Analisi multivariata per osservazioni appaiate con dati mancanti: un caso studio

All parametric approaches require that analysis should be done on complete data sets and so, in presence of missing data, parametric solutions are based either on the so-called deletion principle or imputation methods. But when we delete incomplete vectors we also remove all information they contain, which may be valuable and useful for analysis. And when we replace missing data by suitable functions of actually observed data, that is imputing method, we may introduce biased information which may negatively infuence the analysis. On the other hand, non-parametric solutions in a permutation framework consider data as they are, and units with missing data participate in the permutation mechanism as well as all other units, without deletion or imputing. In this paper we provide a comparison between a parametric solution, represented by ITT principle, and a non parametric one, in a testing problem with multivariate paired observations

Physiological Response to Negative Emotions in Children with Anxiety Symptoms: Many Steps Still to be Taken

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Liver-directed lentiviral gene therapy corrects hemophilia A mice and achieves normal-range factor VIII activity in non-human primates

: Liver gene therapy with adeno-associated viral (AAV) vectors delivering clotting factor transgenes into hepatocytes has shown multiyear therapeutic benefit in adults with hemophilia. However, the mostly episomal nature of AAV vectors challenges their application to young pediatric patients. We developed lentiviral vectors, which integrate in the host cell genome, that achieve efficient liver gene transfer in mice, dogs and non-human primates, by intravenous delivery. Here we first compare engineered coagulation factor VIII transgenes and show that codon-usage optimization improved expression 10-20-fold in hemophilia A mice and that inclusion of an unstructured XTEN peptide, known to increase the half-life of the payload protein, provided an additional >10-fold increase in overall factor VIII output in mice and non-human primates. Stable nearly life-long normal and above-normal factor VIII activity was achieved in hemophilia A mouse models. Overall, we show long-term factor VIII activity and restoration of hemostasis, by lentiviral gene therapy to hemophilia A mice and normal-range factor VIII activity in non-human primate, paving the way for potential clinical application

Immune signature in vaccinated versus non-vaccinated aged people with COVID-19 pneumonia

Background A definition of the immunological features of COVID-19 pneumonia is needed to support clinical management of aged patients. In this study, we characterized the humoral and cellular immune responses in presence or absence of SARS-CoV-2 vaccination, in aged patients admitted to the IRCCS San Raffaele Hospital (Italy) for COVID-19 pneumonia between November 2021 and March 2022. Methods The study was approved by local authorities. Disease severity was evaluated according to WHO guidelines. We tested: (A) anti-SARS-CoV-2 humoral response (anti-RBD-S IgG, anti-S IgM, anti-N IgG, neutralizing activity against Delta, BA1, BA4/5 variants); (B) Lymphocyte B, CD4 and CD8 T-cell phenotype; (C) plasma cytokines. The impact of vaccine administration and different variants on the immunological responses was evaluated using standard linear regression models and Tobit models for censored outcomes adjusted for age, vaccine doses and gender. Result We studied 47 aged patients (median age 78.41), 22 (47%) female, 33 (70%) older than 70 years (elderly). At hospital admission, 36% were unvaccinated (VACno), whilst 63% had received 2 (VAC2) or 3 doses (VAC3) of vaccine. During hospitalization, WHO score > 5 was higher in unvaccinated (14% in VAC3 vs. 43% in VAC2 and 44% VACno). Independently from vaccination doses and gender, elderly had overall reduced anti-SARS-CoV-2 humoral response (IgG-RBD-S, p = 0.0075). By linear regression, the anti-RBD-S (p = 0.0060), B (p = 0.0079), CD8 (p = 0.0043) and Th2 cell counts (p = 0.0131) were higher in VAC2 + 3 compared to VACno. Delta variant was the most representative in VAC2 (n = 13/18, 72%), detected in 41% of VACno, whereas undetected in VAC3, and anti-RBD-S production was higher in VAC2 vs. VACno (p = 0.0001), alongside neutralization against Delta (p = 0141), BA1 (p = 0.0255), BA4/5 (p = 0.0162). Infections with Delta also drove an increase of pro-inflammatory cytokines (IFN-α, p = 0.0463; IL-6, p = 0.0010). Conclusions Administration of 3 vaccination doses reduces the severe symptomatology in aged and elderly. Vaccination showed a strong association with anti-SARS-CoV-2 humoral response and an expansion of Th2 T-cells populations, independently of age. Delta variants and number of vaccine doses affected the magnitude of the humoral response against the original SARS-CoV-2 and emerging variants. A systematic surveillance of the emerging variants is paramount to define future vaccination strategies

Profiling Antibody Response Patterns in COVID-19: Spike S1-Reactive IgA Signature in the Evolution of SARS-CoV-2 Infection

This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies

Coping Mechanisms, Psychological Distress, and Quality of Life Prior to Cancer Genetic Counseling

