Role In Multivariate Analysis Research Articles

Mutations of TP53 Gene in Acute Lymphoblastic Leukemia Do Not Affect the Survival Outcomes after Haploidentical Stem Cell Transplantation

Introduction: Mutations and deletions in TP53 are found in all hematological malignancies, Whereas TP53 mutations (TP53mut) were described to occur quite frequently in acute lymphocytic leukemia (ALL). Previous studies have demonstrated that TP53 mutation was associated with poor prognosis in ALL. Allogeneic hematopoietic stem cell transplantation (HSCT) represents an effective therapy for reducing the chances of relapse of ALL. Recent medical progress has led to haploidentical-SCT (haplo-SCT) achieving transplant outcomes similar to those with matched-sibling donor SCT and matched-unrelated donor SCT in patients with hematological malignancies, haplo-SCT provided an alternative treatment for ALL patients for whom identical donors are unavailable. However, the impact of TP53mut in ALL on survival outcomes in haplo-HSCT setting remains unknown. This study aims to investigate the effect of TP53 mutations on survival outcomes of ALL treated with haplo-SCT at a single institution. Methods: 78 subjects with available TP53 status at diagnosis were retrospectively considered. We excluded 11 subjects who received HLA-matched related transplantation and 2 subjects with HLA-matched unrelated donor transplantation. The remaining 65 subjects with haplo-HSCT were enrolled. TP53 mutation analysis was assessed on bone marrow (BM) samples. LFS and OS were estimated using Kaplan and Meier method and tested between groups using a log-rank test. Cumulative incidence of relapse (CIR) was treated as a competing risk for non-relapse mortality (NRM). Results: A cohort of 65 patients was included with a median(range) age of 30 years (14-51) and was followed up for a median duration of 602 days (range;42-2017 days). 60% of patients were male. 24 of 65 patients showed TP53 mutations. The baseline characteristics including sex, age, white blood cell, diagnosis, Ph/Ph-like chromosomes, IKZF1 mutation, donor-recipient gender, donor-recipient relation, ABO mismatched, CR status before SCT, pre-MRD status were similar between the two groups. 7 (10.8%) patients suffered platelet engraftment failure, the cumulative incidence of grade II-IV aGVHD or cGVHD was comparable between the two groups (TP53mutvs TP53wt:38.8% vs 30.2%, P=0.80; 69.0% vs 63.4%, P=0.98). The 2-year cumulative of CIR rates were 13.1% and 12.5% (P=0.96) among TP53mut and TP53wt patients. The 2-year LFS rates of TP53mut patients were similar to patients with TP53wt (74.2% vs 77.4%, P=0.80). No significant differences in 2-year OS rates (82.9% vs 87.3%, P=0.61) or 2-year NRM rates (12.7% VS 10.2%, P=0.69) were observed in TP53mut and TP53wt patients. TP53 played no prognostic role in multivariate analysis. WBC count at diagnosis (>50x109/L: HR=3.860, P=0.016) and age (>40 years old: HR=4.120, P=0.012) were independent risk factors associated with 2-year LFS, additionally, cGVHD showed protective effect for 2-year LFS in univariate analysis (P= 0.06), but significant was not confirmed in a multivariate analysis. WBC count at diagnosis (>50 x109/L: HR=5.483, P=0.042) was the only independent risk factor of 2-year CIR. To assess the prognostic impact of TP53mut in a homogeneous population, we reanalyzed patients with B-cell immunophenotype. There was no significant difference in survival outcomes between TP53mut and TP53wt groups when only B-ALL were assessed (TP53mutvs TP53wt: 2-year OS: 82.2% vs 93.0%, P=0.23; 2-year LFS: 73.0% VS 82.7%, P=0.44; 2-year NRM:13.3% vs 7.1%, P=0.40; 2-year CIR:13.7% vs 10.2%, P=0.81). Conclusion: Our study showed that TP53 mutations may not be related to the unfavorable impact on survival in ALL patients after treatment with haplo-HSCT. The results imply that haplo-HSCT may be a viable treatment for this subgroup of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Use of a high-sensitivity anti-Mullerian hormone (AMH) assay to determine ovarian function after chemotherapy for early breast cancer.

