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We consider the least squares minimization problem in which both complex- and real-valued parameters are simultaneously present. A prominent example of this is the estimation of the frequency response function (FRF) in the presence of missing output data. In this case, the FRF parameters are complex-valued, while the missing output samples are real-valued. In the extended local polynomial method (ELPM), the missing samples are treated as global variables and are estimated simultaneously with the FRF parameters under the least squares criterion. This returns a mixed-valued least squares problem. We provide a formal setting, in which we show mixed-valued least squares problems are well-defined and have a unique solution. We introduce an iterative method for solving the resulting system of equations, which splits the complex-valued and real-valued least squares designs. We show that the resulting method is algebraically equivalent to applying a 2-cyclic matrix splitting to the mixed-valued normal equations, which ensures its convergence and provides an additional adaptive scheme to improve the convergence speed. Finally, we conduct a detailed case-study on the ELPM and compare our method to the original ad-hoc method. We present impressive improvements to the computation time by exploiting the separate physical structures within both regression matrices.

Purpose: To evaluate alterations in pulmonary function indices after helical tomotherapy and explore potential associations with biologically corrected dosimetric parameters. Patients and methods: In 64 patients with inoperable locally advanced non-small cell lung cancer, pulmonary function tests before and within 6 months after radiotherapy were evaluated retrospectively. In the case of concurrent chemotherapy a total dose of 67.2 Gy was delivered, otherwise 70.5 Gy was provided. In 44 patients, late pulmonary function changes (≥6 months after radiotherapy) could also be assessed. Results: In the entire patient group, there were significant declines in forced expiratory volume in 1s (FEV1) (average change −4.1% predicted; P = 0.007), in forced vital capacity (FVC) (−4.9% predicted; P = 0.002), total lung capacity (TLC) (−5.8% predicted; P = 0.0016) and DLCO (diffusing capacity of the lung for carbon monoxide corrected for hemoglobin level) (−8.6% predicted; P < 0.001) during the first 6 months. CorrespondingFEV1, FVC, TLC and DLCO declines in the subgroup with late measurements (after 11.3 months on average) were −5.7, −7.4, −7.0, −9.8% predicted. A multivariate analysis including V5 Gy, V10 Gy, V20 Gy, V40 Gy, V60 Gy, mean lung dose (MLD), gross tumor volume (GTV) and planning target volume (PTV) as potential covariates showed that GTV was the most consistent contributor, being significant for ∆FEV1 (P = 0.003), ∆FVC (P = 0.003), ∆TLC (P = 0.001) and ∆DLCO (P = 0.01). V5 Gy or V10 Gy did not contribute to any of the lung function changes. Conclusions: The decline in pulmonary function indices after helical tomotherapy was of similar magnitude to that observed in studies reporting the effect of conformal radiotherapy on lung function. Diffusion capacity was the parameter showing the largest decrease following radiation therapy as compared to baseline and correlated with gross tumor volume. None of the alterations in pulmonary function tests were associated with the lung volume receiving low-dose radiation.

Altered frontoparietal network functional connectivity (FPN-fc) has been associated with neurocognitive dysfunction in individuals with (risk for) psychotic disorder. Cannabis use is associated with cognitive and FPN-fc alterations in healthy individuals, but it is not known whether cannabis exposure moderates the FPN-fc-cognition association. We studied FPN-fc in relation to psychosis risk, as well as the moderating effects of psychosis risk and cannabis use on the association between FPN-fc and (social) cognition. This was done by collecting resting-state fMRI scans and (social) cognitive test results from 63 patients with psychotic disorder, 73 unaffected siblings and 59 controls. Dorsolateral prefrontal cortex (DLPFC) seed-based correlation analyses were used to estimate FPN-fc group differences. Additionally, group x FPN-fc and cannabis x FPN-fc interactions in models of cognition were assessed with regression models. Results showed that DLPFC-fc with the left precuneus, right inferior parietal lobule, right middle temporal gyrus (MTG), inferior frontal gyrus (IFG) regions and right insula was decreased in patients compared to controls. Siblings had reduced DLPFC-fc with the right MTG, left middle frontal gyrus, right superior frontal gyrus, IFG regions, and right insula compared to controls, with an intermediate position between patients and controls for DLPFC-IFG/MTG and insula-fc. There were no significant FPN-fc x group or FPN-fc x cannabis interactions in models of cognition. Reduced DLPFC-insula-fc was associated with worse social cognition in the total sample. In conclusion, besides patient- and sibling-specific FPN-fc alterations, there was evidence for trait-related alterations. FPN-fc-cognition associations were not conditional on familial liability or cannabis use. Lower FPN-fc was associated with lower emotion processing in the total group. (C) 2015 Elsevier B.V. and ECNP. All rights reserved

