice. Patients were identified in Danish laboratory information systems and nationwide registries in 2014–2018. Main outcome measures We measured the proportion of patients receiving predefined diagnostic investigations, that is, cancer patient pathway, colonoscopy, gastroscopy, computerised tomography (CT) scan, faecal test for haemoglobin, and bone marrow examination within three months of the anaemia index date. Results We included 59,993 patients, and around half of the patients with ‘iron deficiency anaemia’, ‘anaemia of inflammation’, or ‘combined inflammatory iron deficiency anaemia’ had no cancer-relevant diagnostic investigations performed. Patients aged 60–79 years and patients with severe anaemia were more likely to have investigations performed, while patients with comorbidity were less likely to have investigations performed. Conclusion Around half of the patients with anaemia subtypes that may indicate underlying cancer had no cancer-relevant diagnostic investigations performed. This may represent missed diagnostic opportunities. Future interventions are needed to improve the diagnostic workup of cancer in patients with anaemia, for example, laboratory alert systems and clinical decision support.KEY POINTS The general practitioners are often the first to detect anaemia and its underlying disease (e.g. undiagnosed malignancy). Large-scale studies are needed on the diagnostic workup of patients with anaemia in general practice in relation to an underlying malignancy. This study shows that the majority of patients with anaemia had no cancer-relevant diagnostic investigations performed, which may cause diagnostic delay. Interventions seems needed to improve the diagnostic workup of cancer in these patients to ensure timely diagnosis

Health care utilisation preceding relapse or second malignant neoplasm after childhood acute lymphoblastic leukaemia:a population-based matched cohort study

OBJECTIVES: To investigate health care utilisation including both primary and secondary health care 6 months before the diagnosis of a relapse or a second malignant neoplasm (SMN) in survivors of childhood acute lymphoblastic leukaemia (ALL). DESIGN AND SETTING: A Danish population-based matched cohort study linking multiple nationwide registries. PARTICIPANTS: Participants were recruited from a total of 622 childhood ALL 2.5-year event-free survivors diagnosed between 1994 and 2015. Cases were survivors developing a relapse or an SMN and references were survivors still in first remission. Each case was matched with five references on age, sex, treatment protocol and risk group. PRIMARY OUTCOME MEASURES: Consultations in general practice and hospital the last 6 months before relapse or SMN. Cases and references were compared with monthly incidence rate ratios (IRRs) from negative binomial regression models. RESULTS: Of the 622 childhood ALL survivors, 60 (9.6%) developed a relapse (49) or an SMN (11) and 295 matched references were identified. Health care utilisation in general practice increased among cases the last month before the event compared with references with an IRR of 2.71 (95% CI 1.71 to 4.28). Data showed a bimodal structure with a significantly increased number of visits 4, 5 and 6 months before the event. Hospital health care utilisation increased 2 months before the event in cases with an IRR of 5.01 (3.78 to 6.63) the last month before the event and an IRR of 1.94 (1.32 to 2.85) the second-last month comparing cases and references. CONCLUSIONS: Survivors of childhood ALL developing a relapse or an SMN have a short period of increased health care utilisation before diagnosis. At hospital, this might be explained by pre-diagnostic examinations. In general practice, data suggest a bimodal structure with children later developing a relapse having more contacts also half a year before the relapse, suggesting that there could be early warnings

Insufficient classification of anaemia in general practice:a Danish register-based observational study

BACKGROUND: Anaemia can be a pointer of underlying severe disease, including undiagnosed malignancy. Subsequent blood tests are essential to classify the anaemia into subtypes and to facilitate targeted diagnostic investigation to ensure timely diagnosis of underlying disease. OBJECTIVE: We aimed to describe and classify anaemia based on laboratory tests from patients with new-onset anaemia detected in general practice. An additional aim was to analyse associations between patient characteristics and unclassified anaemia (not classifiable according to an algorithm). DESIGN: Population-based cross-sectional study. SETTING: Danish general practice. SUBJECTS: A total of 62,731 patients (age: 40–90 years) with new-onset anaemia were identified in Danish laboratory information systems and nationwide registries, and data were obtained for 2014–2018. MAIN OUTCOME MEASURES: We measured the proportion of patients classified into subtypes of anaemia based on blood tests requested by general practitioners within 31 days of the anaemia index date. RESULTS: Of the 62,731 patients with new-onset anaemia, we identified unclassified anaemia in 78.9% (95% confidence interval (CI): 77.3–80.5) of men and 65.1% (CI: 63.4–66.9) of women. The likelihood of unclassified anaemia increased with age, increasing comorbidity and decreasing severity of anaemia. CONCLUSION: The majority of patients with new-onset anaemia could not be classified through a simple algorithm due to missing blood tests, which highlights a potential missed opportunity for diagnosis. Standardised laboratory testing of patients with anaemia is warranted to ensure adequate follow-up and early detection of underlying severe disease. KEY POINTS: Anaemia can be a sign of malignancy, and anaemia classification is an important step in the diagnosis of underlying disorders. The majority of patients with anaemia could not be classified according to a simple algorithm due to missing blood tests. Some patient characteristics were associated with a high risk of unclassified anaemia: high age, high comorbidity, and severe anaemia. Standardised laboratory testing in patients with anaemia is needed to inform targeted diagnostic investigation to ensure timely diagnosis

An investigation of routes to cancer diagnosis in 10 international jurisdictions, as part of the International Cancer Benchmarking Partnership: Survey development and implementation

