Collider and reporting biases involved in the analyses of cause of death associations in death certificates: an illustration with cancer and suicide.

BACKGROUND: Mortality data obtained from death certificates have been studied to explore causal associations between diseases. However, these analyses are subject to collider and reporting biases (selection and information biases, respectively). We aimed to assess to what extent associations of causes of death estimated from individual mortality data can be extrapolated as associations of disease states in the general population. METHODS: We used a multistate model to generate populations of individuals and simulate their health states up to death from national health statistics and artificially replicate collider bias. Associations between health states can then be estimated from such simulated deaths by logistic regression and the magnitude of collider bias assessed. Reporting bias can be approximated by comparing the estimates obtained from the observed death certificates (subject to collider and reporting biases) with those obtained from the simulated deaths (subject to collider bias only). As an illustrative example, we estimated the association between cancer and suicide in French death certificates and found that cancer was negatively associated with suicide. Collider bias, due to conditioning inclusion in the study population on death, increasingly downwarded the associations with cancer site lethality. Reporting bias was much stronger than collider bias and depended on the cancer site, but not prognosis. RESULTS: The magnitude of the biases ranged from 1.7 to 9.3 for collider bias, and from 4.7 to 64 for reporting bias. CONCLUSIONS: These results argue for an assessment of the magnitude of both collider and reporting biases before performing analyses of cause of death associations exclusively from mortality data. If these biases cannot be corrected, results from these analyses should not be extrapolated to the general population.

Insulin allergy: a diagnostic and therapeutic strategy based on a retrospective cohort and a case-control study.

AIMS/HYPOTHESIS: Insulin allergy is a rare but significant clinical challenge. We aimed to develop a management workflow by (1) validating clinical criteria to guide diagnosis, based on a retrospective cohort, and (2) assessing the diagnostic performance of confirmatory tests, based on a case-control study. METHODS: In the retrospective cohort, patients with suspected insulin allergy were classified into three likelihood categories according to the presence of all (likely insulin allergy; 26/52, 50%), some (possible insulin allergy; 9/52, 17%) or none (unlikely insulin allergy; 17/52, 33%) of four clinical criteria: (1) recurrent local or systemic immediate or delayed hypersensitivity reactions; (2) reactions elicited by each injection; (3) reactions centred on the injection sites; and (4) reactions observed by the investigator (i.e. in response to an insulin challenge test). All underwent intradermal reaction (IDR) tests. A subsequent case-control study assessed the diagnostic performance of IDR, skin prick and serum anti-insulin IgE tests in ten clinically diagnosed insulin allergy patients, 24 insulin-treated non-allergic patients and 21 insulin-naive patients. RESULTS: In the retrospective cohort, an IDR test validated the clinical diagnosis in 24/26 (92%), 3/9 (33%) and 0/14 (0%) likely, possible and unlikely insulin allergy patients, respectively. In the case-control study, an IDR test was 80% sensitive and 100% specific and identified the index insulin(s). The skin prick and IgE tests had a marginal diagnostic value. Patients with IDR-confirmed insulin allergy were treated using a stepwise strategy. CONCLUSIONS/INTERPRETATION: Subject to validation, clinical likelihood criteria can effectively guide diabetologists towards an insulin allergy diagnosis before undertaking allergology tests. An IDR test shows the best diagnostic performance. A progressive management strategy can subsequently be implemented. Continuous subcutaneous insulin infusion is ultimately required in most patients. CLINICALTRIALS: gov: NCT01407640.

Risk of intracranial meningioma with three potent progestogens: A population-based case-control study.

BACKGROUND AND PURPOSE: A dose-dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75-5 mg/day) and chlormadinone acetate (CMA) (2-10 mg/day). METHODS: In this nationwide population-based case-control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls. RESULTS: In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3-7.1). The OR was 1.2 (1.0-1.4) for short-term use (<1 year) and 9.5 (8.8-10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5-26.4), NOMAC (OR = 6.5, 95% CI 5.8-7.2) and CMA (OR = 4.7, 95% CI 4.5-5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5-48.2) and 23.9 (95% CI 17.8-32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028-2220) (212/year). CONCLUSION: A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk.

Incidence of and Risk Factors for Systemic Adverse Events After Screening or Primary Diagnostic Colonoscopy: A Nationwide Cohort Study.

