Estudo e aplicação de diferentes métodos de resolução para problemas dinâmicos não-lineares em presença de atrito

The friction phenomena is present in mechanical systems with two surfaces that are in contact, which can cause serious damage to structures. Your understanding in many dynamic problems became the target of research due to its nonlinear behavior. It is necessary to know and thoroughly study each existing friction model found in the literature and nonlinear methods to define what will be the most appropriate to the problem in question. One of the most famous friction model is the Coulomb Friction, which is considered in the studied problems in the French research center Laboratoire de Mécanique des Structures et des Systèmes Couplés (LMSSC), where this search began. Regarding the resolution methods, the Harmonic Balance Method is generally used. To expand the knowledge about the friction models and the nonlinear methods, a study was carried out to identify and study potential methodologies that can be applied in the existing research lines in LMSSC and then obtain better final results. The identified friction models are divided into static and dynamic. Static models can be Classical Models, Karnopp Model and Armstrong Model. The dynamic models are Dahl Model, Bliman and Sorine Model and LuGre Model. Concerning about nonlinear methods, we study the Temporal Methods and Approximate Methods. The friction models analyzed with the help of Matlab software are verified from studies in the literature demonstrating the effectiveness of the developed programming

Alternative distributions to estimate usual intake of nutrients for groups

When assessing food intake patterns in groups of individuals, a major problem is finding usual intake distribution. This study aimed at searching for a probability distribution to estimate the usual intake of nutrients using data from a cross-sectional investigation on nutrition students from a public university in São Paulo state, Brazil. Data on 119 women aged 19 to 30 years old were used. All women answered a questionnaire about their lifestyle, diet and demographics. Food intake was evaluated from a non-consecutive three-day 24-hour food record. Different probability distributions were tested for vitamins C and E, panthotenic acid, folate, zinc, copper and calcium where data normalization was not possible. Empirical comparisons were performed, and inadequacy prevalence was calculated by comparing with the NRC method. It was concluded that if a more realistic distribution for usual intake is found, results can be more accurate as compared to those achieved by other methods.

Qualidade das medidas antropométricas produzidas em unidades de atenção básica à saúde da região de Botucatu-SP, Brasil

The aim of this study was to evaluate the quality of weight measurements produced in Primary Health Care Centers in Botucatu and surroundings. 14 Health Care Centers were included, all of them located in four towns in the area of Botucatu (4,555; 5,656; 18,761 and 128,397 inhabitants). General conditions and scale calibration conditions found in those Health Care Centers were evaluated. In order to evaluate the weight accuracy obtained by the local team, 10 adult users of each Center were addressed by the rater during the service routine in order to get a new weight evaluation, immediately after the measurement made by the team. The statistic method applied for checking the weight measurement held in the Heath Care Center and the scales accuracy was the measurement error technique (MET). The results have showed that out of 19 scales, 6 of them overestimated the weight by 50 grams, 1 of them underestimated the weight by 200 grams and the others were accurate. Evaluated as a group, the result of the scale MET was 44.3g. Regarding the conformity of the measures obtained by the MET of the adults weighing in the Health Care Centers compared to the ones obtained by the researcher, the expected result was obtained in only one Center (< 100g). The results have showed data compromise, rather due to lack of health team training than due to the conditions of the equipment used for the measurement.

Cross-cultural adaptation and assessment of the reliability and validity of the Core Outcome Measures Index (COMI) for the Brazilian-Portuguese language