552 Background: It is now well established that AMH can indicate the extent of chemotherapy-induced damage on the ovarian reserve. Very low AMH levels in women after chemotherapy for early breast cancer (eBC) may indicate treatment-induced premature ovarian failure (POI), but the evidence to implement its routine clinical use remains limited. Methods: AMH was measured (Roche cobas autoanalyser) in 197 women aged 40-45 years at diagnosis treated with anthracycline/cyclophosphamide/taxane based chemotherapy for eBC, with no previous endocrine therapy and no subsequent aromatase inhibitor exposure or ovarian suppression. 76% were ER positive and received tamoxifen. The primary objective was to assess the relationships between AMH levels at 6 months after chemotherapy (AMH6) with subsequent ovarian function at 30 months. This included accuracy of prediction of loss of ovarian function at 30 months (E30) after chemotherapy by AMH levels at 6 months (AMH6) and the value of other endocrine/clinical factors pretreatment and at 6 months. Multivariate analysis was performed with data were split into 70% training and 30% testing sets with results reported for model performance on the test set. Results: AMH fell from a median of 0.62 (IQR 0.21-1.31) ng/ml pretreatment to become undetectable ( < 0.01ng/ml) in 137 (70%) of women at 6 months. AMH showed very little recovery, being undetectable in 115 women at 18 months and 119 at 30 months. In those with detectable AMH at 30 months, it remained very low, median 0.07ng/ml, max 0.82ng/ml but nevertheless it reflected ovarian function. Thus median estradiol at 30 months (E30) was 50 pmol/l (IQR 34-68) in women with undetectable AMH at that time, vs 313 pmol/l (IQR 102-1052) in the 80 women with detectable AMH. AMH at 6 months was predictive of ovarian function at 30 months, as E30 was 56 pmol/l (IQR 40-104) in women with undetectable AMH6 vs 258pmol/l (IQR 69-780; p < 0.0001) in women with detectable AMH6, and the positive predictive value (PPV) of AMH being undetectable at 6 months and remaining so at 30 months was 77%. Random forest analysis identified BMI as a non-endocrine predictive factor of E30. Using a stringent cutoff of ≤50pmol/l (13.6 pg/ml) and adding 1:9 weighting to improve PPV gave a test validated PPV of 79.0% while maintaining AUC at 83.7% for prediction of E30. Other classifiers performed less well than random forests. Conclusions: Measurement of AMH at 6 months after chemotherapy has predictive value for later ovarian function, and combining this with other endocrine and baseline data improves discriminative ability. This approach indicates the potential role of multivariate analysis based on AMH measured shortly after chemotherapy to helping optimise subsequent endocrine therapy.

Wavelength Selection Method Based on Partial Least Square from Hyperspectral Unmanned Aerial Vehicle Orthomosaic of Irrigated Olive Orchards

Identifying and mapping irrigated areas is essential for a variety of applications such as agricultural planning and water resource management. Irrigated plots are mainly identified using supervised classification of multispectral images from satellite or manned aerial platforms. Recently, hyperspectral sensors on-board Unmanned Aerial Vehicles (UAV) have proven to be useful analytical tools in agriculture due to their high spectral resolution. However, few efforts have been made to identify which wavelengths could be applied to provide relevant information in specific scenarios. In this study, hyperspectral reflectance data from UAV were used to compare the performance of several wavelength selection methods based on Partial Least Square (PLS) regression with the purpose of discriminating two systems of irrigation commonly used in olive orchards. The tested PLS methods include filter methods (Loading Weights, Regression Coefficient and Variable Importance in Projection); Wrapper methods (Genetic Algorithm-PLS, Uninformative Variable Elimination-PLS, Backward Variable Elimination-PLS, Sub-window Permutation Analysis-PLS, Iterative Predictive Weighting-PLS, Regularized Elimination Procedure-PLS, Backward Interval-PLS, Forward Interval-PLS and Competitive Adaptive Reweighted Sampling-PLS); and an Embedded method (Sparse-PLS). In addition, two non-PLS based methods, Lasso and Boruta, were also used. Linear Discriminant Analysis and nonlinear K-Nearest Neighbors techniques were established for identification and assessment. The results indicate that wavelength selection methods, commonly used in other disciplines, provide utility in remote sensing for agronomical purposes, the identification of irrigation techniques being one such example. In addition to the aforementioned, these PLS and non-PLS based methods can play an important role in multivariate analysis, which can be used for subsequent model analysis. Of all the methods evaluated, Genetic Algorithm-PLS and Boruta eliminated nearly 90% of the original spectral wavelengths acquired from a hyperspectral sensor onboard a UAV while increasing the identification accuracy of the classification.

