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In this study, the risk of debonding failure of the Cu-polyimide structure prepared by using realistic redistribution processes were investigated. The constitutive behavior of the polyimide thin film was first evaluated under tensile loading conditions at various temperatures. It was shown that the polyimide thin film with low glass transition temperature exhibits obvious viscoelastic response. A generalized Maxwell model was adopted to describe the thermoviscoelastic behavior. The debonding growth behavior of the Cu-polyimide interface was then investigated by using the double cantilever beam fracture mechanics tests. A finite-element based numerical model was then developed to evaluate the debonding growth at the Cu-polyimide interface and to investigate the effects of inelastic energy dissipations in the Cu and polyimide layers on the debonding response of the layered structure. The model can be applied to consider complex fan-out designs and would allow development of design rules for extending the Cu-polyimide based redistribution interconnect technology to the regimes of higher I/O densities.

In the present study, sliding tribo tests with reciprocating motion were carried out to simulate the thumb-driven wear arising in indium gallium zinc oxide (IGZO) specimens prepared at five inclination angles during film deposition. Frictional and normal forces, Fx and Fy, and vibrations were used to analyze energy dissipation (ΔW) and composite mean force fluctuation intensities (IFSS). Friction coefficient is lowered by decreasing the mean surface roughness (Ra); its increase can raise ΔW. The friction coefficients of samples prepared with a nonzero inclination angle were lower than that of the IGZO_0° specimen.

In the present study, indium gallium zinc oxide (IGZO) films were deposited onto graphene + Ni/SiO 2 /Si wafer specimens with deposition powers of 60-, 80-, and 100-W, respectively. The effects of deposition power on the microstructure and vacancy defects formed in the graphene + Ni layer are evaluated based on the electrical and mechanical properties of as-received specimens. The role and behavior of the graphene + Ni film on the electrical resistance of the IGZO film with microcracks were evaluated using a tribotester. The variations of the acceleration, a y , in the direction normal to specimen contact surface and the morphology of worn surface and the friction coefficient in a stroke are provided us to identify their wear styles including seizure, stick-slip motion, and running-in instability. After applying a number of swing cycles, the turning angle of the Ni crystalline with respect to the graphene orientation increases with increasing the number of cycles. The mean microcrack length increases with increasing the turning angle. However, the electrical resistance of specimen is not elevated by increasing the microcrack length so long as the connection of the graphene layer with the IGZO film is sustained. Increase in the deposition power promotes the growth of hillocks in the graphene + Ni layer. These hillocks make the graphene + Ni layer convex with an uneven film thickness and lead to void defects in the graphene + Ni layer, they also cause the IGZO film with relatively large mean surface roughness and high friction coefficient.

Genome-wide association studies (GWAS) have become the method of choice for identifying disease susceptibility genes in common disease genetics research. Despite successes in these studies, much of the heritability remains unexplained due to lack of power and low resolution. High-density genotyping arrays can now screen more than 5 million genetic markers. As a result, multiple comparison has become an important issue especially in the era of next-generation sequencing. We propose to use a two-stage maximal segmental score procedure (MSS) which uses region-specific empirical P-values to identify genomic segments most likely harboring the disease gene. We develop scoring systems based on Fisher's P-value combining method to convert locus-specific significance levels into region-specific scores. Through simulations, our result indicated that MSS increased the power to detect genetic association as compared with conventional methods provided type I error was at 5%. We demonstrated the application of MSS on a publicly available case-control dataset of Parkinson's disease and replicated the findings in the literature. MSS provides an efficient exploratory tool for high-density association data in the current era of next-generation sequencing. R source codes to implement the MSS procedure are freely available at http://www.csjfann.ibms.sinica.edu.tw/EAG/program/programlist.htm.

Background Genome-wide association studies have been successful in identifying common genetic variants for human diseases. However, much of the heritable variation associated with diseases such as Parkinson’s disease remains unknown suggesting that many more risk loci are yet to be identified. Rare variants have become important in disease association studies for explaining missing heritability. Methods for detecting this type of association require prior knowledge on candidate genes and combining variants within the region. These methods may suffer from power loss in situations with many neutral variants or causal variants with opposite effects. Results We propose a method capable of scanning genetic variants to identify the region most likely harbouring disease gene with rare and/or common causal variants. Our method assigns a score at each individual variant based on our scoring system. It uses aggregate scores to identify the region with disease association. We evaluate performance by simulation based on 1000 Genomes sequencing data and compare with three commonly used methods. We use a Parkinson’s disease case–control dataset as a model to demonstrate the application of our method. Our method has better power than CMC and WSS and similar power to SKAT-O with well-controlled type I error under simulation based on 1000 Genomes sequencing data. In real data analysis, we confirm the association of α-synuclein gene (SNCA) with Parkinson’s disease (p = 0.005). We further identify association with hyaluronan synthase 2 (HAS2, p = 0.028) and kringle containing transmembrane protein 1 (KREMEN1, p = 0.006). KREMEN1 is associated with Wnt signalling pathway which has been shown to play an important role for neurodegeneration in Parkinson’s disease. Conclusions Our method is time efficient and less sensitive to inclusion of neutral variants and direction effect of causal variants. It can narrow down a genomic region or a chromosome to a disease associated region. Using Parkinson’s disease as a model, our method not only confirms association for a known gene but also identifies two genes previously found by other studies. In spite of many existing methods, we conclude that our method serves as an efficient alternative for exploring genomic data containing both rare and common variants. Electronic supplementary material The online version of this article (doi:10.1186/s12929-014-0088-9) contains supplementary material, which is available to authorized users.

