Дисертації з теми "Subgroups Identification"

Borderline personality disorder (BPD) is a complex psychiatric condition whose severity is compounded by the heterogeneous psychological functioning of those who suffer from the disorder. This heterogeneity has made the identification of a unified treatment strategy difficult and attempts to resolve this variation within the disorder by investigating subtypes of BPD have been made. However, the clinical utility of this approach has not been examined. The major object of this research project was to investigate the presence of subtypes of BPD and to examine whether treatment effectiveness varied as a function of subtype. Data from 61, predominantly female, participants with BPD were entered into a cluster analysis. Using variables that are central to cognitive behavioural models of BPD and have been shown to be heterogeneously distributed in previous BPD samples, two subgroups were identified and defined on the basis of whether participants attributed the causes o f negative events as being themselves or other people. Consistent with hypotheses, the subgroup with a tendency to blame others for negative events showed far lower levels of change between admission and discharge than the subgroup who blamed themselves for negative events, on both measures of statistical and clinical significance. Alternate means of identifying participants who optimally responded to the intervention were explored and a cluster analysis identified two groups of participants that were separated on the basis of whether they had shown clinically significant change on a range of variables. It was found that data from admission to the program could successfully predict which participants would belong in the optimal or mixed response groups upon discharge. Taken together, the findings of this research project suggest that not only can theoretically valid subgroups of BPD be identified, but that they have clinical utility in understanding participants' response to intervention. Further, the findi ngs suggest that profiles of clinical change can be identified and predicted. The findings of this research project are discussed with respect to their methodological limitations, suggestions for future research, and their implications for both theory and practice.

In obesity research, it is assumed that the population is homogeneous. While this approach has yielded important insights, testing this supposition might reveal information that could impact our understanding of the phenomena and its treatment. In this study, data from obese teenagers (N = 248, Mean BMI percentile = 99%; Mean age = 13.9, SD = 1.8) who were predominantly minority (n = 182), female (n = 169), and enrolled in a weight loss intervention were analyzed. Latent profile analysis (LPA) was used to segment patients into groups based on their scores on PedsQL 4.0 scales (physical-, emotional-, social-, and school functioning) and the Coopersmith Self-Esteem Scale. A 3-class solution was parsimonious and demonstrated the best statistical fit (Bayesian information criterion = 10596.96; Lo-Mendell-Rubin-adjusted likelihood ratio test = 73.020, p < .05). The 3 groups were ordinal and composed of respondents with high- (HF; n = 72, 29%), medium- (MF; n = 110, 44%), and low functioning (LF; n = 66, 27%). Further analyses (chi squares and linear regressions) showed that the LF group had a significantly higher proportion of Caucasians and males compared to the HF (referent) group. Also, when controlling for demographics and weight, the LF group had significantly higher blood pressure (diastolic and systolic), lower self-reported physical activity (on two different measures), and a higher total score on a scale of depressed mood. Four groups of ordinal regressions (since the pair of self-reported exercise variables and blood pressure variables were correlated, only one from each pair was included in each set) consistently found that self-reported physical activity and blood pressure improved significantly from the LF to HF groups. However, when depressed mood was included, it became the only significant variable. These findings suggest that LF group members are demographically and clinically distinct and that depressed mood may be the critical factor connecting self-report and metabolic dysfunction. Theory suggests depressed mood is both associated with cognitive schemas that affect responses on self-report measures; skewing them negative, and is also manifested metabolically.