Objectives: This paper describes the methods used in the International Cancer Benchmarking Partnership Module 4 Survey (ICBPM4) which examines time intervals and routes to cancer diagnosis in 10 jurisdictions. We present the study design with defining and measuring time intervals, identifying patients with cancer, questionnaire development, data management and analyses. Design and setting: Recruitment of participants to the ICBPM4 survey is based on cancer registries in each jurisdiction. Questionnaires draw on previous instruments and have been through a process of cognitive testing and piloting in three jurisdictions followed by standardised translation and adaptation. Data analysis focuses on comparing differences in time intervals and routes to diagnosis in the jurisdictions. Participants: Our target is 200 patients with symptomatic breast, lung, colorectal and ovarian cancer in each jurisdiction. Patients are approached directly or via their primary care physician (PCP). Patients’ PCPs and cancer treatment specialists (CTSs) are surveyed, and ‘data rules’ are applied to combine and reconcile conflicting information. Where CTS information is unavailable, audit information is sought from treatment records and databases. Main outcomes: Reliability testing of the patient questionnaire showed that agreement was complete (κ=1) in four items and substantial (κ=0.8, 95% CI 0.333 to 1) in one item. The identification of eligible patients is sufficient to meet the targets for breast, lung and colorectal cancer. Initial patient and PCP survey response rates from the UK and Sweden are comparable with similar published surveys. Data collection was completed in early 2016 for all cancer types. Conclusion: An international questionnaire-based survey of patients with cancer, PCPs and CTSs has been developed and launched in 10 jurisdictions. ICBPM4 will help to further understand international differences in cancer survival by comparing time intervals and routes to cancer diagnosis

Diagnostic routes and time intervals for ovarian cancer in nine international jurisdictions; findings from the International Cancer Benchmarking Partnership (ICBP)

BACKGROUND: International Cancer Benchmarking Partnership Module 4 reports the first international comparison of ovarian cancer (OC) diagnosis routes and intervals (symptom onset to treatment start), which may inform previously reported variations in survival and stage. METHODS: Data were collated from 1110 newly diagnosed OC patients aged >40 surveyed between 2013 and 2015 across five countries (51-272 per jurisdiction), their primary-care physicians (PCPs) and cancer treatment specialists, supplement by treatment records or clinical databases. Diagnosis routes and time interval differences using quantile regression with reference to Denmark (largest survey response) were calculated. RESULTS: There were no significant jurisdictional differences in the proportion diagnosed with symptoms on the Goff Symptom Index (53%; P = 0.179) or National Institute for Health and Care Excellence NG12 guidelines (62%; P = 0.946). Though the main diagnosis route consistently involved primary-care presentation (63-86%; P = 0.068), onward urgent referral rates varied significantly (29-79%; P < 0.001). In most jurisdictions, diagnostic intervals were generally shorter and other intervals, in particular, treatment longer compared to Denmark. CONCLUSION: This study highlights key intervals in the diagnostic pathway where improvements could be made. It provides the opportunity to consider the systems and approaches across different jurisdictions that might allow for more timely ovarian cancer diagnosis and treatment

Time intervals and routes to diagnosis for lung cancer in 10 jurisdictions: cross-sectional study findings from the International Cancer Benchmarking Partnership (ICBP)

OBJECTIVE: Differences in time intervals to diagnosis and treatment between jurisdictions may contribute to previously reported differences in stage at diagnosis and survival. The International Cancer Benchmarking Partnership Module 4 reports the first international comparison of routes to diagnosis and time intervals from symptom onset until treatment start for patients with lung cancer. DESIGN: Newly diagnosed patients with lung cancer, their primary care physicians (PCPs) and cancer treatment specialists (CTSs) were surveyed in Victoria (Australia), Manitoba and Ontario (Canada), Northern Ireland, England, Scotland and Wales (UK), Denmark, Norway and Sweden. Using Wales as the reference jurisdiction, the 50th, 75th and 90th percentiles for intervals were compared using quantile regression adjusted for age, gender and comorbidity. PARTICIPANTS: Consecutive newly diagnosed patients with lung cancer, aged ≥40 years, diagnosed between October 2012 and March 2015 were identified through cancer registries. Of 10 203 eligible symptomatic patients contacted, 2631 (27.5%) responded and 2143 (21.0%) were included in the analysis. Data were also available from 1211 (56.6%) of their PCPs and 643 (37.0%) of their CTS. PRIMARY AND SECONDARY OUTCOME MEASURES: Interval lengths (days; primary), routes to diagnosis and symptoms (secondary). RESULTS: With the exception of Denmark (-49 days), in all other jurisdictions, the median adjusted total interval from symptom onset to treatment, for respondents diagnosed in 2012-2015, was similar to that of Wales (116 days). Denmark had shorter median adjusted primary care interval (-11 days) than Wales (20 days); Sweden had shorter (-20) and Manitoba longer (+40) median adjusted diagnostic intervals compared with Wales (45 days). Denmark (-13), Manitoba (-11), England (-9) and Northern Ireland (-4) had shorter median adjusted treatment intervals than Wales (43 days). The differences were greater for the 10% of patients who waited the longest. Based on overall trends, jurisdictions could be grouped into those with trends of reduced, longer and similar intervals to Wales. The proportion of patients diagnosed following presentation to the PCP ranged from 35% to 75%. CONCLUSION: There are differences between jurisdictions in interval to treatment, which are magnified in patients with lung cancer who wait the longest. The data could help jurisdictions develop more focused lung cancer policy and targeted clinical initiatives. Future analysis will explore if these differences in intervals impact on stage or survival