Limitations of principal components in quantitative genetic association models for human studies.

Principal Component Analysis (PCA) and the Linear Mixed-effects Model (LMM), sometimes in combination, are the most common genetic association models. Previous PCA-LMM comparisons give mixed results, unclear guidance, and have several limitations, including not varying the number of principal components (PCs), simulating simple population structures, and inconsistent use of real data and power evaluations. We evaluate PCA and LMM both varying number of PCs in realistic genotype and complex trait simulations including admixed families, subpopulation trees, and real multiethnic human datasets with simulated traits. We find that LMM without PCs usually performs best, with the largest effects in family simulations and real human datasets and traits without environment effects. Poor PCA performance on human datasets is driven by large numbers of distant relatives more than the smaller number of closer relatives. While PCA was known to fail on family data, we report strong effects of family relatedness in genetically diverse human datasets, not avoided by pruning close relatives. Environment effects driven by geography and ethnicity are better modeled with LMM including those labels instead of PCs. This work better characterizes the severe limitations of PCA compared to LMM in modeling the complex relatedness structures of multiethnic human data for association studies.

Mechanisms of Intervertebral Disc Degeneration Treatment with Deer Antlers Based on Network Pharmacology and Molecular Docking.

Background: With the aging of the population, the prevalence of IVDD increases preoperatively. How to better treat IVDD has become an important clinical issue. Deer antlers proved to have a great effect on the treatment of IVDD in many studies, but the molecular mechanism has not been clarified. Objective: To investigate the molecular mechanism and target of deer antlers in the treatment of IVDD. Methods: Compounds from deer antlers were collected and targets were predicted using HERB, TCMSP, TCMID, SwissADME, and SwissTargetPrediction. Collection of disease targets for IVDD was done using GeneCards, TTD, DrugBank, DisGeNET, and OMIM. Cytoscape 3.7.2, AutoDock Vina (v1.1.2), and R software were used for data analysis and the construction of network diagrams. Results: A total of 5 active compounds from deer antlers were screened and 104 therapeutic targets were predicted. A total of 1023 IVDD disease targets were collected. Subsequently, PPI network prediction analysis was performed for disease and treatment targets, and 112 core targets were collected after screening. After obtaining the core target, we used the clusterProfiler software package of R software to carry out GO and KEGG enrichment analyses for the core target and plot the bubble maps. According to the GO enrichment results, the main biological processes of IVDD treatment by deer antlers lie in the rhythmic process, mRNA catabolic process, and G1/S transition of the mitotic cell cycle. KEGG results were mainly related to the PI3K-Akt signaling pathway, thyroid hormone signaling pathway, and Notch signaling pathway. Molecular docking results showed that estrone had the best docking results on ESR1. Conclusion: Deer antlers are rich in various compounds that can prevent the development of IVDD by upregulating the PI3K-Akt signaling pathway and Notch signaling pathway. Its key compounds estradiol and estrone can reduce the inflammatory response and oxidative stress in tissues and organs, thus slowing down the progression of IVDD. Estrone, the active compound in deer antlers, was found by molecular docking to have good results against ESR1, the target of the disease, which may be a potential site for drug therapy.

Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion Weighted Imaging in Evaluating the Radio-sensitivity of Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiation Therapy.

PURPOSE: Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI)was evaluated regarding its ability to preliminarily predict the short-term treatment response of nasopharyngeal carcinoma (NPC) following intensity-modulated radiation therapy. MATERIALS AND METHODS: IVIM-DWI with 14 b-factors (0-1,000 sec/mm2 ) was performed with a 3T MR system on 47 consecutive NPCs before, during (end of the 5th, 10th, 15th, 20th, and 25th fractions), and after fractional radiotherapy. IVIM parametrics (D, f, and D*) were calculated and compared to the baseline and xth fraction. Patients were categorized into responders and non-responders after radiotherapy. IVIM parametrics were also compared between subgroups. RESULTS: After fractional radiations, the D (except D5 and D at the end of the 5th fraction) after radiations were larger than the baseline D0 (p < 0.05), and the post-radiation D* (except D*5 and D*10) were smaller than D*0 (p < 0.05). f0 was smaller than f5 and f10 (p < 0.001) but larger than fend (p < 0.05). Furthermore, greater D5, D10, D15, and f10 coupled with smaller f0, D*20, and D*25were observed in responders than non-responders (all p < 0.01). Responders also presented larger ΔD10, Δf10, ΔD*20, and δD*20 than non-responders (p < 0.05). Receiver operating characteristic curve analysis indicated that the D5, D*20, and f10 could better differentiate responders from non-responders. CONCLUSION: IVIM-DWI could efficiently assess tumor treatment response to fractional radiotherapy and predict the radio-sensitivity for NPCs.

Dynamic contrast-enhanced MRI of nasopharyngeal carcinoma: a preliminary study of the correlations between quantitative parameters and clinical stage.