Treatment of pediatric acute lymphoblastic leukemia (ALL) is increasingly successful, achieving cure rates of over 80%. Early identification of patients with high risk for relapse has led to improved outcome, however, two third of patients encountering relapse were initially stratified into low-intermediate risk groups. The identification of better upfront prognostic factors remains an important challenge in childhood ALL. In this thesis, gene expression profiling (GEP) was applied to different research approaches aiming to dissect subgroups and to find novel therapeutic targets in B cell precursor ALL (BCP ALL). Among BCP ALL, the patients lacking major genomic aberrations (B-others) represent the subgroup that is most in need of in depth investigations in order to indentify new prognostic factors and improve of risk stratification. To advance biological knowledge of B-others we performed an integrated study of gene and non coding RNAs expression and genetic aberrancies. Chapter 1 reports a study on profiling by gene expression arrays of 145 Italian B-others BCP ALL patients and in a representative subcohort of patients microRNAs (miRNAs) expression profiling and genome-wide DNA copy number variation analysis. In this study we found that 25% of Italian B-others patients fits in a group with unique signature and is associated to a favourable outcome. MicroRNAs expression profiling of this group revealed an unique miRNAs signature characterized by over expression of hsa-miR-125b, -125b-2*, -99a, -100, -125a-3p and has-miR-491-5p. Over expression of cluster miR-125b-2 in region 21q21.1 goes along with over expression of genes in the same chromosomal region. Genome-wide analysis excluded copy number alteration of the 21q21.1 region. The frequent involvement of human chromosome 21 (Hsa21) aberrations in ALL (e.g. hyperdiploidy (HD), t(12;21) or iAmp21) and the involvement of the 21q21.1 region suggest a direct and functional contribution of Hsa21 genes to the malignant transformation of hematopoietic cells. There for there is high interest in studying ALL in children with Down Syndrome (DS), where trisomy 21 is constitutional and where the incidence of ALL is approximately 20-fold higher than in the general population. In Chapter 2 is presented a study of genomic analysis of a large group of DS ALLs that characterizes molecular abnormalities specific of this ALL group. Gene expression analysis revealed that DS ALL is a highly heterogeneous disease not definable as a unique ALL subtype with an enrichment of DNA damage and BCL6 responsive genes suggesting B-cell lymphocytic genomic instability. Surprisingly, only a single Hsa21 gene, SON was included in the DS ALL signature and it was only slightly upregulated. Furthermore gene expression data suggested that DS ALL and HD ALL are very different leukemias, reflecting the fundamental differences between constitutional and acquired trisomy such as the developmental stage in which the trisomy occurs and the fact that a constitutional trisomy is present both in the leukemia cells and in their microenvironment. The study further revealed that 62% of the DS ALL samples were characterized by aberrant expression of the type I cytokine receptor CRLF2. Two kind of aberrations involving CRLF2 were identified: a cryptic translocation involving IGH@ and CRLF2 in the pseudoautosomal region (PAR1) of the sex chromosomes and a deletion within PAR1. This aberration resulted in the P2RY8-CRLF2 fusion and leads to overexpression of CRLF2. Furthermore a novel activating somatic mutation, F232C, in CRLF2 was identified. We demonstrated that CRLF2 and mutated JAK2 cooperate in conferring cytokine independent growth to pro-B cells suggesting that the DS ALL children with CRLF2 aberrant expression may benefit from therapy blocking the CRLF2-JAK2 pathway. Since CRLF2 aberrations were found also among non DS patients, we further analyzed the incidence and prognostic impact of this potential new marker in BCP ALL Italian patients enrolled into the AIEOP-BFM ALL2000 study. Chapter 3, presents the study of a representative cohort of 464 non DS BCP ALL patients that was analyzed for the expression levels of CRLF2 and for the occurrence of CRLF2 rearrangements. In this study we found that the P2RY8-CRLF2 rearrangements in association with 20 times over expression of CRLF2 identifies BCP ALL patients with a very poor prognosis and, among them, an important subset of patients currently stratified in the intermediate risk need to be considered for treatment adaptation. Investigating the pathways highlighted by GEP analysis and testing drug effects require a substantial availability of leukemia samples. Primary ALL samples are difficult to culture in vitro and currently available cell lines poorly reflect the heterogeneous nature of the disease. Mouse xenotransplantation models are therefore widely used for in vivo testing and to amplify the number of leukemia cells to be used for various analyses. In Chapter 4 study we assessed the capability of xenografted samples to recapitulate their respective primary leukemia, and we investigated whether the murine microenvironment selects for leukemia initiating cells leading to a bulk tumor markedly different from the diagnostic patient sample. We analysed the gene expression profiles of 7 primary paediatric ALL samples at diagnosis as well as of their respective xenograft leukaemia samples after serial primary, secondary and tertiary passages in the NOD/SCID/huALL transplant model. In this study we demonstrated that the NOD/SCID/huALL transplant model recapitulates the primary human leukaemia, mimics the features of the primary malignancy and retains these characteristics over serial passages without selection for a subclone of the initial leukaemia. Chapter 5 reports on a study that investigated engraftment properties of 50 pediatric ALL samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. The study shows that short TTL was strongly associated with high risk for early relapse, identifying a new independent prognostic factor. The high risk phenotype is reflected by a gene signature that identified patients with early relapse in an independent patient cohort. Gene expression profiling revealed a set of genes associated with this aggressive phenotype providing a potential strategy to identify these high-risk patients. Most importantly, pathways involving mTOR regulating cell growth were identified, providing targets for alternative therapeutic strategies for these high risk patients. Concluding, ten years after its introduction in oncohematology, GEP constitutes to be a valuable research tool, efficacious in subtype discovery, biomarkers identification and discoveries of deregulated molecular pathways.