Neuropathology suggests an important role for the locus coeruleus (LC) in Alzheimer's disease (AD) pathophysiology. Neuropathology and structural damage in the LC appears to be one of the earliest changes. We hypothesize that reduced functional integration of the LC reflected by lower brain functional connectivity contributes to early memory dysfunction. To test this, we examined resting-state functional connectivity from the LC in 18 healthy older individuals and 18 mildly cognitively impaired patients with possible AD. Connectivity measures were correlated with memory scores. The left LC showed strong connectivity to the left parahippocampal gyrus that correlated with memory performance in healthy persons. This connectivity was reduced in aMCI patients. Lateralization of connectivity-memory correlations was altered in less impaired aMCI patients: greater right LC-left parahippocampal gyrus connectivity was associated with better memory performance, in particular for encoding. Our results provide new evidence that the LC, in interaction with the parahippocampal gyrus, may contribute to episodic memory formation. They suggest functional impairment and the possibility that associated compensatory changes contribute to preserved memory functions in early AD. Structural and functional LC-related measures may provide early AD markers.

Background: Gray matter atrophy, an important biomarker for early Alzheimer's disease, might be due to white matter changes within gray matter. Methods: Twenty older participants with significant memory decline over a 12-year period (T12) were matched to 20 nondeclining participants. All participants were magnetic resonance imaging scanned at T12. Cortical thickness and diffusion tensor imaging analyses were performed. Results: Lower cortical thickness values were associated with lower diffusion values in frontal and parietal gray matter areas. This association was only present in the memory decline group. The cortical thickness diffusion tensor imaging correlations showed significant group differences in the posterior cingulate gyrus, precuneus, and superior frontal gyrus. Conclusions: Decreased gray matter diffusivity in the posterior cingulate/precuneus area might be a disease-specific process and a potential new biomarker for early Alzheimer's disease. Future studies should validate its potential as a biomarker and focus on cellular changes underlying diffusivity changes in gray matter. (C) 2013 The Alzheimer's Association. All rights reserved.

Objectives: Parietal lobe dysfunction is an important characteristic of early Alzheimer disease (AD). Functional studies have shown conflicting parietal activation patterns indicative of either compensatory or dysfunctional mechanisms. This study aimed at examining activation differences in early AD using a visuospatial task. We focused on functional characteristics of the parietal lobe and examined compensation or disconnection mechanisms by combining a fMRI task with effective connectivity measures from Granger causality mapping (GCM). Methods: Eighteen male patients with amnestic mild cognitive impairment (aMCI) and 18 male cognitively healthy older individuals were given a mental rotation task with different rotation angles. Results: There were no behavioral group differences on the fMRI task. Separate measurements at each angle revealed widespread activation group differences. More temporal and parietal activation in the higher angle condition was observed in patients with aMCI. The parametric modulation, which identifies regions associated with increasing angle, confirmed these results. The GCM showed increased connectivity within the parietal lobe and between parietal and temporal regions in patients with aMCI. Decreased connectivity was found between the inferior parietal lobule and posterior cingulate gyrus. Connectivity patterns correlated with memory performance scores in patients with aMCI. Conclusions: Our results demonstrate increased effective temporoparietal connectivity in patients with aMCI, while maintaining intact behavioral performance. This might be a compensational mechanism to counteract a parietal-posterior cingulate gyrus disconnection. These findings highlight the importance of connectivity changes in the pathophysiology of AD. In addition, effective connectivity may be a promising method for evaluating interventions aimed at the promotion of compensatory mechanisms. Copyright © 2012 by AAN Enterprises, Inc.