OBJECTIVES: To estimate the systemic serious adverse event (SAE) rates after colonoscopy and to identify their risk factors. METHODS: A nationwide cohort study was conducted using the comprehensive French claims databases SNDS (National Health Data System). Patients aged 30 years and over who underwent a first screening or diagnostic colonoscopy in 2010-2015 were included. The rates of cardiovascular and renal SAEs were estimated within 5 days after colonoscopy. The standardized incidence ratios were calculated to compare these incidence rates with those of the same events in the general population, and the associated risk factors were assessed by multilevel logistic regression. RESULTS: Among the 4,088,799 included patients (median age, 59 years [interquartile range = 50-67]; 55.2% women; 30.1% with a Charlson index score ≤1), the 5-day SAE incidence rate was 2.8/10,000 procedures for shock, 0.87/10,000 for myocardial infarction, 1.9/10,000 for stroke, 2.9/10,000 for pulmonary embolism, 5.5/10,000 for acute renal failure, and 3.3/10,000 for urolithiasis. These SAEs occurred 3.3 to 15.8 times more often during the first 5 days after colonoscopy than expected in the general population. Thirty-day mortality rates ranged from 2.2/1,000 cases of urolithiasis to 268.1/1,000 cases of shock. Increasing age was associated with an increasing incidence of SAEs. Risks of shock and acute renal failure were associated with a greater number of comorbidities than the other SAEs. Colonoscopies in university hospitals were associated with higher risks, reflecting patient selection processes. DISCUSSION: The systemic SAEs can be associated with a substantial mortality. They should be taken into account when deciding colonoscopy, in addition to perforation and bleeding, particularly in elderly patients with multiple comorbidities.

Patient, Procedure, and Endoscopist Risk Factors for Perforation, Bleeding, and Splenic Injury After Colonoscopies.

BACKGROUND & AIMS: We investigated perforations, bleeding, and splenic injuries after screening or diagnostic colonoscopies to identify patient-, procedure-, endoscopist-, and facility-associated risk factors. METHODS: We analyzed data from the SNIIRAM-PMSI national claims databases in France. A total of 4,088,799 patients, 30 years or older, undergoing a first screening or diagnostic colonoscopy from 2010 through 2015 were identified. Rates of severe adverse events (SAEs) were estimated using stringent and broad definitions. Risk factors associated with perforations and major bleeding were estimated using multilevel logistic regression models, adjusted for patient, colonoscopy, and endoscopist characteristics. RESULTS: Perforation rates ranged from 3.5 (stringent definition) to 7.3 (broad definition) per 10,000 procedures, bleeding rates ranged from 6.5 to 23.1 per 10,000 procedures, and splenic injury rates ranged from 0.20 to 0.34 per 10,000 procedures. Rates of 30-day mortality were 13.2 per 1000 bleeds, 29.2 per 1000 perforations, and 36.1 per 1000 splenic injuries (stringent definitions). Patient characteristics associated with SAEs were increasing age (especially for perforation), cancer, and cardiovascular comorbidities. Procedure characteristics associated with SAEs included polypectomy-especially of polyps larger than 1 cm with an increased risk of perforation (odds ratio, 4.1; 95% CI, 3.4-5.0) and bleeding (odds ratio, 13.3; 95% CI, 11.7-15.1). Less-experienced endoscopists and endoscopists who performed a smaller number of colonoscopies were independently associated with a risk of SAEs. CONCLUSION: In an analysis of national claims databases in France, we found SAEs related to screening and diagnostic colonoscopies to be more frequent in older patients, in patients with comorbidities, and with less-experienced endoscopists. Patients at risk of SAE should be identified and colonoscopies should be performed or supervised by experienced endoscopists.

Impact of the Timing of Initiation of Antiretroviral Therapy During Primary HIV-1 Infection on the Decay of Cell-Associated HIV-DNA.

