Anthropometric indicators of nutritional status and growth in very low birth-weight premature infants hospitalized in a neonatal intensive care unit

Background: Anthropometric indicators are difficult to interpret in very low birth weight (VLBW) premature infants, including both appropriate for gestational age (AGA) and small for gestational age (SGA) infants. Therefore, the purpose was to describe the anthropometric indicators of growth and nutritional status in VLBW premature infants AGA and SGA, hospitalized in a neonatal intensive care unit (NICU). Study design: The descriptive and prospective study design included 114 preterm infants, adequate for gestational age/small for gestational age hospitalized in the intensive care unit. Head, thigh, mid upper arm circumference, skin-fold measurements and weight/age, length/ age, and weight/length indices were obtained. Correlations were made among the anthropometric indices, and a multivariate regression analysis with weight/age as dependent variable was performed. Results: Weight/age in AGA premature infants had high number of significant anthropometric correlations. The SGA premature infants had few and weak correlations. The regression analysis showed that anthropometric indices better explain changes in the weight/age index in adequate for gestational age premature infants. Conclusion: Weight/age in the VLBW/AGA premature infants could reflect growth, nutritional status and energy stored as fat, but in the VLBW/SGA premature infants, thigh circumference and mid arm circumference would be better indicators just of nutritional status.

Movement Sonification: Effects on Motor Learning beyond Rhythmic Adjustments

Motor learning is based on motor perception and emergent perceptual-motor representations. A lot of behavioral research is related to single perceptual modalities but during last two decades the contribution of multimodal perception on motor behavior was discovered more and more. A growing number of studies indicates an enhanced impact of multimodal stimuli on motor perception, motor control and motor learning in terms of better precision and higher reliability of the related actions. Behavioral research is supported by neurophysiological data, revealing that multisensory integration supports motor control and learning. But the overwhelming part of both research lines is dedicated to basic research. Besides research in the domains of music, dance and motor rehabilitation, there is almost no evidence for enhanced effectiveness of multisensory information on learning of gross motor skills. To reduce this gap, movement sonification is used here in applied research on motor learning in sports. Based on the current knowledge on the multimodal organization of the perceptual system, we generate additional real-time movement information being suitable for integration with perceptual feedback streams of visual and proprioceptive modality. With ongoing training, synchronously processed auditory information should be initially integrated into the emerging internal models, enhancing the efficacy of motor learning. This is achieved by a direct mapping of kinematic and dynamic motion parameters to electronic sounds, resulting in continuous auditory and convergent audiovisual or audio-proprioceptive stimulus arrays. In sharp contrast to other approaches using acoustic information as error-feedback in motor learning settings, we try to generate additional movement information suitable for acceleration and enhancement of adequate sensorimotor representations and processible below the level of consciousness. In the experimental setting, participants were asked to learn a closed motor skill (technique acquisition of indoor rowing). One group was treated with visual information and two groups with audiovisual information (sonification vs. natural sounds). For all three groups learning became evident and remained stable. Participants treated with additional movement sonification showed better performance compared to both other groups. Results indicate that movement sonification enhances motor learning of a complex gross motor skill-even exceeding usually expected acoustic rhythmic effects on motor learning.