Background Genetic variation associated with human leukocyte antigen (HLA) genes has immunological functions and is associated with autoimmune diseases. To date, large-scale studies involving classical HLA genes have been limited by time-consuming and expensive HLA-typing technologies. To reduce these costs, single-nucleotide polymorphisms (SNPs) have been used to predict HLA-allele types. Although HLA allelic distributions differ among populations, most prediction model of HLA genes are based on Caucasian samples, with few reported studies involving non-Caucasians. Results Our sample consisted of 437 Han Chinese with Affymetrix 5.0 and Illumina 550 K SNPs, of whom 214 also had data on Affymetrix 6.0 SNPs. All individuals had HLA typings at a 4-digit resolution. Using these data, we have built prediction model of HLA genes that are specific for a Han Chinese population. To optimize our prediction model of HLA genes, we analyzed a number of critical parameters, including flanking-region size, genotyping platform, and imputation. Predictive accuracies generally increased both with sample size and SNP density. Conclusions SNP data from the HapMap Project are about five times more dense than commercially available genotype chip data. Using chips to genotype our samples, however, only reduced the accuracy of our HLA predictions by only ~3%, while saving a great deal of time and expense. We demonstrated that classical HLA alleles can be predicted from SNP genotype data with a high level of accuracy (80.37% (HLA-B) ~95.79% (HLA-DQB1)) in a Han Chinese population. This finding offers new opportunities for researchers in obtaining HLA genotypes via prediction using their already existing chip datasets. Since the genetic variation structure (e.g. SNP, HLA, Linkage disequilibrium) is different between Han Chinese and Caucasians, and has strong impact in building prediction models for HLA genes, our findings emphasize the importance of building ethnic-specific models when analyzing human populations.

Advances in biotechnology have resulted in large-scale studies of DNA methylation. A differentially methylated region (DMR) is a genomic region with multiple adjacent CpG sites that exhibit different methylation statuses among multiple samples. Many so-called “supervised” methods have been established to identify DMRs between two or more comparison groups. Methods for the identification of DMRs without reference to phenotypic information are, however, less well studied. An alternative “unsupervised” approach was proposed, in which DMRs in studied samples were identified with consideration of nature dependence structure of methylation measurements between neighboring probes from tiling arrays. Through simulation study, we investigated effects of dependencies between neighboring probes on determining DMRs where a lot of spurious signals would be produced if the methylation data were analyzed independently of the probe. In contrast, our newly proposed method could successfully correct for this effect with a well-controlled false positive rate and a comparable sensitivity. By applying to two real datasets, we demonstrated that our method could provide a global picture of methylation variation in studied samples. R source codes to implement the proposed method were freely available at http://www.csjfann.ibms.sinica.edu.tw/eag/programlist/ICDMR/ICDMR.html.

In the present study, graphite-like +Ni/SiO2/Si wafer specimens were prepared using a co-sputtering system. Then, indium gallium zinc oxide (IGZO) films were deposited onto the graphite-like +Ni/SiO2/Si wafer specimens at deposition powers of 60, 80, and 100 W, respectively. The effects of IGZO deposition power on the specimen’s microstructure and the vacancy defects in the graphite-like +Ni layer are evaluated in terms of the electrical and mechanical properties of the as-prepared specimens. The effects of the graphite-like +Ni film on the electrical resistance of the IGZO film with microcracks is evaluated using a tribotester. The quantity and mean size of microcracks and variations of electrical resistance of the IGZO/graphite-like +Ni/SiO2/Si wafer specimens with time are used to evaluate the role of the graphite-like +Ni layer as an alternate conductor of electric current when the IGZO film is degraded by microcracks. The growth of hillocks in the graphite-like +Ni layer can be enhanced by increasing the IGZO deposition power. These hillocks cause the graphite-like +Ni layer to be convex and have an uneven film thickness, and lead to vacancy defects in the graphite-like film. The O atoms of IGZO were incorporated into graphene in the graphite-like layer as substitutional impurities. The effects of these impurities on the electrical structure with a characteristic of superconductors occur intermittently in the tribotests, resulting in a sharp reduction in the electrical resistance of a specimen. An increase in the intensity ratio, IRO2, related to oxygen vacancies, increases the peak intensities (PIs) of elemental Ga and the Ga-O bond, and decreases that of the Ga-Ga bond. In the IGZO/Glass specimens, a small reduction of the average transmittance is created in the specimens prepared by increasing the deposition power from 60 W to 100 W. The behavior of reflection is exactly opposite to that of transmittance. An increase in deposition power is favorable for the rise of optical band gap (Eg). Increasing the concentration of Zn2p3/2 or Zn2p1/2 increases PIGreen in photoluminescence profiles. Reductions in either In atoms or C-C and C-O bonds increase PIOrange. PIRed and can be increased by either increasing PIGa-Ga or decreasing the values of PIGa2p3/2, PIGa2p1/2, and PIGa-O.