Advanced age is associated with declines in brain structure and in cognitive performance, but it is unclear which aspects of brain aging mediate cognitive declines. We inquired if individual differences in white matter integrity contribute to age differences in two cognitive domains with established vulnerability to aging: executive functioning and speed of processing. The participants were healthy volunteers aged 50-81, some of whom had elevated blood pressure, a known vascular risk factor. Using latent variable analyses, we examined whether age differences in regional white matter integrity mediated age-related differences in executive functions and speed of processing. Although diffusion-related latent variables showed stronger age differences than white matter volumes and white matter hyperintensity volumes, only one of them was significantly associated with cognitive performance. Smaller linear anisotropy partially mediated age-related reduction in speed of processing. The effect was significant in posterior (temporal-parietal-occipital) but not anterior (frontal) region, and appeared stronger for cognitive rather than reaction time measures of processing speed. The presence of hypertensive participants did not affect the results. We conclude that in healthy adults, deterioration of axonal integrity and ensuing breech of connectivity may underpin age-related slowing of information processing. (C) 2011 Elsevier Inc. All rights reserved.

We investigated differences associated with age and hypertension, a common risk factor for vascular disease, in three aspects of white matter integrity – gross regional volumes of the white matter, volume of the white matter hyperintensities (WMH) and diffusion properties. We acquired MRI scans on 93 adult volunteers (age 50-77 years; 36 with diagnosis of hypertension or elevated blood pressure), and obtained all measures in seven brain regions: frontal, temporal, parietal and occipital white matter, and the genu, body and splenium of the corpus callosum. The results demonstrated robust age-related differences in diffusion-based indices of cerebral white matter integrity and age-related increase in the WMH volume, but no age differences in the gross regional volumes of the white matter. Hypertension was associated with decline in fractional anisotropy, and exacerbated age differences in fractional anisotropy more than those in the volume of WMH. These findings indicate that of all examined measures, diffusion-based indices of white matter integrity may be the most sensitive indicators of global and regional declines and vascular damage in the aging brain.

The objective of this study was to examine executive functioning in children with Specific Language Impairment (SLI) using functional MRI. Six children with SLI and seven control children participated in this study and received a task-switching paradigm. No specific deficit in executive control was observed at the behavioral level in children with SLI. However, the neuroimaging data did show remarkable differences between the SLI and control children. The children with SLI recruited frontal and cingulate areas, normally associated with executive control, even when the task did not require them in the children without SLI. This might indicate that the task was more demanding for the SLI group and that compensatory mechanisms were engaged for successful task performance.

Prolonged exposure to elevated blood pressure (BP) can lead to both structural (white matter lesions (WML) or infarctions) and functional changes in the brain. We studied in previously diagnosed essential hypertensive individuals if diurnal BP variation and ambulatory BP (ABP) profile (daytime, night time and 24-h BP averages) were related to evidence of WML, the presence of 'silent' infarcts, and cognitive performance. A group of 86 patients (mean age 57.4 +/- 10 years, range 40-80) were first screened for hypertension-related organ damage and underwent 24-h ABP monitoring, magnetic resonance imaging (MRI) of the brain, and a comprehensive neurocognitive assessment. Age and ABP profile were related to more periventricular, but not subcortical, WML and to presence of lacunar infarctions on MRI. After correction for demographical group differences, no association was found between night time dipping of BP on the one hand and both WML load and cognitive parameters (verbal memory, sensorimotor speed, cognitive flexibility) on the other. The presence of lacunar infarctions, however, predicted lower performance on verbal memory. Furthermore, daytime and 24-h pulse pressure averages were associated with pWML, whereas systolic BP and mean arterial pressure (MAP) for daytime, night-time and 24-h periods were higher in patients with lacunar infarctions. Notwithstanding the large variability of WML in this sample, the evidence of a connection between diurnal BP variation and early target organ damage in the brain was not convincing. However, the ABP profile may be predictive of cerebral lesion type.