Development of novel therapeutics and in vitro models for spinal cord injury

Spinal cord injury (SCI) is a devastating condition, which results from trauma to the cord, resulting in a primary injury response which leads to a secondary injury cascade, causing damage to both glial and neuronal cells. Following trauma, the central nervous system (CNS) fails to regenerate due to a plethora of both intrinsic and extrinsic factors. Unfortunately, these events lead to loss of both motor and sensory function and lifelong disability and care for sufferers of SCI. There have been tremendous advancements made in our understanding of the mechanisms behind axonal regeneration and remyelination of the damaged cord. These have provided many promising therapeutic targets. However, very few have made it to clinical application, which could potentially be due to inadequate understanding of compound mechanism of action and reliance on poor SCI models. This thesis describes the use of an established neural cell co-culture model of SCI as a medium throughput screen for compounds with potential therapeutic properties. A number of compounds were screened which resulted in a family of compounds, modified heparins, being taken forward for more intense investigation. Modified heparins (mHeps) are made up of the core heparin disaccharide unit with variable sulphation groups on the iduronic acid and glucosamine residues; 2-O-sulphate (C2), 6-O-sulphate (C6) and N-sulphate (N). 2-O-sulphated (mHep6) and N-sulphated (mHep7) heparin isomers were shown to promote both neurite outgrowth and myelination in the SCI model. It was found that both mHeps decreased oligodendrocyte precursor cell (OPC) proliferation and increased oligodendrocyte (OL) number adjacent to the lesion. However, there is a difference in the direct effects on the OL from each of the mHeps; mHep6 increased myelin internode length and mHep7 increased the overall cell size. It was further elucidated that these isoforms interact with and mediate both Wnt and FGF signalling. In OPC monoculture experiments FGF2 treated OPCs displayed increased proliferation but this effect was removed when co-treated with the mHeps. Therefore, suggesting that the mHeps interact with the ligand and inhibit FGF2 signalling. Additionally, it was shown that both mHeps could be partially mediating their effects through the Wnt pathway. mHep effects on both myelination and neurite outgrowth were removed when co-treated with a Wnt signalling inhibitor, suggesting cell signalling mediation by ligand immobilisation and signalling activation as a mechanistic action for the mHeps. However, the initial methods employed in this thesis were not sufficient to provide a more detailed study into the effects the mHeps have on neurite outgrowth. This led to the design and development of a novel microfluidic device (MFD), which provides a platform to study of axonal injury. This novel device is a three chamber device with two chambers converging onto a central open access chamber. This design allows axons from two points of origin to enter a chamber which can be subjected to injury, thus providing a platform in which targeted axonal injury and the regenerative capacity of a compound study can be performed. In conclusion, this thesis contributes to and advances the study of SCI in two ways; 1) identification and investigation of a novel set of compounds with potential therapeutic potential i.e. desulphated modified heparins. These compounds have multiple therapeutic properties and could revolutionise both the understanding of the basic pathological mechanisms underlying SCI but also be a powered therapeutic option. 2) Development of a novel microfluidic device to study in greater detail axonal biology, specifically, targeted axonal injury and treatment, providing a more representative model of SCI than standard in vitro models. Therefore, the MFD could lead to advancements and the identification of factors and compounds relating to axonal regeneration.

Risk perception and correlates of alcohol use among out-of-school youth in motor parks in Lagos State, Nigeria

Background and Aim: The prevalence of alcohol use has increased globally. Out-of-school youth are a vulnerable group who might have missed opportunities for learning healthy behaviours in a formal school environment. The purpose of this study was to determine the risk perception, pattern of use, and correlates of alcohol use among out-of-school youth in Lagos, Nigeria. Methods: A cross-sectional study was conducted among 380 out-of-school youth in motor parks in Lagos State, Nigeria, using interviewer administered questionnaires. Results: The lifetime prevalence of alcohol use was 61.1%, while 55.5% were current drinkers. Beer (57.3%) was the most consumed type of alcohol, followed by distilled spirits (29.8%). Using the CAGE scoring system, more than half (57.8%) of the current drinkers had a drinking problem. Almost three quarters (70.1%) had experienced at least one episode of alcohol intoxication within the past month. A considerable number of current drinkers (63.5%) desired to reduce their alcohol intake or stop drinking, while 45.5% had made unsuccessful attempts to do so within the past year. Only 28.9% had received assistance to quit or reduce their drinking and of these less than half (39.3%) received assistance from a professional or healthcare worker. Males were more likely to be current drinkers and to have experienced episodes of alcohol intoxication. Parental and peer drinking were associated with alcohol use but not with intoxication. Conclusions: It is important to design specific programmes to reduce alcohol use among out-of-school youth in these settings.