The use of patient-orientated questionnaires is of utmost importance in assessing the outcome of spine surgery. Standardisation, using a common set of outcome measures, is essential to aid comparisons across studies/in registries. The Core Outcome Measures Index (COMI) is a short, multidimensional outcome instrument validated for patients with spinal disorders. This study aimed to produce a Brazilian-Portuguese version of the COMI. A cross-cultural adaptation of the COMI into Brazilian-Portuguese was carried out using established guidelines. 104 outpatients with chronic LBP (> 3 months) were recruited from a Public Health Spine Medical Care Centre. They completed a questionnaire booklet containing the newly translated COMI, and other validated symptom-specific questionnaires: Oswestry Disability Index (ODI) and Roland Morris disability scale (RM), and a pain visual analogue scale. All patients completed a second questionnaire within 7-10 days to assess reproducibility. The COMI summary score displayed minimal floor and ceiling effects. On re-test, the responses for each individual domain of the COMI were within 1 category in 98% patients for the domain 'function', 96% for 'symptom-specific well-being', 97% for 'general quality of life', 99% for 'social disability' and 100% for 'work disability'. The intraclass correlation coefficients (ICC2,1) for COMI pain and COMI summary scores were 0.91-0.96, which compared favourably with the corresponding values for the RM (ICC, 0.99) and ODI (ICC, 0.98). The standard error of measurement for the COMI was 0.6, giving a "minimum detectable change" (MDC95%) of approximately 1.7 points i.e., the minimum change to be considered "real change" beyond measurement error. The COMI scores correlated as hypothesised (Rho, 0.4-0.8) with the other symptom-specific questionnaires. The reproducibility of the Brazilian-Portuguese version of the COMI was comparable to that of other language versions. The COMI scores correlated in the expected manner with existing but longer symptom-specific questionnaires suggesting good convergent validity for the COMI. The Brazilian-Portuguese COMI represents a valuable tool for Brazilian study-centres in future multicentre clinical studies and surgical registries.

Near-Term Fetal Hypoxia-Ischemia in Rabbits MRI Can Predict Muscle Tone Abnormalities and Deep Brain Injury

Background and Purpose-The pattern of antenatal brain injury varies with gestational age at the time of insult. Deep brain nuclei are often injured at older gestational ages. Having previously shown postnatal hypertonia after preterm fetal rabbit hypoxia-ischemia, the objective of this study was to investigate the causal relationship between the dynamic regional pattern of brain injury on MRI and the evolution of muscle tone in the near-term rabbit fetus. Methods-Serial MRI was performed on New Zealand white rabbit fetuses to determine equipotency of fetal hypoxia-ischemia during uterine ischemia comparing 29 days gestation (E29, 92% gestation) with E22 and E25. E29 postnatal kits at 4, 24, and 72 hours after hypoxia-ischemia underwent T2- and diffusion-weighted imaging. Quantitative assessments of tone were made serially using a torque apparatus in addition to clinical assessments. Results-Based on the brain apparent diffusion coefficient, 32 minutes of uterine ischemia was selected for E29 fetuses. At E30, 58% of the survivors manifested hind limb hypotonia. By E32, 71% of the hypotonic kits developed dystonic hypertonia. Marked and persistent apparent diffusion coefficient reduction in the basal ganglia, thalamus, and brain stem was predictive of these motor deficits. Conclusions-MRI observation of deep brain injury 6 to 24 hours after near-term hypoxia-ischemia predicts dystonic hypertonia postnatally. Torque-displacement measurements indicate that motor deficits in rabbits progressed from initial hypotonia to hypertonia, similar to human cerebral palsy, but in a compressed timeframe. The presence of deep brain injury and quantitative shift from hypo-to hypertonia may identify patients at risk for developing cerebral palsy. (Stroke. 2012;43:2757-2763.)

Dynamical aspects of atmospheric data assimilation in the tropics

A faithful depiction of the tropical atmosphere requires three-dimensional sets of observations. Despite the increasing amount of observations presently available, these will hardly ever encompass the entire atmosphere and, in addition, observations have errors. Additional (background) information will always be required to complete the picture. Valuable added information comes from the physical laws governing the flow, usually mediated via a numerical weather prediction (NWP) model. These models are, however, never going to be error-free, why a reliable estimate of their errors poses a real challenge since the whole truth will never be within our grasp. The present thesis addresses the question of improving the analysis procedures for NWP in the tropics. Improvements are sought by addressing the following issues: - the efficiency of the internal model adjustment, - the potential of the reliable background-error information, as compared to observations, - the impact of a new, space-borne line-of-sight wind measurements, and - the usefulness of multivariate relationships for data assimilation in the tropics. Most NWP assimilation schemes are effectively univariate near the equator. In this thesis, a multivariate formulation of the variational data assimilation in the tropics has been developed. The proposed background-error model supports the mass-wind coupling based on convectively-coupled equatorial waves. The resulting assimilation model produces balanced analysis increments and hereby increases the efficiency of all types of observations. Idealized adjustment and multivariate analysis experiments highlight the importance of direct wind measurements in the tropics. In particular, the presented results confirm the superiority of wind observations compared to mass data, in spite of the exact multivariate relationships available from the background information. The internal model adjustment is also more efficient for wind observations than for mass data. In accordance with these findings, new satellite wind observations are expected to contribute towards the improvement of NWP and climate modeling in the tropics. Although incomplete, the new wind-field information has the potential to reduce uncertainties in the tropical dynamical fields, if used together with the existing satellite mass-field measurements. The results obtained by applying the new background-error representation to the tropical short-range forecast errors of a state-of-art NWP model suggest that achieving useful tropical multivariate relationships may be feasible within an operational NWP environment.

