Application of machine learning tools for evaluating the impact of premenopausal hysterectomy on serum anti-mullerian hormone levels

245-251Women who have had premenopausal total hysterectomy at a young age could probably experience partial or total loss of ovarian function. The purpose of this retrospective cross-sectional study is to investigate the ovarian function in women underwent hysterectomy at an early age. A total of 1165 subjects comprised of 685 hysterectomised women and 480 age matched controls were enrolled in the study. We found that there is a steady decline in serum Anti Mullerian Hormone (AMH) levels, a marker of ovarian function after every five years post - hysterectomy in early age groups (20-30 yr and 31-40 yr) followed by loss of ovarian function in the age group of 40-50 yr. The application of multiple linear regression and machine learning tools has revealed that AMH is positively correlated with LH and estradiol and negatively correlated with age, FSH, years since hysterectomy and vitamin D. Serum AMH level of <0.08 ng/ml is associated with the increased of FSH, decreased LH and estradiol. The decreased ovarian function is associated with lower calcium levels, which are likely to influence the bone health. In conclusion, by utilizing multiple linear regression and machine learning tools, we found that serum FSH is the most important in predicting the AMH-mediated ovarian function

Application of machine learning tools for evaluating the impact of premenopausal hysterectomy on serum anti-mullerian hormone levels

Women who have had premenopausal total hysterectomy at a young age could probably experience partial or total loss of ovarian function. The purpose of this retrospective cross-sectional study is to investigate the ovarian function in women underwent hysterectomy at an early age. A total of 1165 subjects comprised of 685 hysterectomised women and 480 age matched controls were enrolled in the study. We found that there is a steady decline in serum Anti Mullerian Hormone (AMH) levels, a marker of ovarian function after every five years post - hysterectomy in early age groups (20-30 yr and 31-40 yr) followed by loss of ovarian function in the age group of 40-50 yr. The application of multiple linear regression and machine learning tools has revealed that AMH is positively correlated with LH and estradiol and negatively correlated with age, FSH, years since hysterectomy and vitamin D. Serum AMH level of &lt;0.08 ng/ml is associated with the increased of FSH, decreased LH and estradiol. The decreased ovarian function is associated with lower calcium levels, which are likely to influence the bone health. In conclusion, by utilizing multiple linear regression and machine learning tools, we found that serum FSH is the most important in predicting the AMH-mediated ovarian function

Determining and Validating Thermal Strain in Asphalt Concrete

AbstractThermal strain causes transverse cracks in Asphalt Concrete (AC) pavements. In this study, thermal strain is determined by developing a three-dimensional Finite Element Method (FEM) model and validates the model with measured data using the field installed Horizontal Asphalt Strain Gauge (HASG) in Interstate 40 (I-40) located near the city of Albuquerque in the state of New Mexico. Materials’ properties of the pavement section were determined by laboratory testing on field collected cores from the pavement section after the construction. Viscoelastic material properties of AC were determined from the creep test on the field cored samples. Coefficient of thermal expansion (CTE) and contraction (CTC) of AC were also determined in the laboratory and in the field. Results show that the FEM model can predict thermal strain with maximum variation of 6.0% compared to measured thermal strain in the field, which is very promising

Application of multiple linear regression and machine learning algorithms to elucidate the association of poor glycemic control and hyperhomocysteinemia with microalbuminuria