Outcome Prediction of Consciousness Disorders in the Acute Stage Based on a Complementary Motor Behavioural Tool.

INTRODUCTION: Attaining an accurate diagnosis in the acute phase for severely brain-damaged patients presenting Disorders of Consciousness (DOC) is crucial for prognostic validity; such a diagnosis determines further medical management, in terms of therapeutic choices and end-of-life decisions. However, DOC evaluation based on validated scales, such as the Revised Coma Recovery Scale (CRS-R), can lead to an underestimation of consciousness and to frequent misdiagnoses particularly in cases of cognitive motor dissociation due to other aetiologies. The purpose of this study is to determine the clinical signs that lead to a more accurate consciousness assessment allowing more reliable outcome prediction. METHODS: From the Unit of Acute Neurorehabilitation (University Hospital, Lausanne, Switzerland) between 2011 and 2014, we enrolled 33 DOC patients with a DOC diagnosis according to the CRS-R that had been established within 28 days of brain damage. The first CRS-R assessment established the initial diagnosis of Unresponsive Wakefulness Syndrome (UWS) in 20 patients and a Minimally Consciousness State (MCS) in the remaining13 patients. We clinically evaluated the patients over time using the CRS-R scale and concurrently from the beginning with complementary clinical items of a new observational Motor Behaviour Tool (MBT). Primary endpoint was outcome at unit discharge distinguishing two main classes of patients (DOC patients having emerged from DOC and those remaining in DOC) and 6 subclasses detailing the outcome of UWS and MCS patients, respectively. Based on CRS-R and MBT scores assessed separately and jointly, statistical testing was performed in the acute phase using a non-parametric Mann-Whitney U test; longitudinal CRS-R data were modelled with a Generalized Linear Model. RESULTS: Fifty-five per cent of the UWS patients and 77% of the MCS patients had emerged from DOC. First, statistical prediction of the first CRS-R scores did not permit outcome differentiation between classes; longitudinal regression modelling of the CRS-R data identified distinct outcome evolution, but not earlier than 19 days. Second, the MBT yielded a significant outcome predictability in the acute phase (p<0.02, sensitivity>0.81). Third, a statistical comparison of the CRS-R subscales weighted by MBT became significantly predictive for DOC outcome (p<0.02). DISCUSSION: The association of MBT and CRS-R scoring improves significantly the evaluation of consciousness and the predictability of outcome in the acute phase. Subtle motor behaviour assessment provides accurate insight into the amount and the content of consciousness even in the case of cognitive motor dissociation.

Genome-Wiide estimates of coancestry, in breeding and effective population size in the Spanish Holstein population

Estimates of effective population size in the Holstein cattle breed have usually been low despite the large number of animals that constitute this breed. Effective population size is inversely related to the rates at which coancestry and inbreeding increase and these rates have been high as a consequence of intense and accurate selection. Traditionally, coancestry and inbreeding coefficients have been calculated from pedigree data. However, the development of genome-wide single nucleotide polymorphisms has increased the interest of calculating these coefficients from molecular data in order to improve their accuracy. In this study, genomic estimates of coancestry, inbreeding and effective population size were obtained in the Spanish Holstein population and then compared with pedigree-based estimates. A total of 11,135 animals genotyped with the Illumina BovineSNP50 BeadChip were available for the study. After applying filtering criteria, the final genomic dataset included 36,693 autosomal SNPs and 10,569 animals. Pedigree data from those genotyped animals included 31,203 animals. These individuals represented only the last five generations in order to homogenise the amount of pedigree information across animals. Genomic estimates of coancestry and inbreeding were obtained from identity by descent segments (coancestry) or runs of homozygosity (inbreeding). The results indicate that the percentage of variance of pedigree-based coancestry estimates explained by genomic coancestry estimates was higher than that for inbreeding. Estimates of effective population size obtained from genome-wide and pedigree information were consistent and ranged from about 66 to 79. These low values emphasize the need of controlling the rate of increase of coancestry and inbreeding in Holstein selection programmes.

