Peter Schlattmann

Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations

RATIONALEnReducing the global burden of sepsis, a recognized global health challenge, requires comprehensive data on the incidence and mortality on a global scale.nnnOBJECTIVESnTo estimate the worldwide incidence and mortality of sepsis and identify knowledge gaps based on available evidence from observational studies.nnnMETHODSnWe systematically searched 15 international citation databases for population-level estimates of sepsis incidence rates and fatality in adult populations using consensus criteria and published in the last 36 years.nnnMEASUREMENTS AND MAIN RESULTSnThe search yielded 1,553 reports from 1979 to 2015, of which 45 met our criteria. A total of 27 studies from seven high-income countries provided data for metaanalysis. For these countries, the population incidence rate was 288 (95% confidence interval [CI], 215-386; τ = 0.55) for hospital-treated sepsis cases and 148 (95% CI, 98-226; τ = 0.99) for hospital-treated severe sepsis cases per 100,000 person-years. Restricted to the last decade, the incidence rate was 437 (95% CI, 334-571; τ = 0.38) for sepsis and 270 (95% CI, 176-412; τ = 0.60) for severe sepsis cases per 100,000 person-years. Hospital mortality was 17% for sepsis and 26% for severe sepsis during this period. There were no population-level sepsis incidence estimates from lower-income countries, which limits the prediction of global cases and deaths. However, a tentative extrapolation from high-income country data suggests global estimates of 31.5 million sepsis and 19.4 million severe sepsis cases, with potentially 5.3 million deaths annually.nnnCONCLUSIONSnPopulation-level epidemiologic data for sepsis are scarce and nonexistent for low- and middle-income countries. Our analyses underline the urgent need to implement global strategies to measure sepsis morbidity and mortality, particularly in low- and middle-income countries.

The zero-inflated Poisson model and the decayed, missing and filled teeth index in dental epidemiology

Summary. For frequency counts, the situation of extra zeros often arises in biomedical applications. This is demonstrated with count data from a dental epidemiological study in Belo Horizonte (the Belo Horizonte caries prevention study) which evaluated various programmes for reducing caries. Extra zeros, however, violate the variance-mean relationship of the Poisson error structure. This extraPoisson variation can easily be explained by a special mixture model, the zero-inflated Poisson (ZIP) model. On the basis of the ZIP model, a graphical device is presented which not only summarizes the mixing distribution but also provides visual information about the overall mean. This device can be exploited to evaluate and compare various groups. Ways are discussed to include covariates and to develop an extension of the conventional Poisson regression. Finally, a method to evaluate intervention effects on the basis of the ZIP regression model is described and applied to the data of the Belo Horizonte caries prevention study.

Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing

BACKGROUNDnA common functional polymorphism, G1947A, of the catechol-O-methyltransferase (COMT) enzyme has gained interest in schizophrenia research because of its critical involvement in cortical dopamine catabolism and frontal lobe function. An assumed mechanism of dopamine is the reduction of noise in prefrontal neural networks during information processing. Therefore, the hypothesis was tested whether a variation of the COMT genotype is associated with prefrontal noise, which is in part reflected by the frontal P300 amplitude. It was predicted that homozygous Met allele carriers have a lower frontal P300 amplitude.nnnMETHODSnThe P300 component (auditory oddball) was recorded in 49 schizophrenic patients and 170 healthy control subjects. Three single nucleotide polymorphisms (SNPs) of the COMT gene (G1947A, C1883G, and G1243A) were investigated.nnnRESULTSnWe observed a significant effect of G1947A COMT genotype on frontal P300 amplitude, with evidence for a genotype x diagnosis interaction. Lower frontal P300 amplitudes occurred in homozygous carriers of the Met allele, particularly in schizophrenic patients.nnnCONCLUSIONSnThe association of the frontal P300 amplitude with the G1947A COMT genotype further emphasizes the functional role of this SNP. As the finding was mainly observed in schizophrenic patients, this may indicate that additional factors are required to interact with COMT genotype to affect prefrontal function. The smaller frontal P300 amplitude in Met carriers suggests that the amount of noise in prefrontal neural networks during information processing might be in part under genetic control, which is mediated by dopamine.

