Directional testing for one-way MANOVA in divergent dimensions

Testing the equality of mean vectors across $g$ different groups plays an important role in many scientific fields. In regular frameworks, likelihood-based statistics under the normality assumption offer a general solution to this task. However, the accuracy of standard asymptotic results is not reliable when the dimension $p$ of the data is large relative to the sample size $n_i$ of each group. We propose here an exact directional test for the equality of $g$ normal mean vectors with identical unknown covariance matrix, provided that $\sum_{i=1}^g n_i \ge p+g+1$. In the case of two groups ($g=2$), the directional test is equivalent to the Hotelling's $T^2$ test. In the more general situation where the $g$ independent groups may have different unknown covariance matrices, although exactness does not hold, simulation studies show that the directional test is more accurate than most commonly used likelihood based solutions. Robustness of the directional approach and its competitors under deviation from multivariate normality is also numerically investigated.Comment: 51 pages, 15 figure

Appropriate whole genome amplification and pathogenic loci detection can improve the accuracy of preimplantation genetic diagnosis for deletional α-thalassemia

ObjectiveTo improve the accuracy of preimplantation genetic testing (PGT) in deletional α-thalassemia patients.DesignArticle.Patient(s)fifty-two deletional α-thalassemia couples.Intervention(s)Whole genome amplification (WGA), Next-generation sequencing (NGS) and PCR mutation loci detection.Main outcome measuresWGA, Single nucleotide polymorphism (SNP) and PCR mutation loci detection results; Analysis of embryo chromosome copy number variation (CNV).ResultsMultiple Displacement Amplification (MDA) and Multiple Annealing and Looping–Based Amplification Cycles (MALBAC) methods for PGT for deletional α-thalassemia. Blastocyst biopsy samples (n = 253) were obtained from 52 deletional α-thalassemia couples. The results of the comparison of experimental data between groups MALBAC and MDA are as follows: (i) The average allele drop-out (ADO) rate, MALBAC vs. MDA = 2.27% ± 3.57% vs. 0.97% ± 1.4%, P=0.451); (ii) WGA success rate, MALBAC vs. MDA = 98.61% vs. 98.89%, P=0.851; (iii) SNP haplotype success rate, MALBAC vs. MDA = 94.44% vs. 96.68%, P=0.409; (iv) The result of SNP haplotype analysis is consistent with that of Gap-PCR/Sanger sequencing results, MALBAC vs. MDA = 36(36/72, 50%) vs. 151(151/181, 83.43%), P=0; (v) Valid SNP loci, MALBAC vs. MDA = 30 ± 9 vs. 34 ± 10, P=0.02; (vi) The mean CV values, MALBAC vs. MDA = 0.12 ± 0.263 vs. 0.09 ± 0.40, P=0.916; (vii) The average number of raw reads, MALBAC vs. MDA =3244259 ± 999124 vs. 3713146 ± 1028721, P=0; (viii) The coverage of genome (%), MALBAC vs. MDA = 5.02 ± 1.09 vs. 5.55 ± 1.49, P=0.008.ConclusionsOur findings indicate that MDA is superior to MALBAC for PGT of deletional α-thalassemia. Furthermore, SNP haplotype analysis combined with PCR loci detection can improve the accuracy and detection rate of deletional α-thalassemia

