Etude des variations saisonnières des crues par le modèle de dépassement

Cet article présente les résultats d'une étude traitant de deux aspects importants de l'application du modèle de dépassement en hydrologie. Ce modèle a été utilisé pour l'étude des variations saisonnieres des débits des rivières du Québec et du Nouveau-Brunswick. Ces variations ont généralement un effet important sur l'homogénéité des débits dans différentes périodes de l'année. Les modèles de dépassement sont capables de prendre ces variations saisonnières en considération en tenant compte des dépassements qui ne sont pas identiquement distribués lorsqu'ils proviennent de différentes saisons. L'étude traite spécialement le problème du choix de saisons à entrer dans le modèle. Particulièrement, on souligne l'importance de déterminer les saisons en se basant sur les données disponibles au lieu de se limiter aux quatre saisons habituelles: hiver, printemps, été et automne. On propose une procédure graphique qui, associée au modèle de dépassement, permet de délimiter les saisons dans les stations hydrologiques étudiées. La procédure est appliquée, sous deux formes différentes, à des stations de jaugeage dans les provinces du Québec et du Nouveau-Brunswick. Ceci nous a permis de diviser l'année convenablement en saisons dans différentes parties des deux provinces. Cette partition a été basée uniquement sur les débits de crues dans chaque station, et sans donner aucune considération à la location géographique de ces stations, mais il s'est avéré ultérieurement que cette subdivision des deux provinces représente en fait une partition géographique des stations hydrologiques.L'évaluation du débit de base représente un point d'une importance majeure dans l'application du modèle de dépassement. Une estimation du débit de base est proposée dans ce travail en utilisant l'analyse de régression multiple. Une approche basée sur l'ajustement du nombre de dépassements à une loi de Poisson a été suivie pour la détermination de ce niveau de base dans chaque station de jaugeage. Une forte corrélation est détectée entre le débit de base et la surface drainée, impliquant qu'il est possible de calculer le débit de base dans une station qui ne contient pas d'enregistrements.Les résultats de la régionalisation géographique de la saisonnalité sont analysés pour détecter et interpréter les liens entre les régions déterminées et les caractéristiques physiques et climatologiques des zones étudiées dans les deux provinces. Une association est démontrée entre ces deux paramètres qui semble être justifiable du point de vu hydrologique et climatologique. En conclusion, les résultats de cet article montrent la faisabilité technique et l'efficacité du modèle proposé pour l'étude des variations saisonnières des crues.The partial duration series (pds) method for flood frequency estimation analyzes ail flood peaks above a certain base level, or truncation level, QB, along with the times of occurrence of these flood « exceedances ». It has been shown that seasonal trends in river-flow processes have a significant effect on the distribution of flood exceedances. Two pds models have been presented in the literature for studying these seasonal variations in flood magnitude. The first, which can be called the « discrete seasonal pds mode) », divides the year into n seasons and determines n different distribution functions to fit the exceedances in each of these n seasons. The second, which can be called the « continuous seasonal pds model », accounts for seasonal flood variations by modeling flood magnitude as a continuous time-dependent random variable. The discrete seasonal model makes a few assumptions concerning flood characteristics, but the statistical estimation of its parameters is considerably less complex than in the case of the continuous seasonal model. Results of a study using the discrete seasonal pds modal are presented in this paper, along with two important