Background: An analysis of dietary patterns or combinations of foods may provide insight regarding the influence of diet on the risk of colon and rectal cancer. Objective: A primary aim of the Dietary Patterns and Cancer (DIETSCAN) Project was to develop and apply a common methodologic approach to study dietary patterns and cancer in 4 European cohorts: the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (Finland-ATBC), the Netherlands Cohort Study (NLCS) on Diet and Cancer, the Swedish Mammography Cohort (SMC), and the Ormoni e Dieta nella Eziologia dei Tumori (Italy-ORDET). Three cohorts (ATBC, NLCS, and SMC) provided data on colon and rectal cancer for the present study. Design: The cohorts were established between 1985 and 1992; follow-up data were obtained from national cancer registries. The participants completed validated semiquantitative food-frequency questionnaires at baseline. Results: Exploratory factor analysis, conducted within each cohort, identified 3-5 stable dietary patterns. Two dietary patterns - Vegetables and Pork, Processed Meats, Potatoes (PPP) - were common across all cohorts. After adjustment for potential confounders, PPP was associated with an increased risk of colon cancer in the SMC women (quintile4multivariate relative risk: 1.62; 95% CI: 1.12,2.34; P for trend = 0.01). PPP was also associated with an increased risk of rectal cancer in the ATBC men (quintile 4multivariate relative risk: 2.21; 95% CI: 1.07, 4.57; P for trend = 0.05). Neither pattern was associated with the risk of colon or rectal cancer in the NLCS women and men. Conclusion: Although certain dietary patterns may be consistent across European countries, associations between these dietary patterns and the risk of colon and rectal cancer are not conclusive. © 2004 American Society for Clinical Nutrition.

This article investigates a new, effective browsing approach called metabrowsing. It is an alternative for current information retrieval systems, which still face six prominent difficulties. We identify and classify the difficulties and show that the metabrowsing approach alleviates the difficulties associated with query formulation and missing domain knowledge. Metabrowsing is a high-level way of browsing through information: instead of browsing through document contents or document surrogates, the user browses through a graphical representation of the documents and their relations to the domain. The approach requires other cognitive skills from the user than what is currently required. Yet, a user evaluation in which the metabrowsing system was compared with an ordinary query-oriented system showed only some small indicatory differences in effectiveness, efficiency, and user satisfaction. We expect that more experience with metabrowsing will result in a significantly better performance difference. Hence, our conclusion is that the development of new cognitive skills requires some time before the technologies are ready to be used.

Common and country-specific dietary patterns in four European cohort studies.Balder HF, Virtanen M, Brants HA, Krogh V, Dixon LB, Tan F, Mannisto S, Bellocco R, Pietinen P, Wolk A, Berrino F, Van den Brandt PA, Hartman AM, Goldbohm RA.Department of Nutritional Epidemiology, TNO Nutrition and Food Research, Zeist, The Netherlands. balder@voeding.tno.nlThe association between diet and cancer, predominantly investigated univariately, has often been inconsistent, possibly because of the large number of candidate risk factors and their high intercorrelations. Analysis of dietary patterns is expected to give more insight than analysis of single nutrients or foods. This study aimed to develop and apply a common methodological approach to determine dietary patterns in four cohort studies originating in Finland, the Netherlands, Sweden and Italy. Food items on each of the food frequency questionnaires were aggregated into 51 food groups, defined on the basis of their position in the diet pattern and possible relevance to cancer etiology. Exploratory factor analysis was used to analyze dietary patterns. Using a standardized approach, 3-5 stable dietary patterns were identified, explaining 20-29% of total variance in consumption of the food groups. Two dietary patterns, which explained most of the variance, were consistent across the studies. The first pattern was characterized by high consumption of (salad) vegetables, the second by high consumption of pork, processed meat and potatoes. In addition, a few specifically national food patterns were identified. Sensitivity analyses showed that the identified patterns were robust for number of factors extracted, distribution of input variables and energy adjustment. Our findings suggest that some important eating patterns are shared by the four populations under study, whereas other eating patterns are population specific.

Mixed effects models for longitudinal data with fixed as well as random parameters are often used to describe average profiles. Influence measures are usually constructed to detect influential subjects and observations for the fixed regression parameters, treating the subject-specific parameters as nuisance parameters. One of these measures is the well-known Cook's distance. We show that this statistic may fail to detect or may incorrectly detect influential observations due to the random-effects variances and covariances. A conditional version of Cook's distance is proposed to assess the influence of observations on the estimated regression parameters.