BACKGROUND: Combined antiretroviral therapy (cART) initiation during primary human immunodeficiency virus (HIV) infection (PHI) yields a larger decrease in cell-associated HIV-DNA (CA-HIV-DNA) than initiation during the chronic phase. Our objective was to model the short and long-term decay of CA-HIV-DNA blood reservoir in patients initiating cART during PHI and to assess the impact of the timing of cART initiation on CA-HIV-DNA decay. METHODS: We included patients enrolled during PHI in the Agence Nationale de Recherche sur le Sida PRIMO cohort, treated within the month following enrollment and achieving sustained virologic response. The decay of CA-HIV-DNA over time while on successful cART was modeled with a 3-slope linear mixed-effects model according to the delay between estimated date of infection and cART initiation. RESULTS: Three hundred twenty-seven patients were included, accounting for 1305 CA-HIV-DNA quantifications. Median time between infection and cART initiation was 41 days (interquartile range, 33-54 days). Median follow-up under cART was 2.3 years (range, 0.4-16.6 years). The timing of cART initiation had significant impact on the first slope of decrease: The earlier cART was initiated after HIV infection, the faster CA-HIV-DNA level decreased during the first 8 months of cART: -0.171, -0.131, and -0.068 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs) per month when cART was initiated 15 days, 1 month, and 3 months after infection, respectively (P < .0001). The predicted mean CA-HIV-DNA level achieved after 5 years of successful cART was 1.62 and 2.24 log10 copies/10(6) PBMCs when cART was initiated 15 days and 3 months after infection, respectively (P = .0006). CONCLUSIONS: This study provides strong arguments in favor of cART initiation at the earliest possible time point after HIV infection.

[Mapping of the key oncology indicators available in France]. / Cartographie des principaux indicateurs disponibles en France dans le domaine du cancer.

BACKGROUND: Available data in the field of oncology in France are scattered due to the large number of available indicators and their sources. In order to facilitate identification and analysis of these indicators, the French National Cancer Institute (INCa) has mapped the main indicators available in oncology. METHODS: Mapping was based on the needs of various categories of potential users. Standardized interviews were conducted face-to-face or by email among representatives to determine their needs and expectations. The underlying data sources were also identified: databases, national surveys, websites. A first selection of indicators was proposed in the report entitled "La situation du cancer en France en 2009" ("The state of cancer in France in 2009") and was expanded. Data collection concerning indicators was performed among INCa correspondents for each theme. RESULTS: Several themes were defined: epidemiology, prevention and risk factors, screening, medical demography, health care offer, living conditions, costs and expenses, research. Data were classified according to: geographical coverage, age, gender, type of cancer, occupational categories. This information was collected for each indicator selected and was made available via the cancer data website (http://lesdonnees.e-cancer.fr). CONCLUSIONS: The available oncology indicators are numerous and scattered. Mapping can be a useful tool to facilitate access to these indicators. It should be regularly updated to reflect the most recent data.

Use of the French National Health Data System (SNDS) in pharmacoepidemiology: A systematic review in its maturation phase.

AIM OF THE STUDY: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase. METHODS: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018. RESULTS: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%). CONCLUSION: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.

Suicidal risk associated with finasteride versus dutasteride among men treated for benign prostatic hyperplasia: nationwide cohort study.

Finasteride, a 5α-reductase inhibitor used in benign prostatic hyperplasia and androgenetic alopecia, has been associated with an increased suicidal risk, whereas it is unclear whether such risk is similar to that for another 5α-reductase inhibitor, dutasteride. We aimed to assess the risk of suicidal behaviours with finasteride relative to dutasteride. A nationwide cohort study was conducted using the French National Health Data System (SNDS). Men aged 50 years or older initiating finasteride 5 mg or dutasteride 0.5 mg in France between 01-01-2012 and 30-06-2016 were included and followed until outcome (suicide death identified from death certificate or self-harm hospitalisation), treatment discontinuation or switch, death, or 31-12-2016. Self-harm by violent means or resulting in admission to an intensive care unit were also examined. Cox proportional hazards models controlled for age and psychiatric and non-psychiatric conditions by inverse probability of treatment weighting (IPTW). Analyses were stratified according to psychiatric history. The study compared 69,786 finasteride new users to 217,577 dutasteride new users (median age: 72.0 years [Q1-Q3 = 64.5-80.2] vs. 71.1 [Q1-Q3 = 65.0-79.2]). During follow-up, 18 suicide deaths (0.57/1000 person-years) and 34 self-harm hospitalisations (1.08/1000) occurred among finasteride users versus 47 deaths (0.43/1000) and 87 hospitalisations (0.79/1000) among dutasteride users. Overall, finasteride was not associated with an increased risk of any suicidal outcome (IPTW-adjusted Hazard Ratio = 1.21 [95% Confidence Interval .87-1.67]), suicide death or self-harm hospitalisation. However, among individuals with a history of mood disorders, finasteride was associated with an increased risk of any suicidal outcome (25 versus 46 events; HR = 1.64 [95% CI 1.00-2.68]), suicide death (8 versus 10 events; HR = 2.71 [95% CI 1.07-6.91]), self-harm by violent means (6 versus 6 events; HR = 3.11 [95% CI 1.01-9.61]), and self-harm with admission to an intensive care unit (7 versus 5 events; HR = 3.97 [95% CI 1.26-12.5]). None of these risks was significantly increased among individuals without a psychiatric history. These findings do not support an increased risk of suicide with finasteride used in the treatment of benign prostatic hyperplasia. However, an increased risk cannot be excluded among men with a history of mood disorder, but this result based on a limited number of events should be interpreted with caution.

