Publications by authors named "Jiawei Wei"

22 Publications

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Choosing clinically interpretable summary measures and robust analytic procedures for quantifying the treatment difference in comparative clinical studies.

Stat Med 2021 Dec;40(28):6235-6242

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.

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http://dx.doi.org/10.1002/sim.8971DOI Listing
December 2021

Evaluation of Transbronchial Lung Cryobiopsy Freezing Time, Biopsy Size, Histological Quality, and Incidence of Complication: A Prospective Clinical Trial.

Respiration 2021 Oct 27:1-8. Epub 2021 Oct 27.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: Transbronchial cryobiopsy (TBCB), a novel way of obtaining a specimen of lung tissue using a flexible cryoprobe, can obtain large lung biopsies without crush artifacts. The freezing time of TBCB was empirically selected from 3 to 7 s in the previous studies. However, no consensus has yet been reached regarding the optimal freezing time used in TBCB.

Objectives: The primary endpoint was biopsy size in different freezing times. The secondary endpoints included sample histological quality, diagnostic confidence, and complications in different freezing times.

Methods: Patients who were suspected of DPLD requiring histopathological examination for further evaluation were enrolled in this study. Distinct biopsies were obtained by using different freezing times increased from 3 to 6 s sequentially. Samples were reviewed by 2 external expert pathologists.

Results: A total of 33 patients were enrolled, and 143 transbronchial cryobiopsies were taken in this trial. An average of 4.33 samples were taken from each patient. The mean biopsy size of different freezing times from 3 to 6 s was 9.10 ± 4.37, 13.23 ± 5.83, 16.26 ± 5.67, and 18.83 ± 7.50 mm2, respectively. A strong correlation between freezing time and biopsy size was observed (r = 0.99, p < 0.01). Statistically significant difference of biopsy size was detected in the freezing time of 3 s versus 4 s (p < 0.01) and 4 s versus 5 s (p = 0.02), but not in the freezing time of 5 s versus 6 s (p = 0.10). Overall bleeding in different freezing times from 3 to 6 s was 53.33%, 67.50%, 89.47%, and 77.14%, respectively. A significantly higher overall bleeding was observed when the freezing time exceeded 4 s (RR = 1.67, p < 0.01). Pneumothorax occurred in 4 cases (12.12%). One lethal case (3.03%) was noted 25 days after TBCB. Lung parenchyma was preserved well in all cryobiopsy samples. Thirty-one (93.94%) patients' histopathological findings were identified as sufficient to establish a CRP diagnosis. There was no statistical difference in diagnostic confidence between different freezing times.

Conclusion: A longer freezing time was associated with a larger size of the biopsy sample but a higher risk of bleeding. The optimal transbronchial cryobiopsy freezing time is 3-4 s, which is easily achievable and provides an adequate biopsy size whilst creating a safety threshold from complications.
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http://dx.doi.org/10.1159/000519279DOI Listing
October 2021

The shrinking behavior, mechanism and anti-shrinkage resolution of an electrospun PLGA membrane.

J Mater Chem B 2021 07;9(29):5861-5868

Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu 610064, China.

The deformation shrinkage of a poly(lactide-co-glycolide) (PLGA) fibrous material seriously affects its biomedical application. To demonstrate the underlying shrinking mechanism and to find a method to prevent the shrinkage of an electrospun PLGA membrane, we investigated the shrinking behavior of PLGA electrospun membranes under various test conditions and discussed the underlying shrinking mechanism. The results indicated that the shrinkage of the electrospun PLGA membrane was mainly regulated by the glass transition of its polymer fiber; the temperature and liquid environment were found to be the two main factors leading to the shrinkage of the electrospun PLGA membrane through affecting its glass transition. Then a heat stretching (HS) technique was proposed by us to stabilize the electrospun PLGA membrane. After HS treatment, the glass transition temperature (Tg) of the electrospun PLGA membrane could increase from 48.38 °C to 54.55 °C. Our results indicated that the HS-treated membranes could maintain a high area percentage of 90.89 ± 2.27% and 84.78 ± 3.36% after immersion respectively in PBS and blood at 37 °C for 2 hours. Further experiments confirmed that the HS technique could also stabilize the dimensional structure of the electrospun PDLLA membrane in PBS and blood at 37 °C. This study provides an effective strategy for preventing the shrinkage of electrospun polyester biomaterials in a physiological environment that may benefit both the material structural stability and the in vivo biological performance.
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http://dx.doi.org/10.1039/d1tb00734cDOI Listing
July 2021

A hierarchical scaffold with a highly pore-interconnective 3D printed PLGA/n-HA framework and an extracellular matrix like gelatin network filler for bone regeneration.

J Mater Chem B 2021 06;9(22):4488-4501

Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu 610064, China.