POSE ESTIMATION AND 3D RECONSTRUCTION USING SENSOR FUSION

A camera maps 3-dimensional (3D) world space to a 2-dimensional (2D) image space. In the process it loses the depth information, i.e., the distance from the camera focal point to the imaged objects. It is impossible to recover this information from a single image. However, by using two or more images from different viewing angles this information can be recovered, which in turn can be used to obtain the pose (position and orientation) of the camera. Using this pose, a 3D reconstruction of imaged objects in the world can be computed. Numerous algorithms have been proposed and implemented to solve the above problem; these algorithms are commonly called Structure from Motion (SfM). State-of-the-art SfM techniques have been shown to give promising results. However, unlike a Global Positioning System (GPS) or an Inertial Measurement Unit (IMU) which directly give the position and orientation respectively, the camera system estimates it after implementing SfM as mentioned above. This makes the pose obtained from a camera highly sensitive to the images captured and other effects, such as low lighting conditions, poor focus or improper viewing angles. In some applications, for example, an Unmanned Aerial Vehicle (UAV) inspecting a bridge or a robot mapping an environment using Simultaneous Localization and Mapping (SLAM), it is often difficult to capture images with ideal conditions. This report examines the use of SfM methods in such applications and the role of combining multiple sensors, viz., sensor fusion, to achieve more accurate and usable position and reconstruction information. This project investigates the role of sensor fusion in accurately estimating the pose of a camera for the application of 3D reconstruction of a scene. The first set of experiments is conducted in a motion capture room. These results are assumed as ground truth in order to evaluate the strengths and weaknesses of each sensor and to map their coordinate systems. Then a number of scenarios are targeted where SfM fails. The pose estimates obtained from SfM are replaced by those obtained from other sensors and the 3D reconstruction is completed. Quantitative and qualitative comparisons are made between the 3D reconstruction obtained by using only a camera versus that obtained by using the camera along with a LIDAR and/or an IMU. Additionally, the project also works towards the performance issue faced while handling large data sets of high-resolution images by implementing the system on the Superior high performance computing cluster at Michigan Technological University.

Splitting of a prevalent Mycobacterium bovis spoligotype by variable-number tandem-repeat typing reveals high heterogeneity in an evolving clonal group

Mycobacterium bovis populations in countries with persistent bovine tuberculosis usually show a prevalent spoligotype with a wide geographical distribution. This study applied mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) typing to a random panel of 115 M. bovis isolates that are representative of the most frequent spoligotype in the Iberian Peninsula, SB0121. VNTR typing targeted nine loci: ETR-A (alias VNTR2165), ETR-B (VNTR2461), ETR-D (MIRU4, VNTR580), ETR-E (MIRU31, VNTR3192), MIRU26 (VNTR2996), QUB11a (VNTR2163a), QUB11b (VNTR2163b), QUB26 (VNTR4052), and QUB3232 (VNTR3232). We found a high degree of diversity among the studied isolates (discriminatory index [D] = 0.9856), which were split into 65 different MIRU-VNTR types. An alternative short-format MIRU-VNTR typing targeting only the four loci with the highest variability values was found to offer an equivalent discriminatory index. Minimum spanning trees using the MIRU-VNTR data showed the hypothetical evolution of an apparent clonal group. MIRU-VNTR analysis was also applied to the isolates of 176 animals from 15 farms infected by M. bovis SB0121; in 10 farms, the analysis revealed the coexistence of two to five different MIRU types differing in one to six loci, which highlights the frequency of undetected heterogeneity.