Design and development of new pressure sensors for aerodynamic applications

This artwork reports on two different projects that were carried out during the three years of Doctor of the Philosophy course. In the first years a project regarding Capacitive Pressure Sensors Array for Aerodynamic Applications was developed in the Applied Aerodynamic research team of the Second Faculty of Engineering, University of Bologna, Forlì, Italy, and in collaboration with the ARCES laboratories of the same university. Capacitive pressure sensors were designed and fabricated, investigating theoretically and experimentally the sensor’s mechanical and electrical behaviours by means of finite elements method simulations and by means of wind tunnel tests. During the design phase, the sensor figures of merit are considered and evaluated for specific aerodynamic applications. The aim of this work is the production of low cost MEMS-alternative devices suitable for a sensor network to be implemented in air data system. The last two year was dedicated to a project regarding Wireless Pressure Sensor Network for Nautical Applications. Aim of the developed sensor network is to sense the weak pressure field acting on the sail plan of a full batten sail by means of instrumented battens, providing a real time differential pressure map over the entire sail surface. The wireless sensor network and the sensing unit were designed, fabricated and tested in the faculty laboratories. A static non-linear coupled mechanical-electrostatic simulation, has been developed to predict the pressure versus capacitance static characteristic suitable for the transduction process and to tune the geometry of the transducer to reach the required resolution, sensitivity and time response in the appropriate full scale pressure input A time dependent viscoelastic error model has been inferred and developed by means of experimental data in order to model, predict and reduce the inaccuracy bound due to the viscolelastic phenomena affecting the Mylar® polyester film used for the sensor diaphragm. The development of the two above mentioned subjects are strictly related but presently separately in this artwork.

Bestimmung der Ionisationsenergie von Actinium und Ultraspurenanalyse von Plutonium mit resonanter Ionisationsmassenspektrometrie (RIMS)