BACKGROUND Although narrative reviews have concluded that there is strong support for an association between cigarette smoking and urinary tract cancer, the association has never been quantified systematically in reviews. The purpose of this systematic review was to summarize and quantify the impact of different smoking characteristics (status, amount, duration, cessation, and age at first exposure) both unadjusted and adjusted for age and gender. METHODS The authors included 43 epidemiologic studies (8 cohort and 35 case–control) and calculated summary odds ratios (SORs) by meta-regression analyses for different smoking characteristics. They also evaluated changes in summary estimates according to differences in study methodology. RESULTS Smoking status and increased amount and duration of smoking were associated with a strong increased risk of urinary tract cancer. Smoking cessation and age at first exposure were negatively associated with the risk of urinary tract cancer. The age- and gender-adjusted SORs for current and former cigarette smokers compared with those for nonsmokers were 3.33 (95% confidence interval [CI], 2.63–4.21) and 1.98 (CI, 1.72–2.29), respectively. Even though the component studies differed in methodology, the results were rather consistent. CONCLUSIONS The results suggest a substantial increase in risk of cancer of the urinary tract for cigarette smokers. Based on the results of this study and previous literature, the authors conclude that current cigarette smokers have an approximately threefold higher risk of urinary tract cancer than nonsmokers. In Europe, approximately half of urinary tract cancer cases among males and one-third of cases among females might be attributable to cigarette smoking. Cancer 2000;89:630–9. © 2000 American Cancer Society.

In many clinical laboratories span of control problems make it necessary to divide the clinical laboratory into sections (departments, job shops). A section is in fact a set of workstations where tests are performed on samples. A mathematical programming model is described which clusters workstations in such way that the maximum idle time of staff in staff assignment periods is minimized. An example demonstrates the usefulness of the approach.

As part of the OpenLabs (AIM 2028) programme a decision support system (DSS) for laboratory capacity management has been developed. This DSS contains a simulation module for determining the performance of planning rules given the equipment and staffing of the clinical laboratory and the demand for laboratory services. User requirements are discussed and a method is developed to (re-)define rules concerning various planning decisions. To show the functionality of the simulation module some simulation experiments are described.

The discriminative value of patient characteristics and dyspeptic symptoms for upper gastrointestinal endoscopic findings: a study on the clinical presentation of 1,147 patients.Adang RP, Ambergen AW, Talmon JL, Hasman A, Vismans JF, Stockbrugger RW.Department of Gastroenterology and Hepatology, University Hospital, Maastricht, The Netherlands.The discriminative value of patient characteristics and dyspeptic symptoms for upper gastrointestinal endoscopic findings was prospectively assessed in 1,147 patients attending for their first diagnostic endoscopy and who answered paper (n = 431) or computerized (n = 716) questionnaires. The questionnaires provided detailed information concerning present dyspeptic symptoms, with special attention to provoking and/or relieving factors, and smoking and/or drinking habits. In logistic regression models each of a number of 'specific endoscopic diagnoses' was contrasted with normal endoscopy (n = 390), and 'relevant endoscopic disease' (oesophagitis, peptic ulcers, cancers; n = 269) was contrasted with 'irrelevant' and normal endoscopic findings (n = 878). From the regression model a receiver operating characteristic (ROC) curve could be constructed, and the area under the ROC curve (AUC) was calculated to summarize the discriminative power of the regression model. The best discrimination from patients with a normal endoscopy was achieved for patients with gastric (AUC = 0.86) or duodenal (AUC = 0.85) ulcers, followed by patients with hiatus hernia (AUC = 0.78 or oesophagitis (AUC = 0.77). The discriminative performance of the regression models was somewhat less for duodenitis/bulbitis (AUC = 0.75) and endoscopic gastritis (AUC = 0.73). In an open-access endoscopy unit setting, the value of preinvestigation history-taking for the prediction of clinically relevant endoscopic disease was very limited (AUC = 0.63).