Contacts with Health Services During the Year Prior to Suicide Death and Prevalent Conditions A Nationwide Study.

BACKGROUND: This study was designed to describe contacts with health services during the year before suicide death in France, and prevalent mental and physical conditions. METHODS: Data were extracted from the French National Health Data System (SNDS), which comprises comprehensive claims data for inpatient and outpatient care linked to the national causes-of-death registry. Individuals aged ≥15 years who died from suicide in France in 2013-2015 were included. Medical consultations, emergency room visits, and hospitalisations during the year preceding death were collected. Conditions were identified, and standardised prevalence ratios (SPRs) were estimated to compare prevalence rates in suicide decedents with those of the general population. RESULTS: The study included 19,144 individuals. Overall, 8.5% of suicide decedents consulted a physician or attended an emergency room on the day of death, 34.1% during the week before death, 60.9% during the month before death. Most contacts involved a general practitioner or an emergency room. During the month preceding suicide, 24.4% of individuals were hospitalised at least once. Mental conditions (36.8% of cases) were 7.9-fold more prevalent in suicide decedents than in the general population. The highest SPRs among physical conditions were for liver/pancreatic diseases (SPR=3.3) and epilepsy (SPR=2.7). LIMITATIONS: The study population was restricted to national health insurance general scheme beneficiaries (76% of the population living in France). CONCLUSIONS: Suicide decedents have frequent contacts with general practitioners and emergency departments during the last weeks before death. Improving suicide risk identification and prevention in these somatic healthcare settings is needed.

Impact of unemployment variations on suicide mortality in Western European countries (2000-2010).

BACKGROUND: A scientific debate is currently taking place on whether the 2008 economic crisis caused an increase in suicide rates. Our main objective was to assess the impact of unemployment rate on suicide rate in Western European countries between 2000 and 2010. We then tried to estimate the excess number of suicides attributable to the increase of unemployment during the 2008-2010 economic crisis. METHODS: The yearly suicide rates were modelled using a quasi-Poisson model, controlling for sex, age, country and a linear time trend. For each country, the unemployment-suicide association was assessed, and the excess number of suicides attributable to the increase of unemployment was estimated. Sensitivity analyses were performed, notably in order to evaluate whether the unemployment-suicide association found was biased by a confounding context effect ('crisis effect'). RESULTS: A significant 0.3% overall increase in suicide rate for a 10% increase in unemployment rate (95% CI 0.1% to 0.5%) was highlighted. This association was significant in three countries: 0.7% (95% CI 0.0% to 1.4%) in the Netherlands, 1.0% (95% CI 0.2% to 1.8%) in the UK and 1.9% (95% CI 0.8% to 2.9%) in France, with a significant excess number of suicides attributable to unemployment variations between 2008 and 2010 (respectively 57, 456 and 564). The association was modified inconsistently when adding a 'crisis effect' into the model. CONCLUSIONS: Unemployment and suicide rates are globally statistically associated in the investigated countries. However, this association is weak, and its amplitude and sensitivity to the 'crisis effect' vary across countries. This inconsistency provides arguments against its causal interpretation.

Factors associated with failure to return for HIV test results in a free and anonymous screening centre.

Free and anonymous screening centres (CDAG: Centres de Depistage Anononyme et Gratuit) are public facilities set up for HIV infection diagnosis in France. Some people visiting CDAG fail to return for test results and are not informed of their serology. This study aimed to assess factors associated with failure to return for HIV test results. Patients visiting the Fernand-Widal CDAG (Paris) for an HIV test in January-February 2011 were eligible to take part in the study. Data were collected with an anonymous self-administered questionnaire. Factors associated with failure to return were assessed using logistic regression models. Of the 710 participants (participation rate 88%), 46 patients failed to return. Not specifying birthplace and not living in the region of Paris were associated with failure to return. Those who perceived no risk of HIV infection and those who felt they were more at risk than other people were both statistically associated with failure to return. Self-perceived risk seemed to be of chief concern for failure to return for HIV test results and should be considered during pre-test counselling.