Estimation of the incidence of invasive meningococcal disease using a capture-recapture model based on two independent surveillance systems in Catalonia, Spain.

OBJECTIVES: Invasive meningococcal disease (IMD) is an urgent notifiable disease and its early notification is essential to prevent cases. The objective of the study was to assess the sensitivity of two independent surveillance systems and to estimate the incidence of IMD. DESIGN: We used capture-recapture model based on two independent surveillance systems, the statutory disease reporting (SDR) system and the microbiological reporting system (MRS) of the Public Health Agency of Catalonia, between 2011 and 2015. The capture-recapture analysis and 95% CIs were calculated using the Chapman formula. Multivariate vector generalised linear model was performed for adjusted estimation. MEASURES: The variables collected were age, sex, year of report, size of municipality (<10 000 and ≥10 000), clinical form, death, serogroup, country of birth and type of reporting centre (private and public). RESULTS: The sensitivity of the two combined surveillance systems was 88.5% (85.0-92.0). SDR had greater sensitivity than the MRS (67.9%; 62.7-73.1 vs 64.7%; 59.4-70.0). In 2014-2015, the sensitivity of both systems was higher (80.6%; 73.2-87.9 vs 73.4%; 65.2-81.6) than in 2011-2013 (59.3%; 52.6-66.0 vs 58.3%; 51.6-65.1). In private centres, the sensitivity was higher for SDR than for MRS (100%; 100-100 vs 4.8%; -4.4-13.9). The adjusted estimate of IMD cases was lower than that obtained using the Chapman formula (279; 266-296 vs 313; 295-330). The estimated adjusted incidence of IMD was 0.7/100 000 persons-year. CONCLUSIONS: The sensitivity of enhanced surveillance through the combination of two complementary sources was higher than for the sources individually. Factors associated with under-reporting in different systems should be analysed to improve IMD surveillance.

Adherence to reporting guidelines increases the number of citations: the argument for including a methodologist in the editorial process and peer-review.

BACKGROUND: From 2005 to 2010, we conducted 2 randomized studies on a journal (Medicina Clínica), where we took manuscripts received for publication and randomly assigned them to either the standard editorial process or to additional processes. Both studies were based on the use of methodological reviewers and reporting guidelines (RG). Those interventions slightly improved the items reported on the Manuscript Quality Assessment Instrument (MQAI), which assesses the quality of the research report. However, masked evaluators were able to guess the allocated group in 62% (56/90) of the papers, thus presenting a risk of detection bias. In this post-hoc study, we analyse whether those interventions that were originally designed for improving the completeness of manuscript reporting may have had an effect on the number of citations, which is the measured outcome that we used. METHODS: Masked to the intervention group, one of us used the Web of Science (WoS) to quantify the number of citations that the participating manuscripts received up December 2016. We calculated the mean citation ratio between intervention arms and then quantified the uncertainty of it by means of the Jackknife method, which avoids assumptions about the distribution shape. RESULTS: Our study included 191 articles (99 and 92, respectively) from the two previous studies, which all together received 1336 citations. In both studies, the groups subjected to additional processes showed higher averages, standard deviations and annual rates. The intervention effect was similar in both studies, with a combined estimate of a 43% (95% CI: 3 to 98%) increase in the number of citations. CONCLUSIONS: We interpret that those effects are driven mainly by introducing into the editorial process a senior methodologist to find missing RG items. Those results are promising, but not definitive due to the exploratory nature of the study and some important caveats such as: the limitations of using the number of citations as a measure of scientific impact; and the fact that our study is based on a single journal. We invite journals to perform their own studies to ascertain whether or not scientific repercussion is increased by adhering to reporting guidelines and further involving statisticians in the editorial process.

Transfer to the Local Stroke Center versus Direct Transfer to Endovascular Center of Acute Stroke Patients with Suspected Large Vessel Occlusion in the Catalan Territory (RACECAT): Study protocol of a cluster randomized within a cohort trial.

RATIONALE: Optimal pre-hospital delivery pathways for acute stroke patients suspected to harbor a large vessel occlusion have not been assessed in randomized trials. AIM: To establish whether stroke subjects with rapid arterial occlusion evaluation scale based suspicion of large vessel occlusion evaluated by emergency medical services in the field have higher rates of favorable outcome when transferred directly to an endovascular center (endovascular treatment stroke center), as compared to the standard transfer to the closest local stroke center (local-SC). DESIGN: Multicenter, superiority, cluster randomized within a cohort trial with blinded endpoint assessment. PROCEDURE: Eligible patients must be 18 or older, have acute stroke symptoms and not have an immediate life threatening condition requiring emergent medical intervention. They must be suspected to have intracranial large vessel occlusion based on a pre-hospital rapid arterial occlusion evaluation scale of ≥5, be located in geographical areas where the default health authority assigned referral stroke center is a non-thrombectomy capable hospital, and estimated arrival at a thrombectomy capable stroke hospital in less than 7 h from time last seen well. Cluster randomization is performed according to a pre-established temporal sequence (temporal cluster design) with three strata: day/night, distance to the endovascular treatment stroke center, and week/week-end day. STUDY OUTCOME: The primary endpoint is the modified Rankin Scale score at 90 days. The primary safety outcome is mortality at 90 days. ANALYSIS: The primary endpoint based on the modified intention-to-treat population is the distribution of modified Rankin Scale scores at 90 days analyzed under a sequential triangular design. The maximum sample size is 1754 patients, with two planned interim analyses when 701 (40%) and 1227 patients have completed follow-up. Hypothesized common odds ratio is 1.35.