La cura della leucemia linfoblastica acuta (ALL) sta migliorando con successo, raggiungendo un tasso di guarigione che va oltre l’80%. L’identificazione precoce dei pazienti con alto rischio di ricaduta ha portato ad un miglioramento generale dell’outcome, tuttavia, due terzi dei pazienti che incorrono nell’evento di ricaduta vengono inizialmente stratificati in gruppi a basso rischio o rischio intermedio. L’identificazione di migliori fattori prognostici rimane un’importante sfida nelle ALL pediatriche. In questa tesi, lo studio del profilo di espressione genica è stato applicato a diversi approcci di ricerca, con lo scopo di individuare sottogruppi e trovare nuovi target terapeutici nelle ALL a cellule precursori B (BCP ALL) Tra le BCP ALL, i pazienti privi delle aberrazioni genomiche più riccorrenti (B-others) rappresentano il sottogruppo che più necessita di studi approfonditi, tesi ad identificare nuovi fattori prognostici e migliorare la loro stratificazione nelle classi di rischio. Per aumentare le conoscenze biologiche riferite al gruppo dei B-others, è stato eseguito uno studio integrato di espressione genica, espressione di non coding RNAs e analisi delle aberrazioni genetiche. Il Capitolo 1 riporta lo studio mediante microarrays di espressione genica di 145 pazienti Italiani affetti da BCP ALL e, in una sotto-coorte rappresentativa, lo studio dell’espressione dei microRNAs (miRNAs) e l’analisi di variazione di DNA copy number estesa all’intero genoma. Da questo studio è emerso che il 25% dei pazienti Italiani di tipo B-others rientrano in un gruppo con una signature specifica e sono associati ad un outcome favorevole. Lo studio del profilo di espressione dei miRNAs rivela in questo gruppo una specifica signature di miRNAs caratterizzata dalla sovra espressione di hsa-miR-125b, -125b-2*, -99a, -100, -125a-3p e has-miR-491-5p. La sovra espressione del cluster miR-125b-2 nella regione 21q21.1 è accompagnata dalla concomitante sovra espressione dei geni nella stessa regione cromosomica. Le analisi sul genoma hanno portato ad escludere la presenza di alterazioni di DNA copy number nella regione 21q21.1. Il frequente coinvolgimento di aberrazioni a carico del cromosoma 21 nelle ALL (come nel caso di iperdiploidia (HD), t(12;21) o iAmp21) e il coinvolgimento della regione 21q21.1, suggeriscono un diretto e funzionale contributo dei geni nel cromosoma 21 alla trasformazione maligna delle cellule ematopoietiche. A questo proposito c’è un grande interesse nello studio delle ALL nei bambini affetti dalla Sindrome di Down (DS), nei quali la trisomia 21 è costituzionale e per i quali l’incidenza di ALL è approssimativamente 20 volte maggiore che nel resto della popolazione. Nel Capitolo 2 viene presentato uno studio di analisi genomica di un grande gruppo di DS ALL che mira a caratterizzare le anomalie molecolari specifiche di questo gruppo di ALL. L’analisi di espressione genica ha rivelato che le DS ALL sono leucemie molto eterogenee, non definibili come un unico sottotipo di ALL, con un arricchimento di geni rispondenti al signalling di BCL6 e di risposta al danno al DNA, che suggerisce un’instabilità genomica dei linfociti B. Sorprendentemente, solamente un gene appartenente al cromosoma 21, SON, è compreso nella signature delle DS ALL e risulta solo debolmente up-regolato. Inoltre, i dati di espressione genica suggeriscono che le DS ALL e le HD ALL sono leucemie molto diverse, riflettendo le differenze fondamentali tra trisomia costituzionale e acquisita, quali lo stadio di sviluppo nel quale la leucemia insorge e il fatto che la trisomia costituzionale è presente sia nelle cellule leucemiche che nel microambiente. Lo studio ha inoltre rilevato che il 62% delle DS ALL sono caratterizzate da un’aberrante espressione del recettore per le citochine di tipo I CRLF2. Due tipi di aberrazioni che coinvolgono CRLF2 sono state identificate: una traslocazione criptica che coinvolge il locus IGH@ e CRLF2 nella regione pseudoautosomale PAR1 dei cromosomi sessuali e una delezione in PAR1. Queste aberrazioni danno luogo alla formazione del trascritto di fusione P2RY8-CRLF2 che determina la sovra espressione di