Likelihood-based inference for moderate to high dimensional models

Likelihood based statistics and its standard asymptotic distribution results offer a general solution for hypothesis testing in parametric models. However, such approximate solutions are not reliable when the dimension $p$ of the parameter may increase with the sample size $n$. However, in such divergent dimensional regimes, higher-order likelihood approximations, even though developed in the fixed $p$ scenario, such as the directional test \citep{sartori:2014} and modifications of log-likelihood ratio test \cite{skovgaard:2001}, may still give substantial improvements over standard first-order solutions. Taking inspiration from a classification of asymptotic regimes recently introduced by \cite{battey2022some}, we focus on a moderate dimensional asymptotic setting, in which $p/n \to 0$, for instance with $p=O(n^\tau)$, with $\tau \in (0,1)$, and a high dimensional asymptotic setting, in which $p/n \to \kappa \in (0,1)$. On the other hand, we will not consider ultra-high dimensional settings, in which $p/n$ converges to a constant greater than 1, or even diverges. Within several prominent frameworks, we propose then to provide reliable solutions via higher-order approximations. In particular, the first part of the thesis examines higher-order likelihood solutions for moderate and high dimensional multivariate normal models. In the high dimensional regimes, we prove that the directional $p$-value is exactly uniformly distributed under the null hypothesis for seven prominent hypotheses concerning means and/or covariance matrices of multivariate normal distributions. We also consider a multivariate Behrens-Fisher problem, that is testing a hypothesis of equality of mean vectors in $k$ independent multivariate normal distribution with different covariance matrices. In this case, the parameter being tested is not a canonical parameter of an exponential family and therefore we cannot expect the accuracy of the methods to hold in high dimensional regimes. For this reason, we restrict ourselves to moderate dimensional regimes. Simulation results show that the higher-order approximations outperform the standard first-order solutions. Finally, we also study moderate dimensional logistic regression models. We consider three types of hypotheses: where the whole parameter is of interest, (i.e. no nuisance parameters problem), when a scalar component of the parameter is of interest, and when a vector component of the parameter is of interest. We give a tentative proof that the directional test gives reliable results provided that $p=o(n^{3/4})$ under a particular Gaussian assumption on the design matrix. Extended simulation results showed that the higher-order approximations perform good when the dimension of the parameter of interest is small or the dimension of the nuisance parameter is large. In this model setting, also Skovgaard's modified likelihood ratio statistic is empirically found to provide very accurate results. A more thorough theoretical study of these statistics in this setting is certainly an interesting future development of this thesis.Likelihood based statistics and its standard asymptotic distribution results offer a general solution for hypothesis testing in parametric models. However, such approximate solutions are not reliable when the dimension $p$ of the parameter may increase with the sample size $n$. However, in such divergent dimensional regimes, higher-order likelihood approximations, even though developed in the fixed $p$ scenario, such as the directional test \citep{sartori:2014} and modifications of log-likelihood ratio test \cite{skovgaard:2001}, may still give substantial improvements over standard first-order solutions. Taking inspiration from a classification of asymptotic regimes recently introduced by \cite{battey2022some}, we focus on a moderate dimensional asymptotic setting, in which $p/n \to 0$, for instance with $p=O(n^\tau)$, with $\tau \in (0,1)$, and a high dimensional asymptotic setting, in which $p/n \to \kappa \in (0,1)$. On the other hand, we will not consider ultra-high dimensional settings, in which $p/n$ converges to a constant greater than 1, or even diverges. Within several prominent frameworks, we propose then to provide reliable solutions via higher-order approximations. In particular, the first part of the thesis examines higher-order likelihood solutions for moderate and high dimensional multivariate normal models. In the high dimensional regimes, we prove that the directional $p$-value is exactly uniformly distributed under the null hypothesis for seven prominent hypotheses concerning means and/or covariance matrices of multivariate normal distributions. We also consider a multivariate Behrens-Fisher problem, that is testing a hypothesis of equality of mean vectors in $k$ independent multivariate normal distribution with different covariance matrices. In this case, the parameter being tested is not a canonical parameter of an exponential family and therefore we cannot expect the accuracy of the methods to hold in high dimensional regimes. For this reason, we restrict ourselves to moderate dimensional regimes. Simulation results show that the higher-order approximations outperform the standard first-order solutions. Finally, we also study moderate dimensional logistic regression models. We consider three types of hypotheses: where the whole parameter is of interest, (i.e. no nuisance parameters problem), when a scalar component of the parameter is of interest, and when a vector component of the parameter is of interest. We give a tentative proof that the directional test gives reliable results provided that $p=o(n^{3/4})$ under a particular Gaussian assumption on the design matrix. Extended simulation results showed that the higher-order approximations perform good when the dimension of the parameter of interest is small or the dimension of the nuisance parameter is large. In this model setting, also Skovgaard's modified likelihood ratio statistic is empirically found to provide very accurate results. A more thorough theoretical study of these statistics in this setting is certainly an interesting future development of this thesis

Directional testing for high dimensional multivariate normal distributions

Thanks to its favorable properties, the multivariate normal distribution is still largely employed for modeling phenomena in various scientific fields. However, when the number of components $p$ is of the same asymptotic order as the sample size $n$, standard inferential techniques are generally inadequate to conduct hypothesis testing on the mean vector and/or the covariance matrix. Within several prominent frameworks, we propose then to draw reliable conclusions via a directional test. We show that under the null hypothesis the directional $p$-value is exactly uniformly distributed even when $p$ is of the same order of $n$, provided that conditions for the existence of the maximum likelihood estimate for the normal model are satisfied. Extensive simulation results confirm the theoretical findings across different values of $p/n$, and show that under the null hypothesis the directional test outperforms not only the usual first and higher-order finite-$p$ solutions but also alternative methods tailored for high-dimensional settings. Simulation results also indicate that the power performance of the different tests depends on the specific alternative hypothesis.Comment: 60 pages, 38 figures, 14 table