Occurrence of Mycobacterium avium subspecies paratuberculosis across host species and European countries with evidence for transmission between wildlife and domestic ruminants

BACKGROUND Mycobacterium avium subspecies paratuberculosis (Map) causes an infectious chronic enteritis (paratuberculosis or Johne's disease) principally of ruminants. The epidemiology of Map is poorly understood, particularly with respect to the role of wildlife reservoirs and the controversial issue of zoonotic potential (Crohn's disease). Genotypic discrimination of Map isolates is pivotal to descriptive epidemiology and resolving these issues. This study was undertaken to determine the genetic diversity of Map, enhance our understanding of the host range and distribution and assess the potential for interspecies transmission. RESULTS 164 Map isolates from seven European countries representing 19 different host species were genotyped by standardized IS900--restriction fragment length polymorphism (IS900-RFLP), pulsed-field gel electrophoresis (PFGE), amplified fragment length polymorphisms (AFLP) and mycobacterial interspersed repeat unit-variable number tandem repeat (MIRU-VNTR) analyses. Six PstI and 17 BstEII IS900-RFLP, 31 multiplex [SnaBI-SpeI] PFGE profiles and 23 MIRU-VNTR profiles were detected. AFLP gave insufficient discrimination of isolates for meaningful genetic analysis. Point estimates for Simpson's index of diversity calculated for the individual typing techniques were in the range of 0.636 to 0.664 but a combination of all three methods increased the discriminating power to 0.879, sufficient for investigating transmission dynamics. Two predominant strain types were detected across Europe with all three typing techniques. Evidence for interspecies transmission between wildlife and domestic ruminants on the same property was demonstrated in four cases, between wildlife species on the same property in two cases and between different species of domestic livestock on one property. CONCLUSION The results of this study showed that it is necessary to use multiple genotyping techniques targeting different sources of genetic variation to obtain the level of discrimination necessary to investigate transmission dynamics and trace the source of Map infections. Furthermore, the combination of genotyping techniques may depend on the geographical location of the population to be tested. Identical genotypes were obtained from Map isolated from different host species co-habiting on the same property strongly suggesting that interspecies transmission occurs. Interspecies transmission of Map between wildlife species and domestic livestock on the same property provides further evidence to support a role for wildlife reservoirs of infection.

Detectability of migrating raptors and its effect on bias and precision of trend estimates

Annual counts of migrating raptors at fixed observation points are a widespread practice, and changes in numbers counted over time, adjusted for survey effort, are commonly used as indices of trends in population size. Unmodeled year-to-year variation in detectability may introduce bias, reduce precision of trend estimates, and reduce power to detect trends. We conducted dependent double-observer surveys at the annual fall raptor migration count at Lucky Peak, Idaho, in 2009 and 2010 and applied Huggins closed-capture removal models and information-theoretic model selection to determine the relative importance of factors affecting detectability. The most parsimonious model included effects of observer team identity, distance, species, and day of the season. We then simulated 30 years of counts with heterogeneous individual detectability, a population decline (λ = 0.964), and unexplained random variation in the number of available birds. Imperfect detectability did not bias trend estimation, and increased the time required to achieve 80% power by less than 11%. Results suggested that availability is a greater source of variance in annual counts than detectability; thus, efforts to account for availability would improve the monitoring value of migration counts. According to our models, long-term trends in observer efficiency or migratory flight distance may introduce substantial bias to trend estimates. Estimating detectability with a novel count protocol like our double-observer method is just one potential means of controlling such effects. The traditional approach of modeling the effects of covariates and adjusting the index may also be effective if ancillary data is collected consistently.