On the Letac-Massam conjecture and existence of high dimensional Bayes estimators for graphical models

The Wishart distribution defined on the open cone of positive-definite matrices plays a central role in multivariate analysis and multivariate distribution theory. Its domain of parameters is often referred to as the Gindikin set. In recent years, varieties of useful extensions of the Wishart distribution have been proposed in the literature for the purposes of studying Markov random fields and graphical models. In particular, generalizations of the Wishart distribution, referred to as Type I and Type II (graphical) Wishart distributions introduced by Letac and Massam in Annals of Statistics (2007) play important roles in both frequentist and Bayesian inference for Gaussian graphical models. These distributions have been especially useful in high-dimensional settings due to the flexibility offered by their multiple-shape parameters. Concerning Type I and Type II Wishart distributions, a conjecture of Letac and Massam concerns the domain of multiple-shape parameters of these distributions. The conjecture also has implications for the existence of Bayes estimators corresponding to these high dimensional priors. The conjecture, which was first posed in the Annals of Statistics, has now been an open problem for about 10 years. In this paper, we give a necessary condition for the Letac and Massam conjecture to hold. More precisely, we prove that if the Letac and Massam conjecture holds on a decomposable graph, then no two separators of the graph can be nested within each other. For this, we analyze Type I and Type II Wishart distributions on appropriate Markov equivalent perfect DAG models and succeed in deriving the aforementioned necessary condition. This condition in particular identifies a class of counterexamples to the conjecture.

An Introduction to Wishart Matrix Moments

These lecture notes provide a comprehensive, self-contained introduction to the analysis of Wishart matrix moments. This study may act as an introduction to some particular aspects of random matrix theory, or as a self-contained exposition of Wishart matrix moments. Random matrix theory plays a central role in statistical physics, computational mathematics and engineering sciences, including data assimilation, signal processing, combinatorial optimization, compressed sensing, econometrics and mathematical finance, among numerous others. The mathematical foundations of the theory of random matrices lies at the intersection of combinatorics, non-commutative algebra, geometry, multivariate functional and spectral analysis, and of course statistics and probability theory. As a result, most of the classical topics in random matrix theory are technical, and mathematically difficult to penetrate for non-experts and regular users and practitioners. The technical aim of these notes is to review and extend some important results in random matrix theory in the specific context of real random Wishart matrices. This special class of Gaussian-type sample covariance matrix plays an important role in multivariate analysis and in statistical theory. We derive non-asymptotic formulae for the full matrix moments of real valued Wishart random matrices. As a corollary, we derive and extend a number of spectral and trace-type results for the case of non-isotropic Wishart random matrices. We also derive the full matrix moment analogues of some classic spectral and trace-type moment results. For example, we derive semi-circle and Marchencko-Pastur-type laws in the non-isotropic and full matrix cases. Laplace matrix transforms and matrix moment estimates are also studied, along with new spectral and trace concentration-type inequalities.

Rare-event analysis for extremal eigenvalues of white Wishart matrices

In this paper, we consider the extreme behavior of the extremal eigenvalues of white Wishart matrices, which plays an important role in multivariate analysis. In particular, we focus on the case when the dimension of the feature $p$ is much larger than or comparable to the number of observations $n$, a common situation in modern data analysis. We provide asymptotic approximations and bounds for the tail probabilities of the extremal eigenvalues. Moreover, we construct efficient Monte Carlo simulation algorithms to compute the tail probabilities. Simulation results show that our method has the best performance among known approximation approaches, and furthermore provides an efficient and accurate way for evaluating the tail probabilities in practice.

An RKHS framework for functional data analysis

Linear combinations of random variables play a crucial role in multivariate analysis. Two extension of this concept are considered for functional data and shown to coincide using the Loève–Parzen reproducing kernel Hilbert space representation of a stochastic process. This theory is then used to provide an extension of the multivariate concept of canonical correlation. A solution to the regression problem of best linear unbiased prediction is obtained from this abstract canonical correlation formulation. The classical identities of Lawley and Rao that lead to canonical factor analysis are also generalized to the functional data setting. Finally, the relationship between Fisher's linear discriminant analysis and canonical correlation analysis for random vectors is extended to include situations with function-valued random elements. This allows for classification using the canonical Y scores and related distance measures.