Flexible video endoscope versus Macintosh laryngoscope for orotracheal tracheal intubation in the lateral position: a study protocol for a randomized controlled trial

Abstract Background Tracheal intubation with the patient in the lateral position is difficult because the laryngeal view is compromised during direct laryngoscopy. Flexible video endoscopes may facilitate intubation even when laryngeal views are poor on direct laryngoscopy because the patients are positioned laterally. Thus, this trial aims to compare the efficacy of flexible video endoscopes to Macintosh laryngoscopes for orotracheal intubation in the lateral position and to investigate their feasibility, i.e., whether the use of the two devices in combination can secure the airway when endotracheal intubation in the lateral position has failed using one device. Methods This will be a prospective, randomized, single-center, clinical trial. One hundred and seventy-four patients aged 18–65 years, who have been scheduled to undergo tracheal intubation under uniform general anesthetic techniques for elective kidney surgery in the lateral decubitus position will be randomly divided into the flexible video endoscope and the Macintosh laryngoscope groups. Primary outcomes include intubation time and intubation success rate. Secondary outcomes include overall user satisfaction (graded from 1 to 10 (1 = very poor, 10 = excellent)) and perioperative side effects and complications, such as frequency of esophageal intubation, lip or dental injury, sore throat, and hoarseness. Discussion The trial will clarify the efficacy of intubation with a Macintosh laryngoscope and a flexible video endoscope in the lateral position, and whether the two devices could be used in combination to secure the airway in cases where endotracheal intubation in the lateral position has failed with one device. Trial registration Chinese Clinical Trial Register, ChiCTR- IOR-15007175. Registered on 6 October 2015

Assessment of the Exterior Quality of Traditional Residences: A Genetic Algorithm–Backpropagation Approach

The visual aesthetics of villages are remarkably affected by the exterior quality of traditional residences, influencing the impression and assessment of local culture. A proper scientific assessment of exterior quality can protect traditional cultures and improve the development of villages. This research was conducted in a village consisting of 115 residences (Mengjinglai village, which is on the border between China and Myanmar). The backpropagation (BP) neural network model with genetic algorithm (GA) was applied to evaluate the quality of the dwellings. All the evaluation values of the dwellings were defined by scores. Meanwhile, the score of each residence was affected by three main factors: architectural spatial elements, architectural construction elements, and historical and cultural elements. The results show that the village’s dwellings are well preserved and clearly express the traditional Dai style. Moreover, the GA–BP approach is more suitable than the traditional BP method for the assessment of the exterior quality. The quantitative machine learning model would be useful for other aspects of the assessment of similar villages in the future

A new insight into male fertility preservation for patients with completely immotile spermatozoa

Abstract Background Sperm cryopreservation is the most effective method to preserve male fertility but this is normally used for motile spermatozoa. Thus, only motile spermatozoa are used for cryopreservation in most reproductive medicine centers worldwide. The immotile spermatozoa from some problematic patients are usually discarded, resulting in a missed opportunity of sterility cryopreservation for future assisted reproductive treatments. Many studies have shown that successful fertilization can be obtained after selection of viable sperm from the completely immotile spermatozoa before ICSI. Whether the completely immotile spermatozoa are worth of freezing has not been realized The aim of this study is to explore the clinical value of cryopreservation of immotile spermatozoa. Methods Completely immotile spermatozoa were collected and frozen, and subsequently viable but immotile frozen-thawed spermatozoa were selected by laser plus for ICSI. Main outcomes included spermatozoa survival index, fertilization rate and good quality embryo rate. Results After identification by laser, the fresh samples of spermatozoa presented with a mean survival rate of 54.86% and 26.05%, and this was reduced to 44.13% and 18.13% in frozen-thawed spermatozoa samples, which showed a frozen-thawed spermatozoa survival index of 0.80 and 0.70 in the testicular and ejaculate sperm, respectively. There were no statistically differences in fertilization rate (80% vs80.51%, 75.00% vs 81.48%), cleavage rate (95.45% vs 98.95%, 100.00% vs 95.45%) and good quality embryo rate (40.48% vs 52.13%, 33.33%vs38.10%) between the frozen-thawed immotile spermatozoa group and the routine fresh immotile spermatozoa ICSI group in both testicular and ejaculate sperm, respectively. Conclusions The results of the study show that completely immotile spermatozoa can be frozen in order to preserve male fertility as long as viable spermatozoa are present. This procedure provides a further possibility for fertility preservation for patients with completely immotile spermatozoa

Table_2_Appropriate whole genome amplification and pathogenic loci detection can improve the accuracy of preimplantation genetic diagnosis for deletional α-thalassemia.docx