CRLF2. Inoltre una nuova mutazione somatica attivante, F232C, in CRLF2 è stata identificata. E’ stato dimostrato che CRLF2 e JAK2 mutato cooperano nel conferire capacità di crescita indipendente da citochine a cellule pro-B suggerendo che i bambini affetti da DS e ALL con un’espressione aberrante di CRLF2 possono trarre beneficio da terapie mirate a bloccare il pathway di CRLF2-JAK. Dal momento che le aberrazioni a carico di CRLF2 sono state trovate anche tra i pazienti non affetti dalla Sindrome di Down, è stata analizzata l’incidenza e l’impatto prognostico di questo potenziale nuovo marcatore nei pazienti Italiani con BCP ALL arruolati nello studio AIEOP-BFM ALL2000. Il Capitolo 3 presenta lo studio di una coorte rappresentativa di 464 pazienti con BCP ALL non affetti da DS che è stata analizzata per l’espressione di CRLF2 e per la presenza di riarrangiamenti a carico di CRLF2. Da questo studio è emerso che il riarrangiamento P2RY8-CRLF2 in associazione con la sovra espressione di CRLF2 (di almeno 20 volte maggiore che nel resto della coorte), identifica pazienti con una prognosi molto sfavorevole e, tra essi, un inportante sottogruppo di pazienti attualmente stratificati nella classe di rischio intermedia e che necessitano di essere considerati per un adeguamento della terapia. Per investigare i pathways emersi dalle analisi di espressione genica e per testare l’effetto dei farmaci è necessaria una grande disponibilità di cellule leucemiche. Le cellule da leucemia primaria sono difficili da coltivare in vitro e le linee cellulari attualmente disponibili non riescono a riflettere la natura eterogenea della malattia. Per questo motivo i modelli di xenotrapianto in topo sono ampiamente usati sia per lo studio in vivo che per amplificare il numero di cellule leucemiche da usare nelle varie analisi. Nello studio riportato nel Capitolo 4 è stata verificata la capacità delle cellule leucemiche ottenute da xenotrapianto di ricapitolare la loro rispettiva leucemia primaria ed è stata valutata la possibilità di una selezione da parte del microambiente murino per particolari cellule “inizianti” la leucemia che portino ad una massa tumorale marcatamente diversa da quella dei pazienti alla diagnosi. E’stato analizzato il profilo di espressione genica di 7 ALL primarie pediatriche alla diagnosi e le rispettive cellule leucemiche ottenute da xenotrapianto dopo un primo, un secondo ed un terzo passaggio seriale nel modello di trapianto di leucemia umana in topo NOD/SCID/huALL. In questo studio è stato dimostrato che il modello di trapianto NOD/SCID/huALL ricapitola la leucemia primaria umana, mima le caratteristiche del tumore primario e ne trattiene le caratteristiche durante i passaggi seriali senza selezionare per un sottoclone della leucemia primaria iniziale. Il Capitolo 5 riporta uno studio che ha investigato le proprietà di attecchimento di 50 ALL pediatriche trapiantate in topi NOD/SCID. Il tempo di attecchimento (Time To Leukemia – TTL) è stato determinato per ogni campione attecchito in termini di settimane trascorse dal trapianto alla manifestazione della leucemia. Lo studio ha mostrato che un breve TTL è fortemente associato con un alto rischio di ricaduta precoce, costituendo di fatto un nuovo marcatore prognostico indipendente. Il fenotipo di alto rischio è riflesso in una signature in grado di identificare pazienti incorsi precocemente nell’evento di ricaduta in una coorte di pazienti indipendente. Lo studio di espressione genica rivela una serie di geni associati con questo fenotipo aggressivo, mettendo a diposizione una potenziale strategia per identificare i pazienti ad alto rischio. In modo ancora più importante, pathways che regolano la crescita cellulare e che coinvolgono mTOR sono stati identificati, indicando dei target per strategie terapeutiche alternative per i pazienti ad alto rischio di riaduta. Concludendo, dieci anni dopo la sua introduzione in oncoematologia, lo studio del profilo di espressione genica si conferma essere un valido strumento di ricerca, efficace nella scoperta di nuovi sottotipi, nell’individuazione di biomarcatori e nel portare alla luce pathways molecolari deregolati.