applications of this modal in hydrology.The model is applied to 34 gaging stations in the province of Quebec and 28 stations in the province of New-Brunswick, Canada. Knowing the base level, QB, is essential for applying this model, but there is no universal technique for determining this truncation level. In this study, a technique is proposed that uses multiple regression for estimating QB. Regression equations, using one or more transformed or untransformed independent variables, are derived. Results for the province of Quebec show that the two-year flood estimate QDA explains 92.5 % of the variability of the base flow QB, and the drainage basin area SD explains 83 % of QB variability. The existence of a strong correlation between QB and SD suggests that it is possible to determine the base flow at sites where no historical record is available, by using the physical characteristics of the basin.A graphical procedure associated with the partial duration series model is proposed to study the seasonal trends in flood data at the selected gaging stations. The study deals specifically with the choice of seasons to be entered into the pds model. It is particularly emphasized that the seasons should be determined on the basis of the data on band, instead of taking the four usual seasons (winter, spring, summer, and fall). Two different forms of the graphical procedure are applied to the gaging stations in the provinces of Quebec and New Brunswick. The first, applied to the province of Quebec, consists of plotting the mean number of exceedances A (t) in a lime interval (0, 1•] equal 1a one year, against the lime t, for each station, and for a number of increasing base levels. The behavior of these A (1) plots (change at slope, piecewise linearity, etc.) indicates the significant seasons for each station. The second form of the graphical procedure, applied to stations in the province of New-Brunswick, is slightly different front the procedure mentioned above. For each station of the province, a relatively high base level is selected, corresponding to a mean number of exceedances per year in the order of 0.3 to 1.0. The Limes of occurrence of these exceedances are used to define the significant hydrological seasons in the year, which are then presented in graphical form. Varying the base level gives a fine seasonal partitioning of the year for each station, and allows grouping the stations into geographical regions that are homogeneous In seasonal flood distribution. Both versions of the graphical procedure are based on the same idea, and call far careful graphical examination of the seasonal behavior of floods at different gaging stations.An appropriate partitioning of the year into seasons is obtained for different parts of the two provinces. For bath provinces, and for al' the stations that were investigated, no more than two significant seasons were found necessary for modeling seasonal flood variations. Based on the seasons determined for each station, and the geographical distribution of these stations, a geographical regionalization of seasonality Is obtained for the provinces of Quebec and New-Brunswick. Each province is divided into tour homogeneous regions, and appropriate seasons for each region are proposed.The discrete seasonal model was found adequate and sufficient for the study of the seasonal behavior of floods in the provinces of Quebec and New-Brunswick. However, more detailed studios would be necessary to determine with more certitude if the continuous seasonal model is more appropriate in some cases. In all cases, a graphical examination of the empirical distribution function of flood magnitudes occurring in various periods of the year may help either in identifying homogeneous periods within which flood magnitudes may be considered as identically distributed, or In indicating a need for modeling flood magnitude as a random variable whose distribution varies continuously with time