ObjectiveTo improve the accuracy of preimplantation genetic testing (PGT) in deletional α-thalassemia patients.DesignArticle.Patient(s)fifty-two deletional α-thalassemia couples.Intervention(s)Whole genome amplification (WGA), Next-generation sequencing (NGS) and PCR mutation loci detection.Main outcome measuresWGA, Single nucleotide polymorphism (SNP) and PCR mutation loci detection results; Analysis of embryo chromosome copy number variation (CNV).ResultsMultiple Displacement Amplification (MDA) and Multiple Annealing and Looping–Based Amplification Cycles (MALBAC) methods for PGT for deletional α-thalassemia. Blastocyst biopsy samples (n = 253) were obtained from 52 deletional α-thalassemia couples. The results of the comparison of experimental data between groups MALBAC and MDA are as follows: (i) The average allele drop-out (ADO) rate, MALBAC vs. MDA = 2.27% ± 3.57% vs. 0.97% ± 1.4%, P=0.451); (ii) WGA success rate, MALBAC vs. MDA = 98.61% vs. 98.89%, P=0.851; (iii) SNP haplotype success rate, MALBAC vs. MDA = 94.44% vs. 96.68%, P=0.409; (iv) The result of SNP haplotype analysis is consistent with that of Gap-PCR/Sanger sequencing results, MALBAC vs. MDA = 36(36/72, 50%) vs. 151(151/181, 83.43%), P=0; (v) Valid SNP loci, MALBAC vs. MDA = 30 ± 9 vs. 34 ± 10, P=0.02; (vi) The mean CV values, MALBAC vs. MDA = 0.12 ± 0.263 vs. 0.09 ± 0.40, P=0.916; (vii) The average number of raw reads, MALBAC vs. MDA =3244259 ± 999124 vs. 3713146 ± 1028721, P=0; (viii) The coverage of genome (%), MALBAC vs. MDA = 5.02 ± 1.09 vs. 5.55 ± 1.49, P=0.008.ConclusionsOur findings indicate that MDA is superior to MALBAC for PGT of deletional α-thalassemia. Furthermore, SNP haplotype analysis combined with PCR loci detection can improve the accuracy and detection rate of deletional α-thalassemia.</p

Table_1_Appropriate whole genome amplification and pathogenic loci detection can improve the accuracy of preimplantation genetic diagnosis for deletional α-thalassemia.xlsx

ObjectiveTo improve the accuracy of preimplantation genetic testing (PGT) in deletional α-thalassemia patients.DesignArticle.Patient(s)fifty-two deletional α-thalassemia couples.Intervention(s)Whole genome amplification (WGA), Next-generation sequencing (NGS) and PCR mutation loci detection.Main outcome measuresWGA, Single nucleotide polymorphism (SNP) and PCR mutation loci detection results; Analysis of embryo chromosome copy number variation (CNV).ResultsMultiple Displacement Amplification (MDA) and Multiple Annealing and Looping–Based Amplification Cycles (MALBAC) methods for PGT for deletional α-thalassemia. Blastocyst biopsy samples (n = 253) were obtained from 52 deletional α-thalassemia couples. The results of the comparison of experimental data between groups MALBAC and MDA are as follows: (i) The average allele drop-out (ADO) rate, MALBAC vs. MDA = 2.27% ± 3.57% vs. 0.97% ± 1.4%, P=0.451); (ii) WGA success rate, MALBAC vs. MDA = 98.61% vs. 98.89%, P=0.851; (iii) SNP haplotype success rate, MALBAC vs. MDA = 94.44% vs. 96.68%, P=0.409; (iv) The result of SNP haplotype analysis is consistent with that of Gap-PCR/Sanger sequencing results, MALBAC vs. MDA = 36(36/72, 50%) vs. 151(151/181, 83.43%), P=0; (v) Valid SNP loci, MALBAC vs. MDA = 30 ± 9 vs. 34 ± 10, P=0.02; (vi) The mean CV values, MALBAC vs. MDA = 0.12 ± 0.263 vs. 0.09 ± 0.40, P=0.916; (vii) The average number of raw reads, MALBAC vs. MDA =3244259 ± 999124 vs. 3713146 ± 1028721, P=0; (viii) The coverage of genome (%), MALBAC vs. MDA = 5.02 ± 1.09 vs. 5.55 ± 1.49, P=0.008.ConclusionsOur findings indicate that MDA is superior to MALBAC for PGT of deletional α-thalassemia. Furthermore, SNP haplotype analysis combined with PCR loci detection can improve the accuracy and detection rate of deletional α-thalassemia.</p