ZusammenfassungDie Resonanzionisationsmassenspektrometrie (RIMS) verbindet hohe Elementselektivität mit guter Nachweiseffizienz. Aufgrund dieser Eigenschaften ist die Methode für Ultraspurenanalyse und Untersuchungen an seltenen oder schwer handhabbaren Elementen gut geeignet. Für RIMS werden neutrale Atome mit monochromatischem Laserlicht ein- oder mehrfach resonant auf energetisch hoch liegende Niveaus angeregt und anschließend durch einen weiteren Laserstrahl oder durch ein elektrisches Feld ionisiert. Die Photoionen werden in einem Massenspektrometer massenselektiv registriert.Ein Beispiel für die Anwendung von RIMS ist die präzise Bestimmung der Ionisationsenergie als fundamentale physikalisch-chemische Eigenschaft eines bestimmten Elements; insbesondere bei den Actinoiden ist die Kenntnis der Ionisationsenergie von Interesse, da es dort bis zur Anwendung der laser-massenspektroskopischer Methode nur wenige experimentelle Daten gab. Die Bestimmung der Ionisationsenergie erfolgt durch die Methode der Photoionisation im elektrischen Feld gemäß dem klassischen Sattelpunktsmodell. Im Experiment werden neutrale Atome in einem Atomstrahl mittels Laserlicht zunächst resonant angeregt. Die angeregten Atome befinden sich in einem äußeren, statischen elektrischen Feld und werden durch einen weiteren Laserstrahl, dessen Wellenlänge durchgestimmt wird, ionisiert. Das Überschreiten der Laserschwelle macht sich durch einen starken Anstieg im Ionensignal bemerkbar. Man führt diese Messung bei verschiedenen elektrischen Feldstärken durch und erhält bei Auftragen der Ionisationsschwellen gegen die Wurzel der elektrischen Feldstärke durch Extrapolation auf die Feldstärke Null die Ionisationsenergie.Im Rahmen dieser Arbeit wurde die Ionisationsenergie von Actinium erstmalig zu 43398(3) cm-1 º 5,3807(4) eV experimentell bestimmt. Dazu wurden Actiniumatome zunächst einstufig resonant mit einem Laser mit einer Wellenlänge von 388,67 nm auf einen Zustand bei 25729,03 cm-1 angeregt und anschließend mit Laserlicht mit einer Wellenlänge von ca. 568 nm ionisiert. Damit sind die Ionisationsenergien aller Actinoiden bis einschließlich Einsteinium mit Ausnahme von Protactinium bekannt. Als Atomstrahlquelle wird ein spezielles 'Sandwichfilament' benutzt, bei dem das Actinoid als Hydroxid auf eine Tantalfolie aufgebracht und mit einer reduzierenden Deckschicht überzogen wird. Das Actinoid dampft bei Heizen dieser Anordnung atomar ab. Bei den schwereren Actinoiden wurde Titan als Deckschicht verwendet. Um einen Actiniumatomstrahl zu erzeugen, wurde aufgrund der hohen Abdampftemperaturen statt Titan erstmals Zirkonium eingesetzt. Bei Protactinium wurde Thorium, welches noch stärkere Reduktionseigenschaften aufweist, als Deckmaterial eingesetzt. Trotzdem gelang es mit der 'Sandwichtechnik' nicht, einen Protactiniumatomstrahl zu erzeugen. In der Flugzeitapparatur wurde lediglich ein Protactinium-monoxidionensignal detektiert. Um ein erst seit kurzem verfügbares Fest-körperlasersystem zu explorieren, wurden zusätzlich noch die bekannten Ionisations-ener-gien von Gadolinium und Plutonium erneut bestimmt. Die gemessenen Werte stimmen mit Literaturdaten gut überein.Ferner wurde noch ein bestehender Trennungsgang für Plutonium aus Umweltproben auf die Matrices Meerwasser und Hausstaub angepasst und für die Bestimmung von Plutonium und dessen Isotopenzusammensetzung in verschiedenen Probenreihen mittels RIMS eingesetzt. Der modifizierte Trennungsgang ermöglicht das schnelle Aufarbeiten von großen Probenmengen für Reihenuntersuchungen von Plutoniumkontaminationen. Die ermittelten Gehalten an 239Pu lagen zwischen 8,2*107 Atome pro 10 l Meerwasserprobe und 1,7*109Atome pro Gramm Staubprobe.

Charakterisierung atherosklerotischer Plaques am Beispiel der A. carotis mittels Histologie, CT und semiautomatischer Farbcodierung