A General Method for Constructing Pseudo-Gaussian Tests

A general method for constructing pseudo-Gaussian tests—reducing to traditional Gaussian tests under Gaussian densities but remaining valid under nonGaussian ones—is proposed. This method provides a solution to several open problems in classical multivariate analysis. One of them is the test of the homogeneity of covariance matrices, an assumption that plays a crucial role in multivariate analysis of variance, under elliptical, and possibly heterokurtic densities with finite fourth-order moments.

Telomerase activity and hTERT mRNA expression in glial tumors

Human telomerase is a structurally complex ribonucleoprotein that is responsible for the maintenance of telomeric DNA at the ends of the chromosomes. The enzyme is proposed as having an important role in cell immortalization and oncogenesis. A limited number of studies have been performed on the telomerase system in brain tumors, and these studies are somewhat conflicting. The relative ineffectiveness of current therapies for malignant gliomas led to the need for novel targets for more promising approaches. In order to clarify the prognostic significance of telomerase expression in gliomas and to speculate on therapeutic implications, we examined telomerase activity by the telomeric repeat amplification protocol (TRAP) assay in 42 gliomas, (32 multiform glioblastomas, 4 anaplastic astrocytomas, 4 differentiated astrocytomas, 1 oligoastrocytoma and 1 oligosarcoma). Telomerase messenger expression (hTERT mRNA) was evaluated by reverse transcription-PCR analysis in the same group of tumors. High telomerase activity was detected in 21/42 gliomas (50%). The levels of telomerase in terms of its messenger level expression overlapped the activity; in fact, a significant association between telomerase activity and hTERT mRNA expression was found (chi2 test; p<0.0001). At univariate analysis, advanced age as well as high telomerase activity and hTERT mRNA levels were seen to be significant predictors of worse prognosis regarding both overall survival (p=0.007, p=0.007, p=0.04, respectively) and disease-free interval (p=0.008, p=0.008, p=0.04, respectively). All these variables maintained a significant independent prognostic role in multivariate analysis. Telomerase may represent an indicator of progression and poor prognosis in this type of cancer, with interesting therapeutic implications.

Tumour necrosis factor-α: prognostic role and relationship with interleukin-8 and endothelin-1 in non-small cell lung cancer

Cytokines mediate numerous physiological and immune reactions, which are manifested in various biological effects, including tumouricidal activity. We evaluated the expression of the pleiotropic cytokine, tumour necrosis factor-alpha (TNF-alpha), by competitive PCR technique in 47 non-small cell lung cancer (NSCLC) cases and the impact of TNF-alpha on their clinical behaviour. Using univariate analysis, our study demonstrated a positive correlation between high TNF-alpha expression and favourable prognosis in NSCLC in terms of overall survival and disease free interval (p=0.03 and 0.04, respectively) and TNF-alpha maintained its independent role in multivariate analysis. TNF-alpha can stimulate the expression of many molecules, including interleukin-8 (IL-8) and endothelin-1 (ET-1); in our study, the expression of TNF-alpha was significantly associated with high IL-8 mRNA levels (p=0.008) and ET-1 mRNA positivity (p=0.03). We suggested that TNF-alpha can induce ET-1 mRNA expression in NSCLC, similarly to IL-8 expression. Our study may also contribute to advancing the knowledge of the molecular relationship between cytokines and endothelial functions in NSCLC.

Prognostic role of thymidylate synthase (TS) gene polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy

4044 Background: Previous studies suggest that TS expression in tumor tissue is related with both sensitivity to 5-FU-based chemotherapy and patients’outcome. TS gene has polymorphic sequences in its untranslated region (UTR) which are associated with TS expression. Aim of this study is to evaluate prognostic role of the TS polymorphisms in gastric cancer patients treated with surgery and 5-FU-based adjuvant chemotherapy. Methods: Ninety patients with advanced gastric cancer who had undergone radical surgery and received 5-FU-based adjuvant chemotherapy were included in this study. All patients underwent a 44-months minimum follow-up time. Lymphocyte genomic DNA was extracted from peripheral blood samples of the patients. Genotypes of variable number of tandem repeat (VNTR) and G/C single nucleotide polymorphism (SNP) in the TS 5’-UTR and 6bp deletion polymorphism in the 3’-UTR were determined by PCR and PCR-RFLP. According to previous studies the VNTR and the SNP were combined and the genotypes were grouped as follows; 5’-high (3G/3G, 3G/3C, 2R/3G) and 5’-low (2R/2R, 2R/3C, 3C/3C). Genotypes in 3’-UTR were also classified as follows; 3’-high (ins6/ins6) and 3’-low (del6/ins6, del6/del6). Results: There were no significant relationships between clinico-pathologic features and each TS polymorphism. Ten patients were 5’-high/3’-high (100% relapse/death), 36 patients were 5’-high/3’-low (67% relapse/death, 33% disease-free), 19 patients were 5’-low/3’-high (58% relapse/death, 42% disease-free), 25 patients were 5’-low/3’-low (36% relapse/death, 64% disease-free). Patients with 5’-low/3’-low genotypes showed significantly better outcome than those with 5’-high/3’-low and 5’-high/3’-high genotypes in regard to both 3-year disease-free and overall survival rates. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis. Conclusions: TS polymorphisms showed prognostic influence in the studied population of gastric cancer patients. Analysis of combined TS5’- and TS3’-UTR genotypes may be useful for improving adjuvant treatment strategies with tailored chemotherapy. No significant financial relationships to disclose.