Microalbuminuria is an early biomarker of general vascular dysfunction and a predictor of risk for cardiovascular and renal diseases. It is also considered as a marker of insulin resistance in both diabetic and non-diabetic patients. The rationale of this study was to elucidate threshold values of fasting blood glucose (FBS) and glycosylated hemoglobin (HbA1c) that are associated with microalbuminuria. In the parallel association of microalbuminuria with hyperhomocysteinemia was investigated. Machine learning algorithm and multiple linear regression were applied to study the association of poor glycemic control on microalbuminuria and hyperhomocysteinemia. In non-diabetic subjects with FBS &lt;102 mg/dL and HbA1c &lt;6.3%; and in diabetic subjects with good glycemic control (FBS: 102-118 mg/dL; HbA1c: 6.3-7.0%), urinary microalbumin levels were &lt;40µg/mg creatinine. Poor glycemic control (FBS &gt;172 mg/dL and HbA1c &gt;9.0%) was associated with microalbumin &gt;40µg/mg creatinine. Age, gender, HbA1c and FBS were shown to explain variability in urinary microalbumin to the extent of 54.4% as shown by multiple linear regression model. Analysis of variance (ANOVA) revealed higher levels of FBS (F: 39.77, P &lt;0.0001), HbA1c (F: 64.31, P &lt;0.0001) and total plasma homocysteine (F: 3.69, P =0.04) in microalbuminuria and clinical microalbuminuria groups when compared to subjects with normal microalbumin levels. Diabetic patients with poor glycemic index had a more B12 deficiency. Poor glycemic index and hyperhomocysteinemia were associated with clinical microalbuminuria

Role of parental folate pathway single nucleotide polymorphisms in altering the susceptibility to neural tube defects in South India

Aim: To investigate the role of four parental folate pathway single nucleotide polymorphisms (SNPs) i.e., methylene tetrahydrofolate reductase (MTHFR) 677C&#62;T, MTHFR 1298A&#62;C, methionine synthase reductase (MTRR) 66A&#62;G and glutamate carboxypeptidase (GCP) II 1561C&#62;T on susceptibility to neural tube defects (NTDs) in 50 couples with NTD offspring and 80 couples with normal pregnancy outcome. Results: Maternal MTHFR 677C→T (odds ratio (OR): 2.69, 95% confidence interval (CI): 1.35–5.34) and parental GCP II 1561C→T (maternal: OR: 1.89, 95% CI: 1.12–3.21 and paternal: OR: 3.23, 95% CI: 1.76–5.93) were found to be risk factors for a NTD. Both paternal and maternal GCP II T-variant alleles were found to interact with MTHFR 677T- and MTRR G-variant alleles in increasing the risk for NTD. Segregation of data based on type of defect revealed an association between maternal 677T-allele and meningomyelocele (OR: 9.00, 95% CI: 3.77–21.55, P&#60;0.0001) and an association between parental GCP II 1561T-allele and anencephaly (maternal: OR: 2.25, 95% CI: 1.12–4.50, P&#60;0.05 and paternal: OR: 4.26, 95% CI: 2.01–9.09, P&#60;0.001). Conclusions: Maternal MTHFR C677T and parental GCP II C1561T polymorphisms are associated with increased risk for NTDs. Apart from individual genetic effects, epistatic interactions were also observed.Peer Reviewe

Association of genetic variants of xenobiotic metabolic pathway with systemic lupus erythematosus

447-452In view of documented evidence that catechol estrogen-DNA adducts serve as epitopes for binding of anti-nuclear antibodies, genetic polymorphisms of the xenobiotic metabolic pathway involved in estrogen metabolism might contribute towards pathophysiology of systemic lupus erythematosus (SLE). To test this hypothesis, a case-control study was conducted. Cytochrome P 450 1A1 (CYP1A1) m4 (OR: 4.93, 95% CI: 1.31-18.49), catecholamine-o-methyl transferase (COMT) H108L (OR: 1.39, 95% CI: 1.03-1.88) and glutathione-S-transferase (GST) T1 null (OR: 1.83, 95% CI: 1.11- 3.01) variants showed association with SLE risk. SHEsis web-based platform analysis showed mild to moderate linkage disequilibrium between the CYP1A1 m1, m2 and m4 variants (D’: 0.19-0.37). Among the different haplotypes of CYP1A1, CAC-haplotype harboring CYP1A1 m1 variant showed association with SLE risk (OR: 1.46, 95% CI: 1.11-1.92). Multifactor dimensionality reduction analysis (MDR) showed potential gene-gene interactions between the phase II variants i.e. COMT H108L × GSTT1 null × GSTM1 null (p&lt;0.0001) and also between the phase II and I variants i.e. COMT H108L × GSTT1 null × CYP1A1 m1 × CYP1A1 m2 in inflating the risk of SLE by 3.33-folds (95% CI: 2.30-4.82) and 4.00-folds (95% CI: 2.77-5.78), respectively. To conclude, hyperinducibility of CYP1A1 due to m1 and m4 variants and defective phase-II detoxification due to COMT H108L and GSTT1 null variants increase the susceptibility to SLE