Topic: Technologische ontwikkelingen ten dienste van Farmaceutische Zorg Clinical decision support systems in hospitals: What do physicians expect? Pieter Cornu1, Stephane Steurbaut1, Marc De Beukeleer2, Koen Putman3, Rudi Van de Velde4, Alain G Dupont1 1Departement Klinische Farmacologie & Farmacotherapie UZ Brussel, 2Kwaliteitsmanager UZ Brussel, 3Departement Medische Sociologie VUB, 4Departement ICT en facility management UZ Brussel Laarbeeklaan 101 & 103, 1090 Jette, België Contactpersoon: Pieter Cornu Tel: 02 476 3051 e-mail: Pieter.Cornu@vub.ac.be Introduction As rational pharmacotherapy and medication safety have become central aspects in current healthcare practice, clinical decision support systems (CDSS) are becoming increasingly important. Because developing and implementing CDSS is time-consuming and costly, prioritization of the most relevant systems is warranted. The physician's perspective is an important factor for determining this prioritization. Objective The objective of this study was to investigate the physician's perspective on the perceived usefulness of different types of CDSS in relation to each other and to identify the user needs and expectations regarding future CDSS. Methods This study was a cross-sectional single-center survey (web-based) among physicians with a permanent clinical assignment in a 721-bed university hospital. The physicians were questioned about their current experiences with drug prescribing, knowledge regarding CDSS, and the perceived usefulness and desired features of future CDSS. Results One hundred and sixty-four physicians completed the survey (52.6%). More than half (61.6%) of the respondents did not know what CDSS were before filling in the survey. The majority of the respondents reported that it is very difficult to take all relevant information into account when prescribing drugs. Drug-drug interaction checking, drug-allergy checking, and dosing guidance were considered as most useful. Automated clinical guidelines and adverse drug event monitoring were considered as least useful. The user-friendliness of the systems, clinical relevance of the alerts, and related with it, prevention of alert fatigue, were perceived as important aspects for a successful implementation. Conclusions From the physicians' perspective drug-drug interaction checking, drug-allergy checking, and dosing guidance should receive the highest priority for development and implementation. In order to overcome the physicians' perceived disadvantages, attention should go to making user-friendly systems that deliver clinical relevant alerts.

a b s t r a c t Objective: Development of a good practice guideline to plan and perform scientifically robust evaluation studies in health informatics. Methods: Issues to be addressed in evaluation studies were identified and guidance drafted based on the evaluation literature and on experiences by key players. Successive drafts of the guideline were discussed in several rounds by an increasing number of experts during conferences and by e-mail. At a fairly early point the guideline was put up for comments on the web. Results: Sixty issues were identified that are of potential relevance for planning, implementation and execution of an evaluation study in the health informatics domain. These issues cover all phases of an evaluation study: Preliminary outline, study design, operationalization of methods, project planning, execution and completion of the evaluation study. Issues of risk management and project control as well as reporting and publication of the evaluation results are also addressed. Conclusion: A comprehensive list of issues is presented as a guideline for good evaluation practice in health informatics (GEP-HI). The strengths and weaknesses of the guideline are discussed. Application of this guideline will support better handling of an evaluation study, potentially leading to a higher quality of evaluation studies. This guideline is an important step towards building stronger evidence and thus to progress towards evidence-based health informatics.

Prevailing opinion holds that normal brain aging is characterized by substantial atrophy of cortical gray matter. However, this conclusion is based on earlier studies whose findings may be influenced by the inclusion of subjects with subclinical cognitive disorders like preclinical dementia. The present magnetic resonance imaging study tested this hypothesis. Cognitively healthy subjects (mean age 72 years, range 52-82) who remained cognitively stable over a 3-year period were compared to subjects with significant cognitive decline. Subjects who developed dementia within 6 years after the scan session were excluded. The gray matter volumes of seven cortical regions were delineated on T1-weighted magnetic resonance imaging scans. Participants without cognitive decline did not exhibit an age effect on the gray matter volume. Conversely, participants with cognitive decline exhibited a significant age effect in all the seven areas. These results suggest that cortical gray matter atrophy may have been overestimated in studies on healthy aging, since most studies were unable to exclude participants with a substantial atypical cognitive decline or preclinical dementia. Our results underscore the importance of establishing stringent inclusion criteria for future studies on normal aging. © 2009 American Psychological Association.

SummaryEspecially in knowledge-rich domains such as medicine perfect access to the literature is essential for professionals. Unfortunately, especially in knowledge-rich domains it is difficult to achieve perfect access: it is too difficult and too time consuming for users to formulate queries that yield the maximum of relevant documents and a minimum of non-relevant ones. The paper first discusses the challenges of information retrieval in medicine and various existing approaches. To address the challenges two completely opposite approaches are presented. The first supports the user by means of metabrowsing: a visual way of depicting the relations between domain concepts and documents. Metabrowsing relieves the user from the formulation of queries, while leaving him in full control. The second approach aims to minimize the interaction with the user. Information needs and queries are autonomously and proactively formulated by a software-agent who remains invisible to the user. The agent uses the electronic patient record of a particular patient and domain knowledge. As a result, the agent provides the doctor with literature that is relevant with respect to the patient at hand.