Use of bird carcass removals by urban scavengers to adjust bird-window collision estimates

Carcass removal by scavengers has been identified as one of the largest biases in estimating bird mortality from anthropogenic sources. Only two studies have examined carcass removal by scavengers in an urban environment, and previous estimates of bird-window collision mortality at houses have relied on carcass removal rates from wind turbine studies. We placed a bird carcass and time-lapse camera at 44 houses in Edmonton, Alberta. In total, 166 7-day trials were conducted throughout 2015. Time-to-event (survival) analysis was used to identify covariates that affected removal. The carcass removal rate was determined for use in estimating the number of birds killed from bird-window collisions at houses in Alberta. In total, 67.5% of carcasses were removed. The date the carcass was placed, the year the house was built, and the level of development within 50 m of the house were the covariates that had the largest effect on carcass removal. In calculating our removal rate, the number of detected carcasses in the first 24 hours was adjusted by 1.47 to account for removal by scavengers. Previously collected citizen science data were used to create an estimate of 957,440 bird deaths each year in Alberta as a result of bird-window collisions with houses. This number is based on the most detailed bird-window collision study at houses to date and a carcass removal study conducted in the same area. Similar localized studies across Canada will need to be completed to reduce the biases that exist with the previous bird-window collision mortality estimate for houses in Canada.

Ordonnancement des opérations dans une unité d’extrusion

Les travaux de ce mémoire traitent du problème d’ordonnancement et d’optimisation de la production dans un environnement de plusieurs machines en présence de contraintes sur les ressources matérielles dans une usine d’extrusion plastique. La minimisation de la somme pondérée des retards est le critère économique autour duquel s’articule cette étude car il représente un critère très important pour le respect des délais. Dans ce mémoire, nous proposons une approche exacte via une formulation mathématique capable des donner des solutions optimales et une approche heuristique qui repose sur deux méthodes de construction de solution sérielle et parallèle et un ensemble de méthodes de recherche dans le voisinage (recuit-simulé, recherche avec tabous, GRASP et algorithme génétique) avec cinq variantes de voisinages. Pour être en totale conformité avec la réalité de l’industrie du plastique, nous avons pris en considération certaines caractéristiques très fréquentes telles que les temps de changement d’outils sur les machines lorsqu’un ordre de fabrication succède à un autre sur une machine donnée. La disponibilité des extrudeuses et des matrices d’extrusion représente le goulot d’étranglement dans ce problème d’ordonnancement. Des séries d’expérimentations basées sur des problèmes tests ont été effectuées pour évaluer la qualité de la solution obtenue avec les différents algorithmes proposés. L’analyse des résultats a démontré que les méthodes de construction de solution ne sont pas suffisantes pour assurer de bons résultats et que les méthodes de recherche dans le voisinage donnent des solutions de très bonne qualité. Le choix du voisinage est important pour raffiner la qualité de la solution obtenue. Mots-clés : ordonnancement, optimisation, extrusion, formulation mathématique, heuristique, recuit-simulé, recherche avec tabous, GRASP, algorithme génétique

Registro de pacientes con distrofinopatías en Colombia

INTRODUCCIÓN. La distrofia muscular de Duchenne es una enfermedad neuromuscular con una herencia recesiva ligada al X que afecta a 1 de cada 3500 niños nacidos vivos. Se produce por mutaciones en el gen DMD que codifica para la distrofina. Se caracteriza por manifestaciones clínicas variables típicas de una distrofia muscular proximal progresiva. OBJETIVO. Realizar el primer registro en Colombia de los pacientes identificados con distrofinopatías, teniendo en cuenta características clínicas y paraclínicas, así como las mutaciones causales de esta patología. METODOLOGÍA Es un estudio descriptivo, transversal, de la revisión de historias clínicas de los pacientes con diagnóstico de DMD atendidos en la consulta de Genética de la Universidad del Rosario durante los años 2006 a 2015. RESULTADOS Se identificaron 99 pacientes, de los cuales 56 (56,56%) corresponden al fenotipo Duchenne y 12 (12,12%) al Becker. No fue posible clasificar a 31 pacientes (31,3%) por falta de datos clínicos. La edad de inicio de los síntomas fue en promedio de 4,41 años. Las mutaciones más frecuentes fueron las deleciones (69%), seguidas por las mutaciones puntuales(14%), las duplicaciones (11%) y por otras mutaciones (4%). CONCLUSIONES Este registro de distrofinopatías es el primero reportado en Colombia y el punto de partida para conocer la incidencia de la enfermedad, caracterización clínica y molecular de los pacientes, garantizando así el acceso oportuno a los nuevos tratamientos de medicina de precisión que permitan mejorar la calidad de vida de los pacientes y sus familias.