Utilisation de l'information historique en analyse hydrologique fréquentielle

L'utilisation de l'information historique dans une analyse fréquentielle permet de mieux mobiliser l'information réellement disponible et devrait donc permettre d'améliorer l'estimation des quantiles de grande période de retour. Par information historique, on entend ici de l'information relative à des grandes crues qui se sont produites avant le début de la période de mesure (dite période de jaugeage systématique) des niveaux et débits des lacs et rivières. On observe de manière générale que l'utilisation de l'information historique conduit à une diminution de l'impact des valeurs singulières dans les séries d'enregistrements systématiques et à une diminution de l'écart-type des estimations. Dans le présent article on présente les méthodes statistiques qui permettent la modélisation de l'information historique.Use of information about historical floods, i.e. extreme floods that occurred prior to systematic gauging, can often substantially improve the precision of flood quantile estimates. Such information can be retrieved from archives, newspapers, interviews with local residents, or by use of paleohydrologic and dendohydrologic traces. Various statistical techniques for incorporating historical information into frequency analyses are discussed in this review paper. The basic hypothesis in the statistical modeling of historical information is that a certain perception water level exists and that during a given historical period preceding the period of gauging, all exceedances of this level have been recorded, be it in newpapers, in people's memory, or trough traces in the catchment such as sediment deposits or traces on trees. No information is available on floods that did not exceed the perception threshold. It is further assumed that a period of systematic gauging is available. Figure 1 illustrates this situation. The U.S. Water Resources Council (1982) recommended the use of the method of adjusted moments for fitting the log Pearson type III distribution. A weighting factor is applied to the data below the threshold observed during the gauged period to account for the missing data below the threshold in the historical period. Several studies have pointed out that the method of adjusted moments is inefficient. Maximum likelihood estimators based on partially censored data have been shown to be much more efficient and to provide a practical framework for incorporating imprecise and categorical data. Unfortunately, for some of the most common 3-parameter distributions used in hydrology, the maximum likelihood method poses numerical problems. Recently, some authors have proposed use of the method of expected moments, a variant of the method of adjusted moments which gives less weight to observations below the threshold. According to preliminary studies, estimators based on expected moments are almost as efficient as maximum likelihood estimators, but have the advantage of avoiding the numerical problems related to the maximization of likelihood functions. Several studies have emphasized the potential gain in estimation accuracy with the use of historical information. Because historical floods by definition are large, their introduction in a flood frequency analysis can have a major impact on estimates of rare floods. This is particularly true when 3-parameter distributions are considered. Moreover, use of historical information is a means to increase the representativity of a outlier in the systematic data. For example, an extreme outlier will not get the same weight in the analysis if one can state with certainty that it is the largest flood in, say, 200 years, and not only the largest flood in, say, 20 years of systematic gauging.Historical data are generally imprecise, and their inaccuracy should be properly accounted for in the analysis. However, even with substantial uncertainty in the data, the use of historical information is a viable means to improve estimates of rare floods