Objective: Only a few consistent findings on individual foods or nutrients that influence breast cancer risk have emerged thus far. Since people do not consume individual foods but certain combinations of them, the analysis of dietary patterns may offer an additional aspect for assessing associations between diet and diseases such as breast cancer. It is also important to examine whether the relationships between dietary patterns and breast cancer risk are consistent across populations. Methods: We examined the risk of breast cancer with two dietary patterns, identified as "Vegetables" (VEG) and "Pork, Processed Meat, Potatoes" (PPP), common to all cohorts of the DIETSCAN project. During 7 to 13 years of follow-up, three of the cohorts - the Netherlands Cohort Study on diet and cancer (NLCS), the Swedish Mammography Cohort (SMC), and the Ormoni e Dieta nella Eziologia dei Tumori (Italy-ORDET) - provided data on 3271 breast cancer cases with complete information on their baseline diet measured by a validated food frequency questionnaire. Results: After adjustment for potential confounders, VEG was not associated with the risk of breast cancer across all cohorts. PPP was also not associated with the risk of breast cancer in SMC and ORDET, but a high PPP score tended to be inversely associated with breast cancer in the NLCS study (RR = 0.69; 95% CI, 0.52-0.92, highest versus lowest quartile). PPP differed in one aspect between the cohorts: butter loaded positively on the pattern in all cohorts except NLCS, in which butter loaded negatively and appeared to be substituted by low-fat margarine loading positively. Conclusion: In general, the dietary patterns showed consistent results across the three cohorts except for the possible protective effect of PPP in the NLCS cohort, which could be explained by a difference in that pattern for NLCS. The results supported the suggestion derived from traditional epidemiology that relatively recent diet may not have an important role in the etiology of breast cancer. © Springer 2005.

In this article, the optimal selection and allocation of time points in repeated measures experiments is considered. D-optimal cohort designs are computed numerically for the first- and second-degree polynomial models with random intercept, random slope, and first-order autoregressive serial correlations. Because the optimal designs are locally optimal, it is proposed to use a maximin criterion. It is shown that, for a large class of symmetric designs, the smallest relative efficiency over the model parameter space is substantial.

Int J Epidemiol 2001 Apr;30(2):353-62 Related Articles, Books, LinkOut Are coffee and tea consumption associated with urinary tract cancer risk? A systematic review and meta-analysis.Zeegers MP, Tan FE, Goldbohm RA, van den Brandt PA.Department of Epidemiology, Maastricht University, Maastricht, The Netherlands. mpa.zeegers@epid.unimaas.nlBACKGROUND: Narrative reviews have concluded that there is a small association between coffee consumption and an increased risk of urinary tract cancer, possibly due to confounding by smoking. No association for tea consumption has been indicated. This systematic review attempts to summarize and quantify these associations both unadjusted and adjusted for age, smoking and sex. METHOD: Thirty-four case-control and three follow-up studies were included in this systematic review. Summary odds ratios (OR) were calculated by meta-regression analyses. RESULTS: The unadjusted summary OR indicated a small increased risk of urinary tract cancer for current coffee consumers versus non-drinkers. The adjusted summary OR were: 1.26 (95% CI : 1.09-1.46) for studies with only men, 1.08 (95% CI : 0.79-1.46) for studies with only women and 1.18 (95% CI : 1.01-1.38) for studies with men and women combined. Neither unadjusted nor adjusted summary OR provided evidence for a positive association between tea consumption and urinary tract cancer. Even though studies differed in methodology, the results were rather consistent. We did not perform dose-response analyses for coffee and tea consumption due to sparse data. CONCLUSIONS: In accordance with earlier reviews, we found that coffee consumption increases the risk of urinary tract cancer by approximately 20%. The consumption of tea seems not to be related to an increased risk of urinary tract cancer.

This paper describes and discusses the design and usage of a shareable consumer health record system to investigate whether these systems can assist in the management of chronic diseases. This web-based system that can be used both by care providers and patients contains medical and patient information, provides access to websites that contain quality information, provides guideline-based advice, allows discussion between patients and allows us to interrogate both patients and care providers on a regular basis in order to get a good impression of the utility of such a consumer record for both chronic patients and the physicians and nurses. A health record system that was developed for the area of Diabetes is presented as an example.