The distribution of the likelihood ratio for mixtures of densities from the one-parameter exponential family

We here consider testing the hypothesis ofhomogeneity against the alternative of a two-component mixture of densities. The paper focuses on the asymptotic null distribution of 2 log λn, where λn is the likelihood ratio statistic. The main result, obtained by simulation, is that its limiting distribution appears pivotal (in the sense of constant percentiles over the unknown parameter), but model specific (differs if the model is changed from Poisson to normal, say), and is not at all well approximated by the conventional χ(2)2-distribution obtained by counting parameters. In Section 3, the binomial with sample size parameter 2 is considered. Via a simple geometric characterization the case for which the likelihood ratio is 1 can easily be identified and the corresponding probability is found. Closed form expressions for the likelihood ratio λn are possible and the asymptotic distribution of 2 log λn is shown to be the mixture giving equal weights to the one point distribution with all its mass equal to zero and the χ2-distribution with 1 degree of freedom. A similar result is reached in Section 4 for the Poisson with a small parameter value (θ≤0.1), although the geometric characterization is different. In Section 5 we consider the Poisson case in full generality. There is still a positive asymptotic probability that the likelihood ratio is 1. The upper precentiles of the null distribution of 2 log λn are found by simulation for various populations and shown to be nearly independent of the population parameter, and approximately equal to the (1–2α)100 percentiles of χ(1)2. In Sections 6 and 7, we close with a study of two continuous densities, theexponential and thenormal with known variance. In these models the asymptotic distribution of 2 log λn is pivotal. Selected (1−α) 100 percentiles are presented and shown to differ between the two models.

Reduced Event-Related Current Density in the Anterior Cingulate Cortex in Schizophrenia

There is good evidence from neuroanatomic postmortem and functional imaging studies that dysfunction of the anterior cingulate cortex plays a prominent role in the pathophysiology of schizophrenia. So far, no electrophysiological localization study has been performed to investigate this deficit. We investigated 18 drug-free schizophrenic patients and 25 normal subjects with an auditory choice reaction task and measured event-related activity with 19 electrodes. Estimation of the current source density distribution in Talairach space was performed with low-resolution electromagnetic tomography (LORETA). In normals, we could differentiate between an early event-related potential peak of the N1 (90-100 ms) and a later N1 peak (120-130 ms). Subsequent current-density LORETA analysis in Talairach space showed increased activity in the auditory cortex area during the first N1 peak and increased activity in the anterior cingulate gyrus during the second N1 peak. No activation difference was observed in the auditory cortex between normals and patients with schizophrenia. However, schizophrenics showed significantly less anterior cingulate gyrus activation and slowed reaction times. Our results confirm previous findings of an electrical source in the anterior cingulate and an anterior cingulate dysfunction in schizophrenics. Our data also suggest that anterior cingulate function in schizophrenics is disturbed at a relatively early time point in the information-processing stream (100-140 ms poststimulus).

Computer-assisted analysis of mixtures (C.A.MAN) statistical algorithms

SUMMARY This paper presents various algorithmic approaches for computing the maximum likelihood estimator of the mixing distribution of a one-parameter family of densities and provides a unifying computeroriented concept for the statistical analysis of unobserved heterogeneity (i.e., observations stemming from different subpopulations) in a univariate sample. The case with unknown number of population subgroups as well as the case with known number of population subgroups, with emphasis on the first, is considered in the computer package C.A.MAN (Computer Assisted Mixture ANalysis). It includes an algorithmic menu with choices of the EM algorithm, the vertex exchange algorithm, a combination of both, as well as the vertex direction method. To ensure reliable convergence, a steplength menu is provided for the three latter methods, each achieving monotonicity for the direction of choice. C.A.MAN has the option to work with restricted support size-that is, the case when the number of components is known a priori. In the latter case, the EM algorithm is used. Applications of mixture modelling in medical problems are discussed.