Disertacijos darbo tikslas – aptikti ir identifikuoti Lietuvoje paplitusias fitoplazmas vabzdžiuose, surinktuose nuo įvairių augalų su fitoplazminiais simptomais ir nustatyti fitoplazmų vabzdžius pernešėjus bei atskleisti identifikuotų ir kitų fitoplazmų filogenetinius giminingumus. Lietuvoje jau žinomos keletas labiausiai paplitusių fitoplazmų grupių bei pogrupių, taip pat aptikta nemažai jų augalų-šeimininkų. Duomenų apie galimus šių bakterijų pernešėjus Lietuvoje beveik nėra. Pernešėjų identifikavimas ir tyrimas padės kurti veiksmingesnes strategijas bei sistemas kovai su fitoplazminėmis infekcijomis. Fitoplazmų ir jų pernešėjų identifikavimas suteiks svarbių duomenų tiriant šių patogenų ekologiją, paplitimą, kilmę, epidemiologiją, plitimo kelius. Informacija bus naudinga Lietuvos ir kaimyninių šalių augalų apsaugai. Taip pat galės padėti nustatant galimų invazinių vabzdžių rūšių bei fitoplazmų kamienų atsiradimą Lietuvoje dėl klimato kaitos. Šio darbo metu pirmą kartą Lietuvoje molekuliniais metodais buvo išaiškinti fitoplazmų vabzdžiai pernešėjai. Daugelis aptiktų fitoplazmų pogrupių nustatytos identifikotuose vabzdžiuose pirmą kartą, kaip Lietuvoje taip ir pasaulyje. Penkiose augalų rūšyse fitoplazmos aptiktos pirmą kartą Lietuvoje. Darbo metu nustatytas vienas visiškai naujas Lietuvai ir pasauliui ir vienas naujas Lietuvai fitoplazmų pogrupiai bei jų augalai šeimininkai, kas prisideda prie Lietuvoje bei pasaulyje aptinkamų fitoplazmų paplitimo ir bioįvairovės tyrimo... [toliau žr. visą tekstą]
The aim of the research was to identify the phytoplasmas detected in insects that were found on various phytoplasma-infected plants, and to reveal phytoplasma insect-vectors as well as phytogenetical relationships of identified phytoplasmas. From previous research, we already know a few mostly widespread phytoplasma groups, subgroups, and many of their host plants in Lithuania. The data on potential vectors of these bacteria are very scarce in Lithuania. The identification and research of insect vectors will help to create more effective strategies and systems to fight with phytoplasmal infections. Identification of phytoplasmas and their vectors will provide important data for research of ecology, distribution, origin, epidemiology, and ways of spreading of these pathogens. Such information is beneficial for plant protection institutions and plant growers in Lithuania and neighbouring countries. It will help to ascertain possible invasive insect species and phytoplasma strains in Lithuania. During this research for the first time in Lithuania, we determined possible phytoplasma insect vectors using molecular biology methods. Most of the detected phytoplasma subgroups were found in the identified insect species for the first time in Lithuania and worldwide. Our data on new potential insect vector species extend the spectrum of phytoplasma vectors in our region. Phytoplasmas were detected for the first time in five plant species in Lithuania. We identified in this work one... [to full text]

The aim of the research was to identify the phytoplasmas detected in insects that were found on various phytoplasma-infected plants, and to reveal phytoplasma insect-vectors as well as phytogenetical relationships of identified phytoplasmas. From previous research, we already know a few mostly widespread phytoplasma groups, subgroups, and many of their host plants in Lithuania. The data on potential vectors of these bacteria are very scarce in Lithuania. The identification and research of insect vectors will help to create more effective strategies and systems to fight with phytoplasmal infections. Identification of phytoplasmas and their vectors will provide important data for research of ecology, distribution, origin, epidemiology, and ways of spreading of these pathogens. Such information is beneficial for plant protection institutions and plant growers in Lithuania and neighbouring countries. It will help to ascertain possible invasive insect species and phytoplasma strains in Lithuania. During this research for the first time in Lithuania, we determined possible phytoplasma insect vectors using molecular biology methods. Most of the detected phytoplasma subgroups were found in the identified insect species for the first time in Lithuania and worldwide. Our data on new potential insect vector species extend the spectrum of phytoplasma vectors in our region. Phytoplasmas were detected for the first time in five plant species in Lithuania. We identified in this work one... [to full text]