Prognostic Role of Thymidylate Synthase Polymorphisms in Gastric Cancer Patients Treated with Surgery and Adjuvant Chemotherapy

To investigate the prognostic role of thymidylate synthase (TS) polymorphisms in gastric cancer patients treated with radical surgery and fluorouracil-based adjuvant chemotherapy. Ninety gastric cancer cases were identified among 187 patients previously enrolled in prospective case-control studies for disease susceptibility. Patients were genotyped for a G/C nucleotide change within a triple 28 bp variable number of tandem repeat sequence in the TS 5'-untranslated region (5'-UTR) and a 6 bp deletion in the TS 3'-untranslated region (3'-UTR). According to available functional data, patients with 5'-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (5'-UTRlow) and patients with 5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (5'UTRhigh). Patients with 3'-UTR del6/del6 and del6/ins6 genotypes were classified as low TS producers (3'-UTRlow) and patients with 3'-UTR ins6/ins6 genotype as high TS producers (3'-UTRhigh). The prognostic analysis was based on 5'-UTR/3'-UTR combined genotypes. Ten patients (11%) were 5'-UTRhigh/3'-UTRhigh, 36 patients were 5'-UTRhigh/3'-UTRlow, 19 patients were 5'-UTRlow/3'-UTRhigh, and 25 patients were 5'-UTRlow/3'-UTRlow. 5'-UTRlow/3'-UTRlow patients showed the best outcome and the threshold of statistical significance was achieved in the comparison of disease-free survival and overall survival with 5'-UTRhigh/3'-UTRlow patients and 5'-UTRhigh/3'-UTRhigh patients. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis. The prognostic role of TS polymorphisms in gastric cancer deserves further investigation because the adverse effect of high TS expression genotypes may be a relevant information to improve adjuvant chemotherapeutic strategies.

Non-suppressed thyrotropin and elevated thyroglobulin are independent predictors of recurrence in differentiated thyroid carcinoma.

Although in most cases differentiated thyroid carcinoma (DTC) responds to surgery and radioiodine (RaI) therapy, some patients will have recurrence and eventually cancer-related death. However, although various prognostic factors of DTC have been identified (e.g. staging, suppressed thyrotropin), none of the previous studies have assessed simultaneously their role in multivariate analysis. In this retrospective population-based study, we reviewed the clinicopathological data of 254 DTC patients treated in eastern Finland during the years 1976-1995, for clinical characteristics, primary treatment, follow-up and cancer recurrence. Tumor stage was based on pathological tumor-node-metastasis (pTNM) classification, and histopathological specimens were re-evaluated. DTC recurrence occurred in 33 patients (13%). In univariate analyses, the predictors of recurrence were older age (>60 years, P<0.05), follicular tumor type (P<0.01), pTNM classification system (P<0.05) and post-ablative radioiodine uptake outside the neck (P<0.05). Non-suppressed serum thyrotropin (TSH) and elevated serum thyroglobulin (>3 microg/l) measured one year after operation were both related to tumor recurrence (P<0.05 and P<0.001 respectively). In multivariate analysis the independent predictors for recurrence were both elevated thyroglobulin (P<0.001) and non-suppressed TSH (P<0.05) independent of histology, pTNM stage and RaI uptake. Adjusted risk ratio for recurrence of DTC for unsuppressed thyrotropin was 2.3, for elevated thyroglobulin 14.0 and, if both conditions were present, the risk ratio increased to 45.1. Our results suggest that both non-suppressed serum TSH and elevated serum thyroglobulin are related to an increased risk of DTC recurrence independent of tumor type and pTNM stage.