PURPOSE: To evaluate the relationship between quantitative parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinical stage of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Fifty-one newly diagnosed NPC patients received MRI examination on Philips Achieva 3.0 Tesla TX MR system. We used DCE-Tool (Philips Healthcare, Best, The Netherlands) to investigate parameters from primary tumors. Tumor/node/metastasis and corresponding clinical stages were determined based on 2009 UICC 7th edition. The correlations between quantitative parameters and clinical stage were correlated using Pearson correlation analysis. RESULTS: Mean K(trans) , Kep , ve , and vp for primary tumors were 0.500 ± 0.188/min, 0.744 ± 0.273/min, 0.986 ± 0.595, and 0.052 ± 0.071, respectively. Both K(trans) and Kep of tumors showed moderate negative correlation with clinical stage, T stage and N stage (P < 0.05), while ve showed moderate positive correlation with them (P < 0.05). vp revealed a moderate negative correlation with T stage (r = -0.369; P < 0.004). Kep and ve have significant differences between many early and advanced stages patients. CONCLUSION: DCE-MRI is feasible to assess vascular permeability of NPC patients. Our results first revealed that the quantitative parameters were significantly related to clinical stage of NPC. Thus, DCE-MRI may be valuable to add noninvasive prognostic indicators in evaluating NPC.

Value of magnetic resonance diffusion-weighted imaging for the prediction of radiosensitivity in nasopharyngeal carcinoma.

OBJECTIVE: The effectiveness of radiotherapy in nasopharyngeal carcinoma (NPC) is closely related to the radiosensitivity of the carcinoma; however, there is currently no effective method to predict radiosensitivity in NPC. We explored the predictive value of magnetic resonance diffusion-weighted imaging (MR-DWI) for radiosensitivity in NPC. Study Design Prospective cohort study. Setting Single hospital. SUBJECTS AND METHODS: Patients with NPC who received intensity-modulated radiotherapy (IMRT) with or without chemotherapy were enrolled from April 2010 through November 2011. Primary tumor apparent diffusion coefficient (ADC) was measured before treatment (ADC0) and 2 weeks after the start of IMRT (ADC1). ADC change (ΔADC) was calculated as (ADC1 - ADC0)/ADC0 * 100%. Three months after the end of radiotherapy, the short-term effect of radiotherapy was assessed using the World Health Organization's response evaluation criteria in solid tumors. RESULTS: Of 134 eligible NPC patients, 121 received combination chemotherapy. Three months after radiotherapy, residual local tumors were detected in 23 (17.2%) cases, and no residual tumors were detected in 111 (82.8%) cases. There was no significant difference in the residual tumor rates of patients receiving combination chemotherapy vs those who did not (P = 1.000). There were no significant differences in the ADC0 or ADC1 values of patients with and without residual tumors (P = .083 and .262). The ΔADC values of patients with (49.77% ± 31.02%) and without (68.35% ± 34.22%) residual tumors were significantly different (t = -2.406, P = .017). Logistic regression analysis indicated that ΔADC was an independent prognostic factor for the short-term effect of IMRT in NPC. CONCLUSION: Magnetic resonance diffusion-weighted imaging may potentially have value for predicting radiosensitivity in NPC.

Early changes in apparent diffusion coefficients predict radiosensitivity of human nasopharyngeal carcinoma xenografts.

OBJECTIVES/HYPOTHESIS: Our objective was to predict the radiosensitivity of human nasopharyngeal carcinoma xenografts in nude mice models through an examination of early changes in apparent diffusion coefficient (ADC) values. STUDY DESIGN: Randomized. METHODS: BALB/c-nu nude mice (n = 20) were divided into two groups that were subcutaneously injected with CNE1 or CNE2 cell lines. Xenograft volumes were measured after tumor formation, mice were scanned with a diffusion-weighted imaging sequence, and the mean ADC values were measured (ADC(0) ). Fifteen to 20 hours after tumors received 15 Gy, mice were scanned again and ADC values (ADC(1) ) were measured. RESULTS: ADC(0) and ADC(1) values of the CNE1 group showed no significant difference (P = .692). The difference between the ADC(0) and ADC(1) values of the CNE2 group was statistically significant (P < .001). ADC(0) values of the two groups exhibited no statistically significant difference (P = .204). ADC(1) , ADC(1-0) , and ΔADC of the two groups exhibited statistically significant differences (P < .001; P = .001 and .002, respectively). After irradiation, volume changes ΔV(8) , ΔV(10) , and ΔV(12) of two groups were statistically different (all P < .001). Pearson correlation analysis showed ADC(1-0) and ΔADC were positively correlated with ΔV(8) , ΔV(10) , and ΔV(12) . The cut point was found by means of a receiver operating characteristic curve, and the ΔV(12) of the two redivided groups showed a statistically significant difference (P = .001). CONCLUSIONS: This study found that changes in ADC values correlated with volume changes after irradiation. Therefore, ADC values have the potential to predict the radiosensitivity of nasopharyngeal carcinoma xenografts.