Disertacijos darbo tikslas – aptikti ir identifikuoti Lietuvoje paplitusias fitoplazmas vabzdžiuose, surinktuose nuo įvairių augalų su fitoplazminiais simptomais ir nustatyti fitoplazmų vabzdžius pernešėjus bei atskleisti identifikuotų ir kitų fitoplazmų filogenetinius giminingumus. Lietuvoje jau žinomos keletas labiausiai paplitusių fitoplazmų grupių bei pogrupių, taip pat aptikta nemažai jų augalų-šeimininkų. Duomenų apie galimus šių bakterijų pernešėjus Lietuvoje beveik nėra. Pernešėjų identifikavimas ir tyrimas padės kurti veiksmingesnes strategijas bei sistemas kovai su fitoplazminėmis infekcijomis. Fitoplazmų ir jų pernešėjų identifikavimas suteiks svarbių duomenų tiriant šių patogenų ekologiją, paplitimą, kilmę, epidemiologiją, plitimo kelius. Informacija bus naudinga Lietuvos ir kaimyninių šalių augalų apsaugai. Taip pat galės padėti nustatant galimų invazinių vabzdžių rūšių bei fitoplazmų kamienų atsiradimą Lietuvoje dėl klimato kaitos. Šio darbo metu pirmą kartą Lietuvoje molekuliniais metodais buvo išaiškinti fitoplazmų vabzdžiai pernešėjai. Daugelis aptiktų fitoplazmų pogrupių nustatytos identifikotuose vabzdžiuose pirmą kartą, kaip Lietuvoje taip ir pasaulyje. Penkiose augalų rūšyse fitoplazmos aptiktos pirmą kartą Lietuvoje. Darbo metu nustatytas vienas visiškai naujas Lietuvai ir pasauliui ir vienas naujas Lietuvai fitoplazmų pogrupiai bei jų augalai šeimininkai, kas prisideda prie Lietuvoje bei pasaulyje aptinkamų fitoplazmų paplitimo ir bioįvairovės tyrimo... [toliau žr. visą tekstą]

The subgroup identification field which sometimes is called personalized medicine, tries to group individuals such that the effects of a treatment are the most beneficial for them. One of the methods developed for this purpose is called PSICA. Currently this method works in a setting of multiple treatments and real valued response variables. In this thesis, this methodology is extended to the degree that it can also handle ordinal response variables that can take a finite number of values. It is also compared to a competitor method which results in similar performance but with the added value of a probabilistic output and a model that is interpretable and ready for policy making. This is achieved at the expense of a higher execution time. Finally, this extension is applied to a longitudinal study done in Nicaragua in the los Cuatro Santos population in which some interventions were applied in order to reduce poverty. The results showed which were the most beneficial treatments for different population subgroups.

There is a vast diversity of karyotypes in nature, yet mechanisms that have facilitated such diversity are unclear. Alterations to an organism’s karyotype can have major negative fitness consequences in meiosis through non-disjunction and aneuploidy. Here, I investigated the role of biased segregation in female meiosis, i.e., meiotic drive, as a force that contributes to the evolution of karyotype form. The closely related species pair, Drosophila americana and Drosophila novamexicana, is an exemplar for understanding mechanisms of karyotype evolution. Since their recent divergence nearly half a million years ago, D. americana has evolved two different centromeric fusions: one fusion between the 2nd and 3rd chromosomes (Muller elements C and D), and the other fusion between the X and 4th chromosomes (Muller elements A and B). The 2-3 fusion is fixed in D. americana. However, the X-4 centromeric fusion remains polymorphic within the species. I uncovered biased transmissions for both fused chromosomes in D. americana such that the X-4 fused chromosome was inherited by 57% of the offspring from heterozygous females and the 2-3 chromosome was inherited by 62% of the offspring. Introgression experiments shoed the fused X-4 and the unfused X and 4th chromosomes are segregating at a 50/50 ratio in D. novamexicana. I have isolated the fused X-4 centromeric region as a possible player in the observed meiotic drive. However, the centromere is not sufficient to cause meiotic drive without a secondary factor. I also measured heterochromatin content between the fused and unfused X and 4th homologs. No obvious size differences were uncovered, but possible compositional differences were revealed. This suggests that if the centromere itself is involved in meiotic drive, either differences in the number of centromeres or compositional differences between the centromeres are influencing meiotic drive. Overall, I have identified and characterized meiotic drive as a force driving karyotype evolution in D. americana but appears to be absent in D. novamexicana, and I have begun to dissect the mechanisms of meiotic drive.

