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Abstract Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond.

Abstract Samples used in biomedical research are often collected over years, in some cases from subjects that may have died and thus cannot be retrieved in any way. The value of these samples is priceless. Sample misidentification or mix-up are unfortunately common problems in biomedical research and can eventually result in the publication of incorrect data. Here we have compared the Fluidigm SNPtrace and the Agena iPLEX Sample ID panels for the authentication of human genomic DNA samples. We have tested 14 pure samples and simulated their cross-contamination at different percentages (2%, 5%, 10%, 25% and 50%). For both panels, we report call rate, allele intensity/probability score, performance in distinguishing pure samples and contaminated samples at different percentages, and sex typing. We show that both panels are reliable and efficient methods for sample authentication and we highlight their advantages and disadvantages. We believe that the data provided here is useful for sample authentication especially in biorepositories and core facility settings.

Abstract Background Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. Methods Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. Results In HCM, the analysis of 25 HCM‐associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes. Conclusion We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

A widely used controller tuning method is relay autotuning. Approximate values for ultimate gain (Ku) and critical frequency (ωu) are achieved by this tuning procedure. Astrom and Hagglund have proposed a method of estimating Ku and ωu, which considers only fundamental harmonics, neglecting higher order harmonics, hence resulting in erroneous ultimate gain Ku values. In this paper, the effect of higher order harmonic analysis for simultaneous relay autotuning of open loop unstable series cascade systems is studied. Simultaneous relay autotuning for conventional P/PI cascade control configuration is designed for comparison with the proposed method, which utilizes corrected ultimate controller gain values. Three simulation examples are studied in this paper. The two controllers for the two methods are designed using Ziegler-Nichols tuning rules. The proposed method gives significant improvement in both the servo and regulatory responses for the three examples. Robustness studies using complimentary sensitivity function is carried out and robustness is ensured. [ABSTRACT FROM AUTHOR]

In the present work, the matrix notation is used to derive the Internal Model Control (IMC) decentralized Proportional Integral (PI) controllers. MacLaurin series is applied to the resulting equation to get the controller parameters. For design of the controllers, the diagonal elements of the process are used, whereas for evaluating the performance of the controllers, the full transfer function matrix of the process is used. For a two input-two output (2 × 2) system example, the recently available methods for designing decentralized PI controllers (Equivalent Transfer Function methods, Effective Relative Gain Array method, Direct multi-loop method) are compared with the present method. For a 4 × 4 system, the corresponding recent reported methods are compared. The performance of the present method is better than the above methods. The performances of the control systems are compared in terms of the Integral absolute error and the controller output behaviour is compared in terms of total variation. The robustness of the control system is evaluated by the maximum sensitivity and by the inverse maximum singular value of the input and the output multiplicative uncertainties. [ABSTRACT FROM AUTHOR]

The biggest log modulus tuning (BLT) method is extended to unstable systems. The method is modified to design (i) decentralized Proportional-Integral (PI) controllers and (ii) centralized PI controllers for two-input two-output (TITO) systems. A method is given to specify the value for The internal model controller using Tanttu and Lieslehto method is applied for centralized controller design. The detuning parameter (F) is selected for both the schemes (centralized controller and decentralized controller) to get the value of BLT as +12 dB. Simulation studies are carried out for two TITO systems to evaluate the performance of both the proposed schemes. The centralized controllers produce superior performances and decreased interactions over the decentralized PI controllers. The present method gives robust performances. [ABSTRACT FROM AUTHOR]

Davison (1976) proposed a method to design controllers for multivariable systems using the knowledge of only the Steady-State Gain Matrix (SSGM) of the system. In the present work, Davison's method is suitably modified to design controllers for unstable non-square multivariable systems. A single-stage multivariable PI controller is designed using the SSGM. Simulation results show that the overshoots of the closed loop responses are larger, hence a two-stage P-PI control system is proposed. For the proposed two- stage design (i) the system is first stabilized by a simple proportional controller matrix designed based on SSGM using modified Davison's method (1976). (ii) Diagonal PI controllers are designed for this stabilized system based on gain matrix. Simulation studies are carried out to compare the closed loop performance of the single stage multivariable PI control system with that of the two-stage control system (inner loop centralized P controllers and outer loop diagonal PI controllers). A method to identify the steady state gain matrix of a non-square multivariable (SSGM) unstable system under closed loop control is presented. The effect of disturbances and measurement noise on the identification of SSGM is also discussed. [ABSTRACT FROM AUTHOR]