Auf der Suche nach dem „vulnerablen Plaque“, der ein besonders hohes Risiko für Schlaganfall und Herzinfarkt besitzt, findet momentan ein Paradigmenwechsel statt. Anstelle des klassischen Stenosegrades gewinnt die Darstellung der Plaquemorphologie zunehmend an Bedeutung. Fragestellung: Ziel dieser Arbeit ist es, die Fähigkeiten eines modernen 16-Kanal-CT hinsichtlich der Auflösung des Plaqueinneren bei Atherosklerose der Karotiden zu untersuchen und den Halo-Effekt in vivo zu erforschen. Methoden: Für die Studie wurden von 28 Patienten mit bekannter, symptomatischer Karotisstenose vor der gefäßchirurgischen Intervention CT-Bilder angefertigt, die nachfolgend mit der Histologie der Gefäßpräparate korreliert wurden. Auf diese Weise konnten die mikroskopisch identifizierten Lipidkerne im CT-Bild eingezeichnet und hinsichtlich ihrer Fläche und Dichtewerte evaluiert werden. In einem weiteren Schritt führten 2 Radiologen in Unkenntnis der histologischen Ergebnisse unabhängig voneinander eine Befundung durch und markierten mutmaßliche Lipidkerne. Zudem wurden sowohl in der verblindeten als auch in der histologiekontrollierten Auswertung die Plaquetypen anhand der AHA-Klassifikation bestimmt. Ein dritter Befundungsdurchgang geschah unter Zuhilfenahme einer von uns entwickelten Software, die CT-Bilder farbkodiert um die Detektion der Lipidkerne zu verbessern. Anhand der Farbkodierung wurde zudem ein Indexwert errechnet, der eine objektive Zuordnung zur AHA-Klassifikation ermöglichen sollte. Von 6 Patienten wurde zusätzlich noch eine native CT-Aufnahme angefertigt, die durch MPR exakt an die Kontrastmittelserie angeglichen wurde. Auf diese Weise konnte der Halo-Effekt, der die Plaqueanteile im lumennahen Bereich überstrahlt, quantifiziert und charakterisiert werden. Ergebnisse: Während die Einstufung in die AHA-Klassifikation sowohl durch den Befunder als auch durch den Softwarealgorithmus eine hohe Korrelation mit der Histologie aufweist (Typ IV/Va: 89 %, Typ Vb: 70 %, Typ Vc: 89 %, Typ VI: 55 %), ist die Detektion der Lipidkerne in beiden Fällen nicht ausreichend gut und die Befunderabhängigkeit zu groß (Cohens Kappa: 18 %). Eine Objektivierung der AHA-Klassifikation der Plaques durch Indexberechnung nach Farbkodierung scheint möglich, wenn auch dem Befunder nicht überlegen. Die fibröse Kappe kann nicht abgegrenzt werden, da Überstrahlungseffekte des Kontrastmittels dessen HU-Werte verfälschen. Dieser Halo-Effekt zeigte sich im Median 1,1 mm breit mit einer Standardabweichung von 0,38 mm. Eine Abhängigkeit von der Kontrastmitteldichte im Gefäßlumen konnte dabei nicht nachgewiesen werden. Der Halo-Effekt fiel im Median um -106 HU/mm ab, bei einer Standardabweichung von 33 HU/mm. Schlussfolgerung: Die CT-Technologie zeigt sich, was die Darstellung von einzelnen Plaquekomponenten angeht, den bekannten Fähigkeiten der MRT noch unterlegen, insbesondere in Bezug auf die fibröse Kappe. Ihre Fähigkeiten liegen bisher eher in der Einstufung von Plaques in eine grobe Klassifikation, angelehnt an die der AHA. Die klinische Relevanz dessen jedoch gilt es in Zukunft in größeren Studien weiter zu untersuchen. Auch lässt die Weiterentwicklung der Computertomographie auf eine zukünftig höhere Auflösung der Plaquemorphologie hoffen.

Body Mass Index and Cancer Risk: The Evidence for Causal Association

Increased body mass index (BMI), as an approximation of body adiposity, is a risk factor for developing several adult malignancies. To quantify these risks, we reported a comprehensive systematic review (Lancet 2008; 371: 569-78) of prospective observational studies determining associations between BMI and risk of incident cancer for 20 cancer types. We demonstrated that associations are: (i) sex-specific; (ii) exist for a wider range of malignancies than previously thought; and (iii) are broadly consistent across geographic populations. In the present paper, we tested these data against the Bradford-Hill criteria of causal association, and argue that the available data support strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence and probably analogy. However, the experimental evidence supporting reversibility is currently lacking, though indirect evidence from longitudinal data in cohort studies and long-term follow-up post-bariatric surgery is emerging. We additionally assessed these data against appropriate adjustment for available confounding factors; measurement error and study design; and residual confounding; and found lack of alternative explanations. We conclude that there is considerable evidence to support a causal association between BMI and risk for many cancer types, but in order to establish the role of weight control in cancer prevention, there is a need to develop trial frameworks in which to better test reversibility.