Introduction: Respiratory syncytial virus (RSV) is an important pathogen, especially in children, the elderly, and immunocompromised individuals. Despite RSV being discovered decades ago, there is still no good treatment or prevention for RSV disease. The cell surface receptor for RSV is not known and identification of RSV receptor(s) will provide improved opportunities for understanding the pathogenesis of the viral disease and potential for discovering novel antiviral agents. Hypothesis: RSV infects cells via attachment to cell surface receptor(s) which can be identified by unbiased interrogation of cell membrane constituents and functionally characterized by blocking and competition experiments. Specific Aims: Chemical characterization of RSV receptor(s) by cell surface enzyme treatments,identifying candidate receptor(s), and confirming that any identified candidate has characteristics of a receptor were specific aims of the project. Methods: Chemical characteristics of RSV binding molecule(s) were investigated using enzyme digestion studies. Methods used for identification of candidate receptors included: co-immunoprecipitation of candidate RSV receptors using whole virion; purification of RSV surface proteins (either by chromatography or by cloning), and virus overlay protein binding assay (VOPBA) combined with mass spectrometry (MS) and protein database searching. Neutralization experiments, in which cells were incubated with anti-candidate receptor antibodies prior to RSV exposure, and competition experiments, in which virus was pre-incubated with purified candidate molecule prior to inoculation of cell cultures were performed. Results: The results of enzyme digestion studies showed that the RSV binding molecule is anon-glycosylated, non-glycosyiphosphatidylinositol-anchored protein. Experiments involving co-immunoprecipitation of RSV receptor using whole virion, or purification of RSV surface proteins (either by chromatography or by cloning), were unsuccessful. By contrast, VOPBA combined with MS resulted in cell surface nucleolin being identified as a candidate RSV binding molecule, and was reproducible in several cell lines originating from different species. Neutralization and competition experiments showed decreased RSV infection in vitro. Conclusion: Nucleolin, expressed on the surface of multiple cell types from diverse species, was identified as a candidate receptor for RSV. Subsequent blocking and competition experiments showed evidence of nucleolin having characteristics of a functional receptor. These findings provide a basis for future work to investigate RSV-nucleolin interactions.

This thesis presents two novel approaches for performing subgroup analyses or identifying subgroups in an individual patient data (IPD) meta-analyses setting. The work contained in this thesis originated from an important research priority in the area of low back pain (LBP); identifying subgroups that most (or least) benefit from treatment. Typically, a subgroup is evaluated by applying a statistical test for interaction between a baseline characteristic and treatment. A systematic review found that subgroup analyses in the area of LBP are severely underpowered and are of a rather poor quality (Chapter 4). IPD meta-analyses provide an ideal framework with improved statistical power to investigate and identify subgroups. However, conventional approaches to subgroup analyses applied in both a single trial setting and an IPD setting have a number of issues, one of them being that subgroups are typically investigated one at a time. As individuals have multiple characteristics that may be related to response to treatment, alternative statistical methods are required to overcome the associated issues. Tree based methods are a promising alternative that systematically search the entire covariate space to identify subgroups defined by multiple characteristics. In this work, a number of relevant tree methods, namely the Interaction Tree (IT), Simultaneous Threshold Interaction Modelling Algorithm (STIMA) and Subpopulation Identification based on a Differential Effect Search (SIDES), were identified and evaluated in a single trial setting in a simulation study. The most promising methods (IT and SIDES) were extended for application in an IPD meta-analyses setting by incorporating fixed-effect and mixed-effect models to account for the within trial clustering in the hierarchical data structure, and again assessed in a simulation study. Thus, this work proposes two statistical approaches to subgroup analyses or subgroup identification in an IPD meta-analysis framework. Though the application is based in a LBP setting, the extensions are applicable in any research discipline where subgroup analyses in an IPD meta-analysis setting is of interest.

With new treatments and novel technology available, personalized medicine has become a key topic in the new era of healthcare. Traditional statistical methods for personalized medicine and subgroup identification primarily focus on single treatment or two arm randomized control trials (RCTs). With restricted inclusion and exclusion criteria, data from RCTs may not reflect real world treatment effectiveness. However, electronic medical records (EMR) offers an alternative venue. In this paper, we propose a general framework to identify individualized treatment rule (ITR), which connects the subgroup identification methods and ITR. It is applicable to both RCT and EMR data. Given the large scale of EMR datasets, we develop a recursive partitioning algorithm to solve the problem (ITR-Tree). A variable importance measure is also developed for personalized medicine using random forest. We demonstrate our method through simulations, and apply ITR-Tree to datasets from diabetes studies using both RCT and EMR data. Software package is available at https://github.com/jinjinzhou/ITR.Tree.