P300 and LORETA : comparison of normal subjects and schizophrenic patients

It was the aim of the present study 1) to investigate how many cortical activity maxima of scalp-recorded P300 are detected by Low Resolution Electromagentic Tomography (LORETA) when analyses are performed with high time-resolution, 2) to see if the resulting LORETA-solution is in accordance with intracortical recordings as reported by others and 3) to compare the given pattern of cortical activation maxima in the P300-timeframe between schizophrenic patients and normal controls. Current density analysis was performed in 3-D Talairach space with high time resolution i.e. in 6 ms steps. This was done during an auditory choice reaction paradigm separately for normal subjects and schizophrenic patients with subsequent group comparisons. In normal subjects, a sequence of at least seven cortical activation maxima was found between 240-420ms poststimulus: the prefrontal cortex, anterior or medial cingulum, posterior cingulum, parietal cortex, temporal lobe, prefrontal cortex, medial or anterior cingulum. Within the given limits of spatial resolution, this sequential maxima distribution largely met the expectations from reports on intracranial recordings and functional neuroimaging studies. However, localization accuracy was higher near the central midline than at lateral aspects of the brain. Schizophrenic patients less activated their cortex in a widespread area mainly in the left hemisphere including the prefrontal cortex, posterior cingulum and the temporal lobe. From these analyses and comparsions with intracranial recordings as reported by others, it is concluded that LORETA correctly localizes P300-related cortical activity maxima on the basis of 19 electrodes except for lateral cortical aspects which is most likely an edge-phenomenon. The data further suggest that the P300-deficit in schizophrenics involves an extended cortical network of the left hemisphere at several steps in time during the information processing stream.

Head-to-Head Comparison of Left Ventricular Function Assessment with 64-Row Computed Tomography, Biplane Left Cineventriculography, and Both 2- and 3-Dimensional Transthoracic Echocardiography Comparison With Magnetic Resonance Imaging as the Reference Standard

OBJECTIVESnThis study was designed to compare the accuracy of 64-row contrast computed tomography (CT), invasive cineventriculography (CVG), 2-dimensional echocardiography (2D Echo), and 3-dimensional echocardiography (3D Echo) for left ventricular (LV) function assessment with magnetic resonance imaging (MRI).nnnBACKGROUNDnCardiac function is an important determinant of therapy and is a major predictor for long-term survival in patients with coronary artery disease. A number of methods are available for assessment of function, but there are limited data on the comparison between these multiple methods in the same patients.nnnMETHODSnA total of 36 patients prospectively underwent 64-row CT, CVG, 2D Echo, 3D Echo, and MRI (as the reference standard). Global and regional LV wall motion and ejection fraction (EF) were measured. In addition, assessment of interobserver agreement was performed.nnnRESULTSnFor the global EF, Bland-Altman analysis showed significantly higher agreement between CT and MRI (p < 0.005, 95% confidence interval: ±14.2%) than for CVG (±20.2%) and 3D Echo (±21.2%). Only CVG (59.5 ± 13.9%, p = 0.03) significantly overestimated EF in comparison with MRI (55.6 ± 16.0%). CT showed significantly better agreement for stroke volume than 2D Echo, 3D Echo, and CVG. In comparison with MRI, CVG-but not CT-significantly overestimated the end-diastolic volume (p < 0.001), whereas 2D Echo and 3D Echo significantly underestimated the EDV (p < 0.05). There was no significant difference in diagnostic accuracy (range: 76% to 88%) for regional LV function assessment between the 4 methods when compared with MRI. Interobserver agreement for EF showed high intraclass correlation for 64-row CT, MRI, 2D Echo, and 3D Echo (intraclass correlation coefficient >0.8), whereas agreement was lower for CVG (intraclass correlation coefficient = 0.58).nnnCONCLUSIONSn64-row CT may be more accurate than CVG, 2D Echo, and 3D Echo in comparison with MRI as the reference standard for assessment of global LV function.

Use of 3x2 tables with an intention to diagnose approach to assess clinical performance of diagnostic tests: meta-analytical evaluation of coronary CT angiography studies.