In this paper, the simple method of designing decentralized Proportional–Integral-Derivative (PID) controllers by the synthesis method is extended to design centralized PID controllers. The centralized controllers give improved responses and reduced interactions when applied to systems withλij < 1. The effectiveness of the proposed method is compared with that of the available decentralized and separately with the centralized controllers. The robustness of these controllers is evaluated by the inverse maximum singular value versus frequency plot for both the input uncertainty and the output multiplicative uncertainty. Simulation results for two 2 × 2 systems demonstrate that the proposed method guarantees robust stability and provides best servo and regulatory responses. [ABSTRACT FROM PUBLISHER]

Earlier studies have provided evidence that the gestational diabetes mellitus (GDM) and Type 2 diabetes mellitus (T2DM) share common genetic background. A recent genome wide association study (GWAS) showed a strong association of six novel gene variants with T2DM among south Asians but not with Europeans. The aim of this study was to investigate whether these variants that confer susceptibility to T2DM in Asian Indian population also correlate with GDM in Asian Indian population. In addition to these novel variants, three T2DM associated SNPs that were previously identified by GWAS in Caucasian populations, which also showed association with T2DM in south Indian population in our previous study were also evaluated for their susceptibility to GDM in our population. The study groups comprised unrelated pregnant women with GDM ( n = 518) and pregnant women with normal glucose tolerance (NGT) ( n = 1220). A total of nine SNPs in or near nine loci, namely AP3S2 (rs2028299), BAZ1B (rs12056034), CDKN2A/ B (rs7020996), GRB14 (rs3923113), HHEX (rs7923837), HMG20A (rs7178572), HNF4A (rs4812829), ST6GAL1 (rs16861329) and VPS26A (rs1802295) were genotyped using the MassARRAY system. Among these nine SNPs that previously showed an association with T2DM in Asian Indians, HMG20A (rs7178572) and HNF4A (rs4812829) gene variants showed a significant association with GDM. The risk alleles of rs7178572 in HMG20A and rs4812829 in HNF4A gene conferred 1.24 and 1.28 times higher risk independently and about 1.44 and 1.97 times increased susceptibility to GDM for one and two risk genotypes, respectively. We report that the HMG20A (rs7178572) and HNF4A (rs4812829) variants that have previously shown a strong association with T2DM in Asian Indians also contributes significant risk to GDM in this population. This is the first report of the association of HMG20A (rs7178572) and HNF4A (rs4812829) variants with GDM. [ABSTRACT FROM AUTHOR]

This study reports on the association of genetic variants selected from previous genome-wide association studies for type 2 diabetic nephropathy in south Indians. Eight variants were genotyped in 601 type 2 diabetic subjects without nephropathy (DM) and 583 type 2 diabetic subjects with nephropathy (DN) by MassARRAY. The minor allele frequencies of rs11643718 SLC12A3 variant and rs741301 ELMO1 variant were significantly different between DM and DN groups ( P = 0.029 and 0.016, respectively). A combined analysis showed that the subjects carrying the risk genotypes of both these variants (GG of rs11643718 + AG/AA of rs741301) had a significant association with DN with an odds ratio [adjusted for age, sex, Body Mass Index (BMI), HbA1c, and systolic Blood Pressure (BP)] of 1.73 (1.30-2.30, P = 1.72 × 10-4) as compared to subjects carrying all other genotype combinations. This is the first study to report a significant association of the SLC12A3 rs11643718 and ELMO1 rs741301 (Single nucleotide Polymorphism) SNPs with diabetic nephropathy in south Indians. [ABSTRACT FROM AUTHOR]

The design of decentralized proportional integral (PI) controller based on biggest log modulus tuning (BLT) tuning method is extended to design centralized PI controllers for two-input–two-output (TITO) systems. The multivariable PI control structure proposed by Tanttu and Lieslehto (1991) is considered. The single detuning parameter (F) is selected in order to get the biggest log modulus as 4 dB. Decentralized PI controllers are also designed using the IMC to get the biggest log modulus as 4 dB. The centralized PI controllers give improved main responses and decreased interactions. This improvement is shown particularly for TITO systems having the relative gain element, λij < 1. The robustness of these controllers is evaluated by the inverse maximum singular value versus frequency plot for both the input and output multiplicative uncertainties. Simulation results are given for two TITO examples. The present controllers give better performances over that of the original Tanttu and Lieslehto (TL) method. The present decentralized PI controllers give improved performances over the decentralized PI controllers proposed by Xiong and Cai (2006). [ABSTRACT FROM AUTHOR]

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.