<span style="font-size:11.0pt;mso-bidi-font-size: 10.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-bidi-font-family:"Times New Roman";mso-ansi-language:EN-GB;mso-fareast-language: EN-US;mso-bidi-language:AR-SA" lang="EN-GB">Association of estrogen receptor 1 (<i style="mso-bidi-font-style:normal">ESR1</i>) haplotypes with risk for systemic lupus erythematosus among South Indians</span>

714-718Systemic lupus erythematosus (SLE) is a complex autoimmune disorder involving genetic, epigenetic and environmental factors and has higher incidence in women. In this study, we explored the association of estrogen receptor 1 (ESR1) rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms with susceptibility to SLE. PCR-RFLP and ELISA were used for genetic analysis and determination of specific autoantibodies, respectively. The univariate analysis showed no independent association of rs2234693 (OR: 1.14, 95% CI: 0.87 - 1.49, p = 0.36) and rs9340799 (OR: 0.87, 95% CI: 0.66-1.14, p = 0.34). The haplotype analysis using SHEsis platform revealed strong linkage disequilibrium between these two polymorphisms (D': 0.81, r2: 0.55). Among the four haplotype groups, the C-A haplotype (rs2234693-rs9340799) was strongly associated with the risk for SLE (OR: 2.10, 95% CI: 1.32 - 3.34, p = 0.001). The homozygous variant genotype of rs2234693 exhibited elevated TNF-α and depleted IFN-α, while the effects of rs9340799 were contradictory. The wild genotype of rs2234693 exhibited lower levels of IL-12 with number of rs9340799 variant alleles pronouncing this effect. From this study, it is concluded that the ESR1 haplotypes may influence the Th2 cytokine profile and susceptibility to SLE among the South Indians

The role of TLR7 agonists in modulating COVID-19 severity in subjects with loss-of-function TLR7 variants

Abstract We investigate the mechanism associated with the severity of COVID-19 in men with TLR7 mutation. Men with loss-of-function (LOF) mutations in TLR7 had severe COVID-19. LOF mutations in TLR7 increased the risk of critical COVID by 16.00-fold (95% confidence interval 2.40–106.73). The deleterious mutations affect the binding of SARS-CoV2 RNA (− 328.66 ± 26.03 vs. − 354.08 ± 27.70, p = 0.03) and MYD88 (β: 40.279, p = 0.003) to TLR7 resulting in the disruption of TLR7-MyD88-TIRAP complex. In certain hypofunctional variants and all neutral/benign variants, there is no disruption of TLR7-MyD88-TIRAP complex and four TLR7 agonists showed binding affinity comparable to that of wild protein. N-acetylcysteine (NAC) also showed a higher binding affinity for the LOF variants (p = 0.03). To conclude, TLR7 LOF mutations increase the risk of critical COVID-19 due to loss of viral RNA sensing ability and disrupted MyD88 signaling. Majority of hypofunctional and neutral variants of TLR7 are capable of carrying MyD88 signaling by binding to different TLR7 agonists and NAC

Glutamate carboxypeptidase II (<i style="mso-bidi-font-style:normal">GCPII</i>) genetic variants as determinants of hyperhomocysteinemia: Implications in stroke susceptibility