Modeling, Component Selection and Optimization of Servo-controlled Automatic Machinery

A servo-controlled automatic machine can perform tasks that involve synchronized actuation of a significant number of servo-axes, namely one degree-of-freedom (DoF) electromechanical actuators. Each servo-axis comprises a servo-motor, a mechanical transmission and an end-effector, and is responsible for generating the desired motion profile and providing the power required to achieve the overall task. The design of a such a machine must involve a detailed study from a mechatronic viewpoint, due to its electric and mechanical nature. The first objective of this thesis is the development of an overarching electromechanical model for a servo-axis. Every loss source is taken into account, be it mechanical or electrical. The mechanical transmission is modeled by means of a sequence of lumped-parameter blocks. The electric model of the motor and the inverter takes into account winding losses, iron losses and controller switching losses. No experimental characterizations are needed to implement the electric model, since the parameters are inferred from the data available in commercial catalogs. With the global model at disposal, a second objective of this work is to perform the optimization analysis, in particular, the selection of the motor-reducer unit. The optimal transmission ratios that minimize several objective functions are found. An optimization process is carried out and repeated for each candidate motor. Then, we present a novel method where the discrete set of available motor is extended to a continuous domain, by fitting manufacturer data. The problem becomes a two-dimensional nonlinear optimization subject to nonlinear constraints, and the solution gives the optimal choice for the motor-reducer system. The presented electromechanical model, along with the implementation of optimization algorithms, forms a complete and powerful simulation tool for servo-controlled automatic machines. The tool allows for determining a wide range of electric and mechanical parameters and the behavior of the system in different operating conditions.

TiMMing: developing an innovative suite of bioinformatic tools to harmonize and track the origin of copy number alterations in the evolutive history of multiple myeloma

Multiple Myeloma (MM) is a hematologic cancer with heterogeneous and complex genomic landscape, where Copy Number Alterations (CNAs) play a key role in the disease's pathogenesis and prognosis. It is of biological and clinical interest to study the temporal occurrence of early alterations, as they play a disease "driver" function by deregulating key tumor pathways. This study presents an innovative bioinformatic tools suite created for harmonizing and tracing the origin of CNAs throughout the evolutionary history of MM. To this aim, large cohorts of newly-diagnosed MM (NDMM, N=1582) and Smoldering-MM (SMM, N=282) were aggregated. The tools developed in this study enable the harmonization of CNAs as obtained from different genomic platforms in such a way that a high statistical power can be obtained. By doing so, the high numerosity of those cohorts was harnessed for the identification of novel genes characterized as "driver" (NFKB2, NOTCH2, MAX, EVI5 and MYC-ME2-enhancer), and the generation of an innovative timing model, implemented with a statistical method to introduce confidence intervals in the CNAs-calls. By applying this model on both NDMM and SMM cohorts, it was possible to identify specific CNAs (1q(CKS1B)amp, 13q(RB1)del, 11q(CCND1)amp and 14q(MAX)del) and categorize them as "early"/ "driver" events. A high level of precision was guaranteed by the narrow confidence intervals in the timing estimates. These CNAs were proposed as critical MM alterations, which play a foundational role in the evolutionary history of both SMM and NDMM. Finally, a multivariate survival model was able to identify the independent genomic alterations with the greatest effect on patients’ survival, including RB1-del, CKS1B-amp, MYC-amp, NOTCH2-amp and TRAF3-del/mut. In conclusion, the alterations that were identified as both "early-drivers” and correlated with patients’ survival were proposed as biomarkers that, if included in wider survival models, could provide a better disease stratification and an improved prognosis definition.