OBJECTIVES: 1. SFM subtypes identification.2. Determining differences in personality characteristics, presence of psychopathology and the received perception of quality of life related to health (HRQOL). 3. Identifying personality characteristics associated with different subtypes of FMS. HYPOTHESIS: Patients with major indicators of physical and psychopathological symptoms and lower HRQOL will present differences in personality characteristics that allow identifying of significant differences in personality factors between subtypes. METHODOLOGY: Observational, analytical and cross-sectional study of 66 patients diagnosed with FMS (ACR, 1990). RESULTS: Identification of subtypes with significant symptomatology differences. The results support the existence of differences in daily functioning, HRQOL, intensity of psychopathology and personality characteristics. CONCLUSIONS: Subgroups differ in levels of physical symptoms, psychopathology and HRQOL. The personality characteristics of each subtype are relevant to the group membership of greater or lesser involvement
OBJETIVOS: 1. Clasificación de subtipos de SFM. 2. Determinación de diferencias de características de personalidad, psicopatología concomitante y calidad de vida percibida relacionada con la salud (CVRS) 3. Identificar características de personalidad asociadas a subtipos de SFM. HIPOTESIS: Pacientes con mayores indicadores en sintomatología física y psicopatológica y menor CVRS presentaran diferencias en las características de personalidad que permitirán identificar diferencias significativas respecto factores de personalidad entre subtipos. METODOLOGÍA: Estudio observacional, analítico y transversal de 66 pacientes diagnosticados de SFM (ACR,1990). RESULTADOS: Identificación de subtipos con diferencias sintomatológicas significativas. Los resultados apoyan la existencia de diferencias en funcionamiento diario, CVRS, intensidad de psicopatología y características de personalidad. CONCLUSIONES: Los subgrupos se diferencian por niveles de sintomatología física, psicopatología y CVRS. Las características de personalidad de cada subtipo son relevantes para la pertenencia al grupo de menor o mayor afectación

The aggregate of a sport team's fans may be viewed as a consumption community that surrounds the team and its brand (Devasagayam & Buff, 2008; Hickman & Ward, 2007). Beneath this larger consumption umbrella, smaller groups of consumers may exist (Dholakia, Bagozzi, & Pearo, 2004), such as specific supporter groups for a team. Individuals thus may identify with multiple layers of the consumption group simultaneously (Brodsky & Marx, 2001; Hornsey & Hogg, 2000). Although past researchers have studied supporter groups (Giulianotti, 1996, 1999a; Parry & Malcolm, 2004) and consumption communities (Kozinets, 2001; Muñiz & O'Guinn, 2001; McAlexander, Schouten, & Koenig, 2002), there has been limited research on the interaction among subgroups within the superordinate group. The current study examines the American Outlaws (AO), a supporter group for the United States men's national soccer team (USMNT). AO members belong to local AO chapters (subgroups) as well the national (superordinate) group. This structure creates multiple levels of identification and is conducive to studying the phenomenon in question. Through employing a grounded theory methodology, data were collected via participant observation and ethnographic interviews over a two year period. The current study identifies six prominent foci of identification among AO members: the USMNT, the United States of America (national identity), the sport of soccer, AO National, AO Local, and one's small social group. These identities are found to be mutually reinforcing and shape members' interactions with the team, the supporter group, and social groups therein. Specifically, the regional subgroups (AO Local chapters) create opportunities for social interaction, which fosters members' sense of community and group identification. In turn, this strengthens group cohesion at the subgroup and superordinate group levels. Further, supporter group members alter their team consumption experiences by creating places of prolonged identity salience at live games and when watching games on television. These events increase identification with the supporter group and its related identities. For practitioners, implications of this study include the understanding of supporter groups' impact on members' frequency and duration of brand-related consumption.

Indiana University-Purdue University Indianapolis (IUPUI)
Subgroup analyses assess the heterogeneity of treatment effects in groups of patients defined by patients’ baseline characteristics. Identifying subgroup of patients with differential treatment effect is crucial for tailored therapeutics and personalized medicine. Model-based variable selection methods are well developed and widely applied to select significant treatment-by-covariate interactions for subgroup analyses. Machine learning and data-driven based methods for subgroup identification have also been developed. In this dissertation, I consider two different types of subgroup identification methods: one is nonparametric machine learning based and the other is model based. In the first part, the problem of subgroup identification was transferred to an optimization problem and a stochastic search technique was implemented to partition the whole population into disjoint subgroups with differential treatment effect. In the second approach, an integrative three-step model-based variable selection method was proposed for subgroup analyses in longitudinal data. Using this three steps variable selection framework, informative features and their interaction with the treatment indicator can be identified for subgroup analysis in longitudinal data. This method can be extended to longitudinal binary or categorical data. Simulation studies and real data examples were used to demonstrate the performance of the proposed methods.
2022-05-06