Revue bibliographique des méthodes de prévision des débits

Dans le domaine de la prévision des débits, une grande variété de méthodes sont disponibles: des modèles stochastiques et conceptuels mais aussi des approches plus novatrices telles que les réseaux de neurones artificiels, les modèles à base de règles floues, la méthode des k plus proches voisins, la régression floue et les splines de régression. Après avoir effectué une revue détaillée de ces méthodes et de leurs applications récentes, nous proposons une classification qui permet de mettre en lumière les différences mais aussi les ressemblances entre ces approches. Elles sont ensuite comparées pour les problèmes différents de la prévision à court, moyen et long terme. Les recommandations que nous effectuons varient aussi avec le niveau d'information a priori. Par exemple, lorsque l'on dispose de séries chronologiques stationnaires de longue durée, nous recommandons l'emploi de la méthode non paramétrique des k plus proches voisins pour les prévisions à court et moyen terme. Au contraire, pour la prévision à plus long terme à partir d'un nombre restreint d'observations, nous suggérons l'emploi d'un modèle conceptuel couplé à un modèle météorologique basé sur l'historique. Bien que l'emphase soit mise sur le problème de la prévision des débits, une grande partie de cette revue, principalement celle traitant des modèles empiriques, est aussi pertinente pour la prévision d'autres variables.A large number of models are available for streamflow forecasting. In this paper we classify and compare nine types of models for short, medium and long-term flow forecasting, according to six criteria: 1. validity of underlying hypotheses, 2. difficulties encountered when building and calibrating the model, 3. difficulties in computing the forecasts, 4. uncertainty modeling, 5. information required by each type of model, and 6. parameter updating. We first distinguish between empirical and conceptual models, the difference being that conceptual models correspond to simplified representations of the watershed, while empirical model only try to capture the structural relationships between inputs to the watershed and outputs, such as streamflow. Amongst empirical models, we distinguish between stochastic models, i.e. models based on the theory of probability, and non-stochastic models. Three types of stochastic models are presented: statistical regression models, Box-Jenkins models, and the nonparametric k-nearest neighbor method. Statistical linear regression is only applicable for long term forecasting (monthly flows, for example), since it requires independent and identically distributed observations. It is a simple method of forecasting, and its hypotheses can be validated a posteriori if sufficient data are available. Box-Jenkins models include linear autoregressive models (AR), linear moving average models (MA), linear autoregressive - moving average models (ARMA), periodic ARMA models (PARMA) and ARMA models with auxiliary inputs (ARMAX). They are more adapted for weekly or daily flow forecasting, since the yallow for the explicit modeling of time dependence. Efficient methods are available for designing the model and updating the parameters as more data become available. For both statistical linear regression and Box-Jenkins models, the inputs must be uncorrelated and linearly related to the output. Furthermore, the process must be stationary. When it is suspected that the inputs are correlated or have a nonlinear effect on the output, the k-nearest neighbor method may be considered. This data-based nonparametric approach simply consists in looking, among past observations of the process, for the k events which are most similar to the present situation. A forecast is then built from the flows which were observed for these k events. Obviously, this approach requires a large database and a stationary process. Furthermore, the time required to calibrate the model and compute the forecasts increases rapidly with the size of the database. A clear advantage of stochastic models is that forecast uncertainty may be quantified by constructing a confidence interval. Three types of non-stochastic empirical models are also discussed: artificial neural networks (ANN), fuzzy linear regression and multivariate adaptive regression splines (MARS). ANNs were originally designed as simple conceptual models of the brain. However, for forecasting purposes, these models can be thought of simply as a subset of non linear empirical models. In fact, the ANN model most commonly used in forecasting, a multi-layer feed-forward network, corresponds to a non linear autoregressive model (NAR). To capture the moving average components of a time series, it is necessary to use recurrent architectures. ANNs are difficult to design and calibrate, and the computation of forecasts is also complex. Fuzzy linear regression makes it possible to extract linear relationships from small data sets, with fewer hypotheses than statistical linear regression. It does not require the observations to be uncorrelated, nor does it ask for the error variance to be homogeneous. However, the model is very sensitive to outliers. Furthermore, a posteriori validation of the hypothesis of linearity is not possible for small data sets. MARS models are based on the hypothesis that time series are chaotic instead of stochastic. The main advantage of the method is its ability to model non-stationary processes. The approach is non-parametric, and therefore requires a large data set.Amongst conceptual models, we distinguish between physical models, hydraulic machines, and fuzzy rule-based systems. Most conceptual hydrologic models are hydraulic machines, in which the watershed is considered to behave like a network of reservoirs. Physical modeling of a watershed would imply using fundamental physical equations at a small scale, such as the law of conservation of mass. Given the complexity of a watershed, this can be done in practice only for water routing. Consequently, only short term flow forecasts can be obtained from a physical model, since the effects of precipitation, infiltration and evaporation must be negligible. Fuzzy rule-based systems make it possible to model the water cycle using fuzzy IF-THEN rules, such as IF it rains a lot in a short period of time, THEN there will be a large flow increase following the concentration time. Each fuzzy quantifier is modeled using a fuzzy number to take into account the uncertainty surrounding it. When sufficient data are available, the fuzzy quantifiers can be constructed from the data. In general, conceptual models require more effort to develop than empirical models. However, for exceptional events, conceptual models can often provide more realistic forecasts, since empirical models are not well suited for extrapolation.A fruitful approach is to combine conceptual and empirical models. One way of doing this, called extended streamflow prediction or ESP, is to combine a stochastic model for generating meteorological scenarios with a conceptual model of the watershed.Based on this review of flow forecasting models, we recommend for short term forecasting (hourly and daily flows) the use of the k-nearest neighbor method, Box-Jenkins models, water routing models or hydraulic machines. For medium term forecasting (weekly flows, for example), we recommend the k-nearest neighbor method and Box-Jenkins models, as well as fuzzy-rule based and ESP models. For long term forecasting (monthly flows), we recommend statistical and fuzzy regression, Box-Jenkins, MARS and ESP models. It is important to choose a type of model which is appropriate for the problem at hand and for which the information available is sufficient. Each type of model having its advantages, it can be more efficient to combine different approaches when forecasting streamflow