The Lower Limb Functional Index: development and clinimetric properties

Background Existing lower-limb, region-specific, patient-reported outcome measures have clinimetric limitations, including limitations in psychometric characteristics (eg, lack of internal consistency, lack of responsiveness, measurement error) and the lack of reported practical and general characteristics. A new patient-reported outcome measure, the Lower Limb Functional Index (LLFI), was developed to address these limitations. Objective The purpose of this study was to overcome recognized deficiencies in existing lower-limb, region-specific, patient-reported outcome measures through: (1) development of a new lower-extremity outcome scale (ie, the LLFI) and (2) evaluation of the clinimetric properties of the LLFI using the Lower Extremity Functional Scale (LEFS) as a criterion measure. Design This was a prospective observational study. Methods The LLFI was developed in a 3-stage process of: (1) item generation, (2) item reduction with an expert panel, and (3) pilot field testing (n=18) for reliability, responsiveness, and sample size requirements for a larger study. The main study used a convenience sample (n=127) from 10 physical therapy clinics. Participants completed the LLFI and LEFS every 2 weeks for 6 weeks and then every 4 weeks until discharge. Data were used to assess the psychometric, practical, and general characteristics of the LLFI and the LEFS. The characteristics also were evaluated for overall performance using the Measurement of Outcome Measures and Bot clinimetric assessment scales. Results The LLFI and LEFS demonstrated a single-factor structure, comparable reliability (intraclass correlation coefficient [2,1]=.97), scale width, and high criterion validity (Pearson r=.88, with 95% confidence interval [CI]). Clinimetric performance was higher for the LLFI compared with the LEFS on the Measurement of Outcome Measures scale (96% and 95%, respectively) and the Bot scale (100% and 83%, respectively). The LLFI, compared with the LEFS, had improved responsiveness (standardized response mean=1.75 and 1.64, respectively), minimal detectable change with 90% CI (6.6% and 8.1%, respectively), and internal consistency (α=.91 and .95, respectively), as well as readability with reduced user error and completion and scoring times. Limitations Limitations of the study were that only participants recruited from outpatient physical therapy clinics were included and that no specific conditions or diagnostic subgroups were investigated. Conclusion The LLFI demonstrated sound clinimetric properties. There was lower response error, efficient completion and scoring, and improved responsiveness and overall performance compared with the LEFS. The LLFI is suitable for assessment of lower-limb function.

First middle-atmospheric zonal wind profile measurements with a new ground-based microwave Doppler-spectro-radiometer

We report on the wind radiometer WIRA, a new ground-based microwave Doppler-spectro-radiometer specifically designed for the measurement of middle-atmospheric horizontal wind by observing ozone emission spectra at 142.17504 GHz. Currently, wind speeds in five levels between 30 and 79 km can be retrieved which makes WIRA the first instrument able to continuously measure horizontal wind in this altitude range. For an integration time of one day the measurement error on each level lies at around 25 m s−1. With a planned upgrade this value is expected to be reduced by a factor of 2 in the near future. On the altitude levels where our measurement can be compared to wind data from the European Centre for Medium-Range Weather Forecasts (ECMWF) very good agreement in the long-term statistics as well as in short time structures with a duration of a few days has been found. WIRA uses a passive double sideband heterodyne receiver together with a digital Fourier transform spectrometer for the data acquisition. A big advantage of the radiometric approach is that such instruments can also operate under adverse weather conditions and thus provide a continuous time series for the given location. The optics enables the instrument to scan a wide range of azimuth angles including the directions east, west, north, and south for zonal and meridional wind measurements. The design of the radiometer is fairly compact and its calibration does not rely on liquid nitrogen which makes it transportable and suitable for campaign use. WIRA is conceived in a way that it can be operated remotely and does hardly require any maintenance. In the present paper, a description of the instrument is given, and the techniques used for the wind retrieval based on the determination of the Doppler shift of the measured atmospheric ozone emission spectra are outlined. Their reliability was tested using Monte Carlo simulations. Finally, a time series of 11 months of zonal wind measurements over Bern (46°57′ N, 7°26′ E) is presented and compared to ECMWF wind data.