356-362<span style="mso-bidi-font-size:9.0pt;letter-spacing: -.1pt" lang="EN-GB">The rationale of this case-control study is to ascertain whether glutamate carboxypeptidase II (GCPII) variants serve as determinants of hyperhomocysteinemia and contribute to the etiology of stroke. Hyperhomocysteinemia was observed in stroke cases compared to controls (14.09 ± 7.62 <span style="mso-bidi-font-size:9.0pt;font-family:Symbol; mso-ascii-font-family:" times="" new="" roman";mso-hansi-font-family:"times="" roman";="" letter-spacing:-.1pt;mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">mmol/L vs. 8.71 ± 4.35, P GCPII sequencing revealed two known variants (R190W and H475Y) and six novel variants (V108A, P160S, Y176H, G206R, G245S and D520E). Among the haplotypes of GCPII, all wild-haplotype H0 showed independent association with stroke risk (OR: 9.89, 95% CI: 4.13-23.68), while H2 representing P160S variant showed reduced risk (OR: 0.17, 95% CI: 0.06-0.50). When compared to subjects with H2 haplotype, H0 haplotype showed elevated homocysteine levels (18.26 ± 4.31 <span style="mso-bidi-font-size:9.0pt;font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-hansi-font-family:"times="" roman";letter-spacing:-.1pt;="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">mmol/L vs. 13.66 ± 3.72 <span style="mso-bidi-font-size:9.0pt;font-family:Symbol;mso-ascii-font-family: " times="" new="" roman";mso-hansi-font-family:"times="" roman";letter-spacing:-.1pt;="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="EN-GB">mmol/L, P = 0.002) and reduced plasma folate levels (<span style="mso-bidi-font-size:9.0pt;letter-spacing: -.1pt;mso-ansi-language:EN-US" lang="EN-US">7.09 ± 1.19 ng/ml vs. 8.21 ± 1.14 ng/ml, P = 0.007). Using GCPII genetic variants, dietary folate and gender as predictor variables and homocysteine as outcome variable, a multiple linear regression model was developed. This model explained 36% variability in plasma homocysteine levels. To conclude, GCPII haplotypes influenced susceptibility to stroke by influencing homocysteine levels. </span

Role of CYP1A1 haplotypes in modulating susceptibility to coronary artery disease

349-355To investigate the role of cytochrome P450 1A1 (CYP1A1) haplotypes in modulating susceptibility to coronary artery disease (CAD), a case-control study was conducted by enrolling 352 CAD cases and 282 healthy controls. PCR-RFLP, multiplex PCR, competitive ELISA techniques were employed for the analysis of CYP1A1 [m1 (T→C), m2 (A→G) and m4 (C→A)] haplotypes, glutathione-S-transferase (GST)T1/GSTM1 null variants and plasma 8-oxo-2’deoxyguanosine (8-oxodG) respectively. Two CYP1A1 haplotypes, i.e. CAC and TGC showed independent association with CAD risk, while all-wild CYP1A1 haplotype i.e. TAC showed reduced risk for CAD. All the three variants showed mild linkage disequilibrium (D’: 0.05 to 0.17). GSTT1 null variant also exerted independent association with CAD risk (OR: 2.53, 95% CI 1.55–4.12). Among the conventional risk factors, smoking showed synergetic interaction with CAC haplotype of CYP1A1 and GSTT1 null genotype in inflating CAD risk. High risk alleles of this pathway showed dose-dependent association with percentage of stenosis and number of vessels affected. Elevated 8-oxodG levels were observed in subjects with CYP1A1 CAC haplotype and GSTT1 null variant. Multiple linear regression model of these xenobiotic variants explained 36% variability in 8-oxodG levels. This study demonstrated the association of CYP1A1 haplotypes and GSTT1 null variant with CAD risk and this association was attributed to increased oxidative DNA damage. </span