Identifying susceptibility genes that influence complex diseases is extremely difficult because loci often influence the disease state through genetic interactions. Numerous approaches to detect disease-associated SNP-SNP interactions have been developed, but none consistently generates high-quality results under different disease scenarios. Using summarizing techniques to combine a number of existing methods may provide a solution to this problem. Here we used three popular non-parametric methods-Gini, absolute probability difference (APD), and entropy-to develop two novel summary scores, namely principle component score (PCS) and Z-sum score (ZSS), with which to predict disease-associated genetic interactions. We used a simulation study to compare performance of the non-parametric scores, the summary scores, the scaled-sum score (SSS; used in polymorphism interaction analysis (PIA)), and the multifactor dimensionality reduction (MDR). The non-parametric methods achieved high power, but no non-parametric method outperformed all others under a variety of epistatic scenarios. PCS and ZSS, however, outperformed MDR. PCS, ZSS and SSS displayed controlled type-I-errors (0.05) compared to GS, APDS, ES (0.05). A real data study using the genetic-analysis-workshop 16 (GAW 16) rheumatoid arthritis dataset identified a number of interesting SNP-SNP interactions.

Complex diseases are typically caused by combinations of molecular disturbances that vary widely among different patients. Endophenotypes, a combination of genetic factors associated with a disease, offer a simplified approach to dissect complex trait by reducing genetic heterogeneity. Because molecular dissimilarities often exist between patients with indistinguishable disease symptoms, these unique molecular features may reflect pathogenic heterogeneity. To detect molecular dissimilarities among patients and reduce the complexity of high-dimension data, we have explored an endophenotype-identification analytical procedure that combines non-negative matrix factorization (NMF) and adjusted rand index (ARI), a measure of the similarity of two clusterings of a data set. To evaluate this procedure, we compared it with a commonly used method, principal component analysis with k-means clustering (PCA-K). A simulation study with gene expression dataset and genotype information was conducted to examine the performance of our procedure and PCA-K. The results showed that NMF mostly outperformed PCA-K. Additionally, we applied our endophenotype-identification analytical procedure to a publicly available dataset containing data derived from patients with late-onset Alzheimer's disease (LOAD). NMF distilled information associated with 1,116 transcripts into three metagenes and three molecular subtypes (MS) for patients in the LOAD dataset: MS1 (n1=80), MS2 (n2=73), and MS3 (n3=23). ARI was then used to determine the most representative transcripts for each metagene; 123, 89, and 71 metagene-specific transcripts were identified for MS1, MS2, and MS3, respectively. These metagene-specific transcripts were identified as the endophenotypes. Our results showed that 14, 38, 0, and 28 candidate susceptibility genes listed in AlzGene database were found by all patients, MS1, MS2, and MS3, respectively. Moreover, we found that MS2 might be a normal-like subtype. Our proposed procedure provides an alternative approach to investigate the pathogenic mechanism of disease and better understand the relationship between phenotype and genotype.

Genome-wide association studies (GWAS) have become the method of choice for identifying disease susceptibility genes in common disease genetics research. Despite successes in these studies, much of the heritability remains unexplained due to lack of power and low resolution. High-density genotyping arrays can now screen more than 5 million genetic markers. As a result, multiple comparison has become an important issue especially in the era of next-generation sequencing. We propose to use a two-stage maximal segmental score procedure (MSS) which uses region-specific empirical P-values to identify genomic segments most likely harboring the disease gene. We develop scoring systems based on Fisher's P-value combining method to convert locus-specific significance levels into region-specific scores. Through simulations, our result indicated that MSS increased the power to detect genetic association as compared with conventional methods provided type I error was at 5%. We demonstrated the application of MSS on a publicly available case-control dataset of Parkinson's disease and replicated the findings in the literature. MSS provides an efficient exploratory tool for high-density association data in the current era of next-generation sequencing. R source codes to implement the MSS procedure are freely available at http://www.csjfann.ibms.sinica.edu.tw/EAG/program/programlist.htm.

Haplotype-based approaches may have greater power than single-locus analyses when the SNPs are in strong linkage disequilibrium with the risk locus. To overcome potential complexities owing to large numbers of haplotypes in genetic studies, we evaluated two data mining approaches, multifactor dimensionality reduction (MDR) and classification and regression tree (CART), with the concept of haplotypes considering their haplotype uncertainty to detect haplotype–haplotype (HH) interactions. In evaluation of performance for detecting HH interactions, MDR had higher power than CART, but MDR gave a slightly higher type I error. Additionally, we performed an HH interaction analysis with a publicly available dataset of Parkinson's disease and confirmed previous findings that the RET proto-oncogene is associated with the disease. In this study, we showed that using HH interaction analysis is possible to assist researchers in gaining more insight into identifying genetic risk factors for complex diseases.