Acute respiratory syndrome after inhalation of waterproofing sprays: a posteriori exposure-response assessment in 102 cases

Waterproofing agents are widely used to protect leather and textiles in both domestic and occupational activities. An outbreak of acute respiratory syndrome following exposure to waterproofing sprays occurred during the winter 2002-2003 in Switzerland. About 180 cases were reported by the Swiss Toxicological Information Centre between October 2002 and March 2003, whereas fewer than 10 cases per year had been recorded previously. The reported cases involved three brands of sprays containing a common waterproofing mixture, that had undergone a formulation change in the months preceding the outbreak. A retrospective analysis was undertaken in collaboration with the Swiss Toxicological Information Centre and the Swiss Registries for Interstitial and Orphan Lung Diseases to clarify the circumstances and possible causes of the observed health effects. Individual exposure data were generated with questionnaires and experimental emission measurements. The collected data was used to conduct numeric simulation for 102 cases of exposure. A classical two-zone model was used to assess the aerosol dispersion in the near- and far-field during spraying. The resulting assessed dose and exposure levels obtained were spread on large scales, of several orders of magnitude. No dose-response relationship was found between exposure indicators and health effects indicators (perceived severity and clinical indicators). Weak relationships were found between unspecific inflammatory response indicators (leukocytes, C-reactive protein) and the maximal exposure concentration. The results obtained disclose a high interindividual response variability and suggest that some indirect mechanism(s) predominates in the respiratory disease occurrence. Furthermore, no threshold could be found to define a safe level of exposure. These findings suggest that the improvement of environmental exposure conditions during spraying alone does not constitute a sufficient measure to prevent future outbreaks of waterproofing spray toxicity. More efficient preventive measures are needed prior to the marketing and distribution of new waterproofing agents.

A Data-Analytic Strategy for Protein-Biomarker Discovery: Profiling of High-Dimensional Proteomic Data for Cancer Detection

With recent advances in mass spectrometry techniques, it is now possible to investigate proteins over a wide range of molecular weights in small biological specimens. This advance has generated data-analytic challenges in proteomics, similar to those created by microarray technologies in genetics, namely, discovery of "signature" protein profiles specific to each pathologic state (e.g., normal vs. cancer) or differential profiles between experimental conditions (e.g., treated by a drug of interest vs. untreated) from high-dimensional data. We propose a data analytic strategy for discovering protein biomarkers based on such high-dimensional mass-spectrometry data. A real biomarker-discovery project on prostate cancer is taken as a concrete example throughout the paper: the project aims to identify proteins in serum that distinguish cancer, benign hyperplasia, and normal states of prostate using the Surface Enhanced Laser Desorption/Ionization (SELDI) technology, a recently developed mass spectrometry technique. Our data analytic strategy takes properties of the SELDI mass-spectrometer into account: the SELDI output of a specimen contains about 48,000 (x, y) points where x is the protein mass divided by the number of charges introduced by ionization and y is the protein intensity of the corresponding mass per charge value, x, in that specimen. Given high coefficients of variation and other characteristics of protein intensity measures (y values), we reduce the measures of protein intensities to a set of binary variables that indicate peaks in the y-axis direction in the nearest neighborhoods of each mass per charge point in the x-axis direction. We then account for a shifting (measurement error) problem of the x-axis in SELDI output. After these pre-analysis processing of data, we combine the binary predictors to generate classification rules for cancer, benign hyperplasia, and normal states of prostate. Our approach is to apply the boosting algorithm to select binary predictors and construct a summary classifier. We empirically evaluate sensitivity and specificity of the resulting summary classifiers with a test dataset that is independent from the training dataset used to construct the summary classifiers. The proposed method performed nearly perfectly in distinguishing cancer and benign hyperplasia from normal. In the classification of cancer vs. benign hyperplasia, however, an appreciable proportion of the benign specimens were classified incorrectly as cancer. We discuss practical issues associated with our proposed approach to the analysis of SELDI output and its application in cancer biomarker discovery.

Semiparametric Estimation in General Repeated Measures Problems

This paper considers a wide class of semiparametric problems with a parametric part for some covariate effects and repeated evaluations of a nonparametric function. Special cases in our approach include marginal models for longitudinal/clustered data, conditional logistic regression for matched case-control studies, multivariate measurement error models, generalized linear mixed models with a semiparametric component, and many others. We propose profile-kernel and backfitting estimation methods for these problems, derive their asymptotic distributions, and show that in likelihood problems the methods are semiparametric efficient. While generally not true, with our methods profiling and backfitting are asymptotically equivalent. We also consider pseudolikelihood methods where some nuisance parameters are estimated from a different algorithm. The proposed methods are evaluated using simulation studies and applied to the Kenya hemoglobin data.