Objective To determine whether a 3×2 table, using an intention to diagnose approach, is better than the “classic” 2×2 table at handling transparent reporting and non-evaluable results, when assessing the accuracy of a diagnostic test. Design Based on a systematic search for diagnostic accuracy studies of coronary computed tomography (CT) angiography, full texts of relevant studies were evaluated to determine whether they could calculate an alternative 3×2 table. To quantify an overall effect, we pooled diagnostic accuracy values according to a meta-analytical approach. Data sources Medline (via PubMed), Embase (via Ovid), and ISI Web of Science electronic databases. Eligibility criteria Prospective English or German language studies comparing coronary CT with conventional coronary angiography in all patients and providing sufficient data for a patient level analysis. Results 120 studies (10u2009287 patients) were eligible. Studies varied greatly in their approaches to handling non-evaluable findings. We found 26 studies (including 2298 patients) that allowed us to calculate both 2×2 tables and 3×2 tables. Using a bivariate random effects model, we compared the 2×2 table with the 3×2 table, and found significant differences for pooled sensitivity (98.2 (95% confidence interval 96.7 to 99.1) v 92.7 (88.5 to 95.3)), area under the curve (0.99 (0.98 to 1.00) v 0.93 (0.91 to 0.95)), positive likelihood ratio (9.1 (6.2 to 13.3) v 4.4 (3.3 to 6.0)), and negative likelihood ratio (0.02 (0.01 to 0.04) v 0.09 (0.06 to 0.15); (P<0.05)). Conclusion Parameters for diagnostic performance significantly decrease if non-evaluable results are included by a 3×2 table for analysis (intention to diagnose approach). This approach provides a more realistic picture of the clinical potential of diagnostic tests.

Computed Tomography Angiography and Myocardial Computed Tomography Perfusion in Patients With Coronary Stents: Prospective Intraindividual Comparison With Conventional Coronary Angiography

OBJECTIVESnThis study sought to determine whether adding myocardial computed tomography perfusion (CTP) to computed tomography angiography (CTA) improves diagnostic performance for coronary stents.nnnBACKGROUNDnCTA of coronary stents has been limited by nondiagnostic studies caused by metallic stent material and coronary motion.nnnMETHODSnCTA and CTP were performed in 91 consecutive patients with stents before quantitative coronary angiography, the reference standard for obstructive stenosis (≥50%). If a coronary stent or vessel was nondiagnostic on CTA, adenosine stress CTP in the corresponding myocardial territory was read for combined CTA/CTP.nnnRESULTSnPatients had an average of 2.5 ± 1.8 coronary stents (1 to 10), with a diameter of 3.0 ± 0.5 mm. Significantly more patients were nondiagnostic for stent assessment by CTA (22%; mainly due to metal artifacts [75%] or motion [25%]) versus CTP (1%; p < 0.001; severe angina precluded CTP in 1 case). The per-patient diagnostic accuracy of CTA/CTP for stents (87%, 95% confidence interval [CI]: 78% to 93%) was significantly higher than that of CTA alone (71%, 95% CI: 61% to 80%; p < 0.001), mainly because nondiagnostic examinations were significantly reduced (p < 0.001). In the analysis of any coronary artery disease, diagnostic accuracy and nondiagnostic rate were also significantly improved by the addition of CTP (p < 0.001). CTA/CTP (7.9 ± 2.8 mSv) had a significantly lower effective radiation dose than angiography (9.5 ± 5.1 mSv; p = 0.005). The area under the receiver-operating characteristic curve for CTA/CTP (0.82, 95% CI: 0.69 to 0.95) was superior to that for CTA (0.69, 95% CI: 0.57 to 0.82; p < 0.001) in identifying patients requiring stent revascularization.nnnCONCLUSIONSnCombined coronary CTA and myocardial CTP improves diagnosis of CAD and in-stent restenosis in patients with stents compared with CTA alone. (Coronary Artery Stent Evaluation With 320-Slice Computed Tomography-The CArS 320 Study [CARS-320]; NCT00967876).