Identification d'un réseau hydrométrique pour le suivi des modifications climatiques dans la province de Québec

Depuis une dizaine d'années, la communauté scientifique s'est beaucoup intéressée à l'hypothèse d'un réchauffement à l'échelle planétaire. De nombreuses études ont porté sur l'analyse de ces modifications climatiques éventuelles ainsi que sur la modélisation de leurs impacts sur les ressources en eau. Cependant, malgré l'attention croissante que reçoit le sujet des modifications climatiques, très peu de travail a été accompli pour mettre en place des réseaux de mesure spécialement conçus pour l'étude des modifications climatiques et leurs impacts sur les ressources en eau, et pour créer des bases de données adaptées à cet objectif. Cette tâche est encore plus nécessaire dans le cadre des réductions budgétaires auxquelles sont soumis les réseaux hydrométriques dans certains pays développés. Cet article présente les bases d'une étude dont l'objectif est la conception d'un réseau hydrométrique pour le suivi des modifications climatiques dans la province de Québec, Canada. Le but est d'identifier, afin de les conserver, les stations de jaugeage les plus adéquates pour accomplir cette tâche. L'article présente aussi une brève revue des types de modifications climatiques qui peuvent être observés et de certains tests qui existent pour leur détection et leur quantification. Une procédure bayésienne de détection des sauts de la moyenne a été sélectionnée sur la base de ses avantages théoriques, et appliquée aux séries de données des stations retenues au Québec.The 1980s and 1990s contained most of the warmest years since the beginning of worldwide temperature recording nearly 140 years ago. Widely accepted estimates project that the earth's average temperature might increase by about 2°C over the next 100 years. It is also expected that, as a result of global warming, the frequency and intensity of floods and droughts may change. However, despite the increasing attention that the issue of climate change receives, there has been little effort to develop a systematic approach for the collection of relevant data, and to establish observational networks specifically designed for the analysis of climate variability and change and their impact on hydrologic regimes and water resources in general. This task is particularly important given the major network reductions that result from recent cutbacks in the funding of monitoring programs in Canada and other countries. This paper presents the results of a rigorous study that was carried out recently, and aimed at establishing a hydrometric network for the study of the attributes of climate change and variability across the province of Quebec (Canada) and their impact on water resources. The approach is based on identifying and maintaining stations that can help provide an understanding of the physical processes within the hydrological cycle and account for climate variations across the province. This network will be of fundamental importance in establishing scientific evidence of the magnitude and direction of possible shifts in climate patterns across the province. These aspects are of global significance and must be considered during the rationalization of monitoring networks. The results of the application of this procedure to the hydrometric network of the province of Quebec are presented. The paper presents also a brief review of the various types of non-stationarities that can be observed in hydrologic data series, and some of the current approaches that can be used for the detection of these non-stationarities. Several statistical tests and procedures have been proposed in the literature for the analysis of the characteristics of data samples and for hypothesis testing, for various types of non-stationarity. A Bayesian procedure, proposed by Lee and Heghinian (1977) and generalized by Bernier (1994), for the detection of shifts in the mean of hydrological and meteorological time-series is selected based on its theoretical advantages (Faucher et al., 1997). The procedure is then applied for the analysis of all streamflow series of selected stations in the province of Quebec with the objective of extracting information on possible climatic changes. Results indicate the presence of significant non-stationarities for a number of the series analyzed. For five stations, the most probable date for the shift in the mean level falls in the period 1983-1985. Recommandations are made for future research activities

Musical hallucinations, secondary delusions, and lack of insight:results from a cohort study

Introduction: Although musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities. Methods: The present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing. Results: Five patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions. Conclusion: The pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount.</p

Musical hallucinations, secondary delusions, and lack of insight:results from a cohort study

Introduction: Although musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities. Methods: The present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing. Results: Five patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions. Conclusion: The pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount.</p