Hepatitis A surveillance: sensitivity of two information sources.

BACKGROUND: The frequency of mild forms of hepatitis A, especially in children, could lead to underreporting. The objective of the study was to investigate the sensitivity of two surveillance systems, mandatory Statutory Disease Reports and the Microbiological Reporting System of Catalonia, using capture-recapture techniques. METHODS: The study was conducted in Catalonia between 2011 and 2015. Hepatitis A cases reported to two independent surveillance systems were included: Statutory Disease Reports (SDR) and Microbiological Reporting System of Catalonia (MRS). The variables collected were: age, sex, year of declaration, size of municipality (< 10,000 and ≥ 10,000), country of birth (Spain or abroad), reporting centre (primary care/hospital) and notification method (electronic or paper). The capture-recapture analysis and the estimate of 95% confidence intervals were made using the Chapman formula for comparison of two sources, both for the estimate of the total number of cases and the stratification according to variables. Multinomial logistic regression was performed to obtain an adjusted estimate. RESULTS: The SDR had a greater overall sensitivity than the MRS (48.8%; 43.5-55.6 vs. 19.3%; 17.2-21.9). In cases aged < 15 years the sensitivity of both systems was higher (76.6%; 72.7-81 vs. 25.2%; 20.9-29.5) than in cases aged > 15 years (25.5%; 22.8-28.3 vs. 12.1%; 10-14.2). For those born in Spain, the sensitivity was 57.2% (49.6-67.4) in the SDR and 27.1% (23.5-31.9) in the MRS, lower than that for foreign-born patients (58%; 51.2-66.8 vs. 49.1%; 43.4-56.6). In electronically-reported cases, the sensitivity was much higher in the SDR than in the MRS (47.2%; 42.3-52.1 vs. 9.4%; 6.5-12.3). No differences were observed according to sex, size of municipality, and year of declaration or reporting centre. The estimated total number of cases using the Chapman formula was very similar to the adjusted estimate (1121; 985-1258 vs. 1120; 876-1525), indicating the robustness of the results. CONCLUSIONS: The sensitivity of the SDR was greater than that of MRS, especially in patients aged < 15 years, although for patients born abroad the difference in sensitivity was lower. Reinforced surveillance combining the SDR and MRS improves the efficiency in the detection of cases.

Does evidence support the high expectations placed in precision medicine? A bibliographic review.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient's individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although only an ideal, a constant effect of treatment would facilitate individual management. A direct consequence of a constant effect is that the variance of the outcome measure would be the same in the treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively required. Methods: We reviewed parallel clinical trials with numerical primary endpoints published in 2004, 2007, 2010 and 2013. We collected the baseline and final standard deviations of the main outcome measure. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of five studies (n = 40, 19.2%) had statistically different variances between groups, implying a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: The mean variance ratio is significantly lower than 1 and the lower variance was found more often in the intervention group than in the control group, suggesting it is more usual for treated patients to be stable. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit from treatment. This would require further study as to whether the treatment effect outweighs the side effects as well as the economic costs. We have shown that there are ways to analyze the apparently unobservable constant effect.

Analysis of mutant allele fractions in driver genes in colorectal cancer - biological and clinical insights.

Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.

High HER2 protein levels correlate with increased survival in breast cancer patients treated with anti-HER2 therapy.

INTRODUCTION: Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. METHODS: Using selected reaction monitoring mass spectrometry (SRM-MS), we quantified HER2 protein levels in formalin-fixed, paraffin-embedded (FFPE) tissue samples that had been classified as HER2 0, 1+, 2+ or 3+ by immunohistochemistry (IHC). Receiver operator curve (ROC) analysis was conducted to obtain optimal HER2 protein expression thresholds predictive of HER2 status (by standard IHC or in situ hybridization [ISH]) and of survival benefit after anti-HER2 therapy. RESULTS: Absolute HER2 amol/µg levels were significantly correlated with both HER2 IHC and amplification status by ISH (p < 0.0001). A HER2 threshold of 740 amol/µg showed an agreement rate of 94% with IHC and ISH standard HER2 testing (p < 0.0001). Discordant cases (SRM-MS-negative/ISH-positive) showed a characteristic amplification pattern known as double minutes. HER2 levels >2200 amol/µg were significantly associated with longer disease-free survival (DFS) and overall survival (OS) in an adjuvant setting and with longer OS in a metastatic setting. CONCLUSION: Quantitative HER2 measurement by SRM-MS is superior to IHC and ISH in predicting outcome after treatment with anti-HER2 therapy.

Thermal damage influences endonasal dacryocystorhinostomy success.

OBJECTIVE: To compare the success rates of two surgical methods of endonasal dacryocystorhinostomy (DCR) at the stage of ostium creation. In procedure 1, a Colorado needle is used to create the mucosectomy, while in procedure 2 no heated instruments are applied to the mucosa. METHODS: A total of 173 patients (218 eyes) underwent endonasal DCR between 2006 and 2009. Efficacy was assessed by a fluorescein endoscopic test at 6 months of follow-up. RESULTS: The success rate in group 2 was higher than in group 1 (91 vs. 81%, p < 0.05). CONCLUSIONS: We have found a significant difference, which supports that a 'cold' surgical technique may be better than the use of heated instruments.