Background: Breast Cancer susceptibility genes 1 and 2 are implicated in hereditary breast and ovarian cancer and women can test for the presence of these genes prior to developing cancer. The goal of this study is to examine psychological distress, quality of life, and active coping mechanisms in a sample of women during the pre-test stage of the genetic counseling process, considering that pre-test distress can be an indicator of post-test distress. We also wanted to identify if subgroups of women, defined based on their health status, were more vulnerable to developing distress during the genetic counseling process.Methods: This study included 181 female participants who accessed a Cancer Genetic Counseling Clinic. The participants were subdivided into three groups on the basis of the presence of a cancer diagnosis: Affected patients, Ex-patients, and Unaffected participants. Following a self-report questionnaire, a battery of tests was administered to examine psychological symptomatology, quality of life, and coping mechanisms.Results: The results confirm that the genetic counseling procedure is not a source of psychological distress. Certain participants were identified as being more vulnerable than others; in the pre-test phase, they reported on average higher levels of distress and lower quality of life. These participants were predominantly Ex-patients and Affected patients, who may be at risk of distress during the counseling process.Conclusions: These findings highlight that individuals who take part in the genetic counseling process are not all the same regarding pre-test psychological distress. Attention should be paid particularly to Ex-patients and Affected patients by the multidisciplinary treating team

A nonparametric permutation approach to statistical shape analysis

The statistical community has shown an increased interest in shape analysis in the last decade, in particular with reference to the development of robust inferential statistical methods. In this Ph.D. thesis we present an extension of NonParametric Combination (NPC) methodology (Pesarin, 2001) to shape analysis. At first we review inferential methods known in the shape analysis literature, highlighting some drawbacks of using Hotelling's T^2 test statistic. Then, focussing on the two independent sample case, through an exhaustive comparative simulation study, we evaluate the behaviour of traditional tests along with nonparametric permutation tests using also Multiple Aspect (MA) procedures and domain combinations. The case of heterogeneous and dependent variation at each landmark is also investigated, along with the effects of superimposition on the power of NPC tests. Permutation tests have been evaluated also in the particular case in which the number of variables is larger than the cardinality of permutation sample space. We have performed a simulation study to evaluate the power of multivariate NPC tests, showing that the power for the proposed tests increases when increasing the number of the processed variables provided that the noncentrality parameter increases, even when the number of covariates is larger than the permutation sample space. These preliminary results allowed us to extend the notion of finite-sample consistency for permutation tests combination-based to the shape analysis field. Sufficient conditions are given in order that the rejection rate converges to one, for fixed sample sizes at any attainable alpha-value, when the number of variables diverges, provided that the noncentrality induced by test statistics also diverges. On the basis of these findings, we emphasize that the proposed tests provide efficient solutions to multivariate small sample problems, like those encountered in the shape analysis field. Along with simulation studies, we present two applications to real data sets concerning Mediterranean monk seal skulls and aortic valve morphology.Nell'ultimo decennio la comunità statistica ha mostrato un crescente interesse per i problemi di shape analysis, con particolare riferimento allo sviluppo di tecniche inferenziali robuste. In questa tesi di dottorato presentiamo un'estensione della metodologia NPC per la combinazione non parametrica di test di permutazione dipendenti (Pesarin, 2001) nell'ambito della shape analysis. Inizialmente si introduce una revisione dei metodi inferenziali noti in letteratura, evidenziando alcune problematiche legate all'uso della statistica test T^2 di Hotelling. Focalizzandoci poi sul caso di due campioni indipendenti, tramite un esauriente studio di simulazione, abbiamo confrontato il comportamento, in termini di potenza, dei test parametrici tradizionali con quello dei test non parametrici proposti. Sono state utilizzate anche procedure di tipo multi aspetto (MA) e combinazioni per domini. E’ stato anche esaminato il caso in cui i landmark sono correlati tra loro. Inoltre è stato valutato l'impatto della superimposizione sulla potenza dei test NPC. I test di permutazione sono stati valutati in potenza e sotto H_0 nel caso in cui il numero di variabili processate è superiore alla cardinalità dello spazio di permutazione. Abbiamo inoltre effettuato uno studio di simulazione per valutare la potenza dei test multivariati NPC, evidenziando che la potenza di questi test cresce al crescere del numero di variabili processate, qualora apportino un aumento della non centralità, anche quando il numero di variabili è superiore alla cardinalità dello spazio di permutazione. Questi risultati preliminari ci hanno consentito di estendere la nozione di finite-sample consistency per i test NPC nell'ambito della shape analysis. Vengono fornite condizioni sufficienti tali per cui la potenza del test converge a uno, per ampiezze campionarie fissate ad ogni livello raggiungibile alpha, quando il numero di variabili diverge, posto che diverga anche la non centralità indotta dall'aumento del numero di variabili. Sulla base dei risultati ottenuti, possiamo affermare che i test NPC forniscono soluzioni efficienti per i problemi multivariati di shape analysis in presenza di bassa numerosità campionarie, problemi del resto frequenti nell'ambito della shape analysis. Oltre agli studi di simulazione, vengono presentati due casi studio, uno relativo allo studio della forma del cranio della foca monaca del Mediterraneo e l'altro relativo alla morfologia della valvola aortica

Chiara Brombin's Quick Files

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