Summary effect measures in meta-analysis of published epidemiological cohort or case control studies are often based on odds ratios reported for several exposure levels with varying arrangements and number of levels across primary studies. Usually only two-way contingency tables together with exposure specific adjusted odds ratios and corresponding standard errors are presented in articles. An a symptotically unbiased estimate of exposed versus non-exposed adjusted odds ratio from reported dose-response data is proposed. This estimate is based on the weighted sum of the exposure specific odds ratios, with the prevalences of the control group as weights. Large sample variance is derived accounting for the dependency between exposure specific adjusted odds ratios. The exposed versus non-exposed adjusted odds ratio could then be used in systematic reviewing.

Biometrics 2001 Dec;57(4):1166-72 Related Articles, Books, LinkOut Local influence to detect influential data structures for generalized linear mixed models.Ouwens MJ, Tan FE, Berger MP.Department of Methodology and Statistics, Maastricht University, The Netherlands. mario.ouwens@stat.unimaas.nlThis article discusses the generalization of the local influence measures for normally distributed responses to local influence measures for generalized linear models with random effects. For these models, it is shown that the subject-oriented influence measure is a special case of the proposed observation-oriented influence measure. A two-step diagnostic procedure is proposed. The first step is to search for influential subjects. A search for influential observations is proposed as the second step. An illustration of a two-treatment, multiple-period crossover trial demonstrates the practical importance of the detection of influential observations in addition to the detection of influential subjects.

Department of Epidemiology, Maastricht University, The Netherlands. mpa.zeegers@epid.unimaas.nl OBJECTIVES: Recent narrative reviews have concluded that there is no support for an association between alcohol consumption and urinary tract cancer. Many individual studies, however, have reported positive associations, although rarely statistically significant. The purpose of this meta-analysis is to summarize and quantify this relationship with more statistical power and to perform a sensitivity analysis on the study characteristics. METHODS: We included 16 epidemiological studies published up to April 1999 and calculated summary odds ratios (SORs), both upgraded and adjusted for age, sex and smoking by meta-regression analyses. The age- and smoking-adjusted SORs (current alcohol drinking vs. non-drinking) were 1.3 (95% CI 0.9-2.0) for six studies with men and 1.0 (95% CI 0.4-2.6) for four studies with women. RESULTS: The age-, sex- and smoking-adjusted SOR was 1.2 (95% CI 0.9-1.7) for seven studies with men and women combined. CONCLUSION: Even though studies differed in methodology, the results were rather consistent. Subgroup analyses by type or amount of alcohol were not possible due to sparse data. We conclude that the available data suggest a slightly increased risk of urinary tract cancer from alcohol consumption for men. The risk related to alcohol consumption for women and the influence of the amount and type of alcohol remain unclear. Publication Types: Meta-Analysis

Keywords: closed form estimators, IRT, longitudinal In this paper, the one parameter Item Response Theory (IRT) model with normal Item Characteristic Curves (ICC) in longitudinal context has been studied. The abilities are structured according to a general mixed effects linear regression model. The items are supposed to be a sample from a large bank of items with constant mean difficulty. If the number of repeated measures is large, then commonly used simultaneous estimation procedures often lead to practical problems with respect to multidimensional numerical integrations. In this article, an approximation of the normal ICC is introduced that leads to simple ability and difficulty estimators with nice asymptotic properties. The relative efficiency and bias of the ability estimator are studied. An illustration with real data shows high relative efficiency within an accaptable range of the domain of the ICC. Moreover, the bias is very small. A simulation study shows the effect of non-normal item parameters on the regression estimates. The results suggest that the proposed procedure is rather robust against departures from normality. However, the estimation of the correlations between regression parameters can be seriously biased.

In this contribution the protocol information system ProtoVIEW is presented. The system provides the necessary information to physicians about diagnostic procedures and therapies. It is implemented as a stand alone system. The design criteria are discussed and the results of a first evaluation presented. It appears that interns can easily find the required information with the help of the system. The time that they need for accessing the relevant information is relatively short (about 1 min). The users expressed the opinion that the system is easy to use and does support them in the management of their patients. On the basis of this evaluation and evaluations reported elsewhere it is concluded (a) that stand-alone protocol. systems carl support daily patient management in a positive way and (b) that the design criteria for a protocol information system as presented in this paper are useful for prospective protocol information system developers.