Modeling Menstrual Cycle Length and Variability at the Approach of Menopause Using Bayesian Changepoint Models

As women approach menopause, the patterns of their menstruation cycle lengths change. To study these changes, we need to jointly model both the mean and variability of the cycle length. The model incorporates separate mean and variance change points for each woman and a hierarchical model to link them together, along with regression components to include predictors of menopausal onset such as age at menarche and parity. Data are from TREMIN, an ongoing 70-year old longitudinal study that has obtained menstrual calendar data of women throughout their reproductive life course. An additional complexity arises from the fact that these calendars have substantial missingness due to hormone use, surgery, failure to report, and loss of contact. We integrate multiple imputation and time-to event modeling in our Bayesian estimation procedure to deal with different forms of the missingness. Posterior predictive model checks are applied to evaluate the model fit. Our method successfully modeled patterns of women’s menstrual cycle trajectories throughout their late reproductive life and identified the change points for mean and variability of segment length, which provides insight into the menopausal process. More generally, our model points the way toward increasing use of joint mean-variance models to predict health outcomes and better understand disease processes

Rapid Aqueous-Phase Hydrolysis of Ester Hydroperoxides Arising from Criegee Intermediates and Organic Acids

Stabilized Criegee intermediates react with organic acids in the gas phase and at the air–water interface to form a class of ester hydroperoxides, α-acyloxyalkyl hydroperoxides (αAAHPs). A number of recent studies have proposed the importance of αAAHPs to the formation and growth of secondary organic aerosol (SOA). The chemistry of αAAHPs has not been investigated due to a lack of commercially available chemical standards. In this work, the behavior of αAAHPs in condensed phases is investigated for the first time. Experiments were performed with two synthesized αAAHP species. αAAHPs decomposed rapidly in the aqueous phase, with the rate highly dependent on the solvent, temperature, solution pH, and other compounds present in the solution. The measured 1st-order decomposition rate coefficient varied between 10^(–3) and 10^(–5) s^(–1) under the conditions examined in this work. Elucidation of the reaction mechanism is complicated by byproducts arising from the synthetic procedure, but observations are consistent with a base-catalyzed hydrolysis of αAAHPs. The rapid hydrolysis of αAAHPs observed in this work implies their short lifetimes in ambient cloud and fog waters. Decomposition of αAAHPs likely gives rise to smaller peroxides, such as H_2O_2. The loss of αAAHPs is also relevant to filter extraction, which is commonly practiced in laboratory experiments, potentially explaining contradictory results reported in the existing literature regarding the importance of αAAHPs in SOA

Rapid Aqueous-Phase Hydrolysis of Ester Hydroperoxides Arising from Criegee Intermediates and Organic Acids

Stabilized Criegee intermediates react with organic acids in the gas phase and at the air–water interface to form a class of ester hydroperoxides, α-acyloxyalkyl hydroperoxides (αAAHPs). A number of recent studies have proposed the importance of αAAHPs to the formation and growth of secondary organic aerosol (SOA). The chemistry of αAAHPs has not been investigated due to a lack of commercially available chemical standards. In this work, the behavior of αAAHPs in condensed phases is investigated for the first time. Experiments were performed with two synthesized αAAHP species. αAAHPs decomposed rapidly in the aqueous phase, with the rate highly dependent on the solvent, temperature, solution pH, and other compounds present in the solution. The measured 1st-order decomposition rate coefficient varied between 10^(–3) and 10^(–5) s^(–1) under the conditions examined in this work. Elucidation of the reaction mechanism is complicated by byproducts arising from the synthetic procedure, but observations are consistent with a base-catalyzed hydrolysis of αAAHPs. The rapid hydrolysis of αAAHPs observed in this work implies their short lifetimes in ambient cloud and fog waters. Decomposition of αAAHPs likely gives rise to smaller peroxides, such as H_2O_2. The loss of αAAHPs is also relevant to filter extraction, which is commonly practiced in laboratory experiments, potentially explaining contradictory results reported in the existing literature regarding the importance of αAAHPs in SOA

Innovative Statistical Models for Inference from Complex Design Surveys and Longitudinal Studies.

Bayesian inference is a method of statistical inference which combines two sources of information, prior information and data, into the posterior distribution. It is widely applied in different areas and has the advantage of being "data driven". This dissertation develops Bayesian statistical models in complex design surveys and women’s reproductive study. Highly disproportional sample designs have large weights, which can introduce undesirable variability in estimates of population statistics. Previous work developed Bayesian "weight smoothing" or "weight pooling" models to produce general model-based weight trimming estimators of population statistics, but application has been limited to the context of stratified and post-stratified sample designs. In the first part of this dissertation, we extend "weight smoothing" estimators to a more general class of complex sample designs that include multi-stage cluster samples and/or strata that "cross" the weight strata. As women mature, menstrual cycles typically begin to decline slowly in length and stabilize until a point at which the hormone cycles begin to break down, leading to a rapid increase in variability and a concomitant increase in cycle length until the onset of menopause. In order to study the structure of menstrual cycle lengths, we build a Bayesian change point model for the mean and variability of cycle lengths for data from the TREMIN cohort, a 70-year long longitudinal study of multiple cohorts of women’s reproductive life. This Bayesian hierarchical model summarizes the cycle length profiles at both a subject and population level. We integrate multiple imputation in our Bayesian estimation procedure to deal with different forms of missingness. Based on results from this analysis, menstrual patterns are classified into subgroups using a K-medoids algorithm. We then relate these subgroups to age of menopause, age at menarche, number of births, as well as to existing standard menopausal transition markers. Our results suggest mean and variance changepoints, which are identified using data throughout women’s late reproductive life, provide more comprehensive information about menopausal transition than previously defined transition markers.Ph.D.BiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/84514/1/xiaobih_1.pd

Radiation-induced late dysphagia after intensity-modulated radiotherapy in nasopharyngeal carcinoma patients: a dose-volume effect analysis

Abstract Dysphagia is a side effect of nasopharyngeal carcinoma chemo-radiotherapy (CRT) which greatly influences the quality of life of the patients. We analyzed late dysphagia in 134 patients with nasopharyngeal cancer undergoing radical radiotherapy (RT), and correlated these findings with dose–volume histogram (DVH) parameters of the swallowing organs at risk (SWOARs). DVH parameters of SWOARs were correlated with late dysphagia, and with RTOG/EORTC scale score and the M. D. Anderson dysphagia inventory (MDADI) score. The mean dose (Dmean) to the superior and inferior constrictor muscles (SCM and ICM) and age were associated with grade 2 late dysphagia. Receiver operating characteristic (ROC) curves showed that the threshold values for grade 2 late dysphagia were: Dmean to SCM ≥ 67 Gy, partial volume receiving specified dose of 60 Gy (V60) of SCM ≥ 95%, Dmean to ICM ≥ 47 Gy, and V50 of ICM ≥ 23%. The areas under the ROC curve were 0.681 (p = 0.02), 0.677 (p = 0.002), 0.71 (p < 0.001) and 0.726 (p < 0.001) respectively. Our study demonstrates a significant relationship between late dysphagia and the radiation doses delivered to the SCM and ICM. Our findings suggest that physicians should be cautious in reducing the RT dose to SWOARs in order to avoid severe dysphagia. Further prospective trials are necessary to recommend this as part of routine clinical practice

Circular RNA‐mediated ceRNA network was identified in human lung adenocarcinoma by high‐throughput sequencing

Abstract Objectives Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). Methods This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second‐generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. Results We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA–microRNA (miRNA)–messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer‐related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP‐activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. Conclusions These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. ClinicalTrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial.

BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553