Musical hallucinations, secondary delusions, and lack of insight:results from a cohort study

Introduction: Although musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities. Methods: The present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing. Results: Five patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions. Conclusion: The pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount.</p

Musical hallucinations, secondary delusions, and lack of insight: results from a cohort study

IntroductionAlthough musical hallucinations do not tend to be accompanied by delusions, occasionally patients persistently accuse others of being responsible for causing the music they perceive, sometimes with severe social consequences such as frequently calling the police or moving house. In this study we seek to broaden our understanding of this rare type of musical hallucination that comes with secondary delusions and lack of insight, and to explore associations, underlying mechanisms, and treatment possibilities.MethodsThe present study is part of a cohort study on musical hallucinations carried out in the Netherlands from 2010 through 2023. Participants underwent testing with the aid of the MuHa Questionnaire, Launay-Slade Hallucinations Scale (LSHS), Schizotypal Personality Questionnaire (SPQ), Hamilton Depression Rating Scale (HDRS), and Mini Mental State Examination (MMSE). Additionally, they underwent a brain MRI, electroencephalogram, and audiological testing.ResultsFive patients out of a group of N = 81 (6%) lacked insight and presented with secondary delusions regarding the perceived music. They were all female, of advanced age, and hearing-impaired, and were diagnosed with cognitive impairment. In three patients (60%), risperidone was started. This had a positive effect on the hallucinations and secondary delusions.ConclusionThe pathophysiological process underlying musical hallucinations is multifactorial in nature. We consider cognitive impairment the most likely contributing factor of the secondary delusions and lack of insight encountered in our patients, and antipsychotics the most beneficial treatment. On the basis of these small numbers, no definite conclusions can be drawn, so further research is needed to elucidate the underlying mechanisms and to develop evidence-based treatment methods for people experiencing this rare and debilitating combination of symptoms. Since the black box warning of risperidone cautions against the use of this drug in elderly persons with dementia, a proper comparison with the efficacy and safety of other antipsychotics for this group is paramount

Over-Expression of DSCAM and COL6A2 Cooperatively Generates Congenital Heart Defects

A significant current challenge in human genetics is the identification of interacting genetic loci mediating complex polygenic disorders. One of the best characterized polygenic diseases is Down syndrome (DS), which results from an extra copy of part or all of chromosome 21. A short interval near the distal tip of chromosome 21 contributes to congenital heart defects (CHD), and a variety of indirect genetic evidence suggests that multiple candidate genes in this region may contribute to this phenotype. We devised a tiered genetic approach to identify interacting CHD candidate genes. We first used the well vetted Drosophila heart as an assay to identify interacting CHD candidate genes by expressing them alone and in all possible pairwise combinations and testing for effects on rhythmicity or heart failure following stress. This comprehensive analysis identified DSCAM and COL6A2 as the most strongly interacting pair of genes. We then over-expressed these two genes alone or in combination in the mouse heart. While over-expression of either gene alone did not affect viability and had little or no effect on heart physiology or morphology, co-expression of the two genes resulted in ≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy. Cooperative interactions between DSCAM and COL6A2 were also observed in the H9C2 cardiac cell line and transcriptional analysis of this interaction points to genes involved in adhesion and cardiac hypertrophy. Our success in defining a cooperative interaction between DSCAM and COL6A2 suggests that the multi-tiered genetic approach we have taken involving human mapping data, comprehensive combinatorial screening in Drosophila, and validation in vivo in mice and in mammalian cells lines should be applicable to identifying specific loci mediating a broad variety of other polygenic disorders

Chronic Hypoxia Impairs Muscle Function in the Drosophila Model of Duchenne's Muscular Dystrophy (DMD)

Duchenne's muscular dystrophy (DMD) is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH). To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys) to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level). Additionally, dmDys and wild type (WT) flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins) were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys). These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s) and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s) to hypoxia may offer a novel therapeutic strategy in DMD