The ideal scaffold for bone repair should have a hierarchical pore structure and gradient degradation performance to satisfy the uniform adhesion and proliferation of cells in the scaffold at the early stage of implantation, as well as providing space for the subsequent regeneration of bone tissue. To this end, we developed a hierarchical polylactic acid glycolic acid copolymer (PLGA)/nano-hydroxyapatite (n-HA)/gelatin (Gel) (PHG) scaffold with a printed PLGA/n-HA (PH) framework and a Gel network filler for bone regeneration by the combination of 3D printing and freeze-drying technologies. The fabricated PHG scaffold features large front hole size (>1100 μm × 1100 μm) and side hole size (>500 μm) to provide sufficient open space and reliable integrated support for cell and tissue ingrowth. The gelatin network filled in the PH framework played the role of a cell holder just like an extracellular matrix (ECM) in the early stage. In vitro degradation experiments revealed that the gelatin network completely degraded within 5 weeks while the structural integrity of the framework still remained at the 32nd week. The results of cell culture confirmed that the PHG scaffold was more conducive to cell attachment. In vivo assessments in a rat femoral defect model showed that PHG scaffolds were more favored for new bone formation and achieving a tighter bond between the scaffold and the original tissues. The hierarchical PHG scaffold has great application potential in bone tissue engineering and will provide a reference for the model design of bone scaffolds.
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http://dx.doi.org/10.1039/d1tb00662bDOI Listing
June 2021

Loading and Releasing Behavior of Selenium and Doxorubicin Hydrochloride in Hydroxyapatite with Different Morphologies.

ACS Omega 2021 Mar 16;6(12):8365-8375. Epub 2021 Mar 16.

Research Center for Nano Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu 610064, P. R. China.

Doxorubicin (Dox)-loaded or selenium-substituted hydroxyapatite (HA) has been developed to achieve anti-osteosarcoma or bone regeneration in a number of studies. However, currently, there is a lack of studies on the combination of Dox and selenium loading in/on HA and comparative research studies on which form and size of HA are more suitable for drug loading and release in the treatment osteogenesis after osteosarcoma resection. Herein, selenium-doped rod-shaped nano-HA (n-HA) and spherical mesoporous HA (m-HA) were successfully prepared. The doping efficiency of selenium and the Dox loading capacity of selenium-doped HA with different morphologies were studied. The release kinetics of Dox and the selenium element in phosphate-buffered saline with different pH values was also comparatively investigated. The drug loading results showed that n-HA exhibited 3 times higher selenium doping amount than m-HA, and the Dox entrapment efficiency of selenium-doped n-HA (0.1Se-n-HA) presented 20% higher than that of selenium-doped m-HA (0.1Se-m-HA). The Dox release behaviors of HA in two different morphologies showed similar release kinetics, with almost the same Dox releasing ratio but slightly more Dox releasing amount in selenium-doped HA than in HA without selenium. The selenium release from selenium-doped n-HA-D (0.1Se-n-HA-D) particles was 2 times as much as that of selenium-doped m-HA-D (0.1Se-m-HA) particles. Our study indicated that n-HA loaded with Dox and selenium may be a promising drug delivery strategy for inhibition of osteosarcoma recurrence and promoting osteogenesis simultaneously.
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http://dx.doi.org/10.1021/acsomega.1c00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015115PMC
March 2021

Clinical characteristics and potential factors for recurrence of positive SARS-CoV-2 RNA in convalescent patients: a retrospective cohort study.

Clin Exp Med 2021 Aug 4;21(3):361-367. Epub 2021 Feb 4.

Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Background: The recurrence of positive SARS-CoV-2 RT-PCR is frequently found in discharged COVID-19 patients but its clinical significance remains unclear. The potential cause, clinical characteristics and infectiousness of the recurrent positive RT-PCR patients need to be answered.

Methods: A single-centered, retrospective study of 51 discharged COVID-19 patients was carried out at a designated hospital for COVID-19. The demographic data, clinical records and laboratory findings of 25 patients with recurrent positive RT-PCR from hospitalization to follow-up were collected and compared to 26 patients with negative RT-PCR discharged regularly during the same period. Discharged patients' family members and close contacts were also interviewed by telephone to evaluate patients' potential infectiousness.

Results: The titer of both IgG and IgM antibodies was significantly lower (p = 0.027, p = 0.011) in patients with recurrent positive RT-PCR. Median duration of viral shedding significantly prolonged in patients with recurrent positive RT-PCR (36.0 days vs 9.0 days, p = 0.000). There was no significant difference in demographic features, clinical features, lymphocyte subsets count and inflammatory cytokines levels between the two groups of patients. No fatal case was noted in two groups. As of the last day of follow-up, none of the discharged patients' family members or close contact developed any symptoms of COVID-19.

Conclusions: Patients with low levels of IgG and IgM are more likely to have recurrent positive SARS-CoV-2 RT-PCR results and lead to a prolonged viral shedding. The recurrent positive of SARS-CoV-2 RT-PCR may not indicate the recurrence or aggravation of COVID-19. The detection of SARS-CoV-2 by RT-PCR in the patients recovered from COVID-19 is not necessarily correlated with the ability of transmission.
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http://dx.doi.org/10.1007/s10238-021-00687-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860998PMC
August 2021

Key Factors Influencing Low-Carbon Behaviors of Staff in Star-Rated Hotels-An Empirical Study of Eastern China.

Int J Environ Res Public Health 2020 11 6;17(21). Epub 2020 Nov 6.

School of Civil Engineering, Southeast University, Nanjing 210096, China.

To guide sustainable development in the hospitality industry requires hotel staff engagement, so what causes and how to facilitate the implementation of low-carbon behaviors should be high priorities. However, most prior studies focused on hotel guest behavior or discussed, on an individual level, the psychological aspects of the factors of the low-carbon behavior of either managers or employees. Therefore, this research aims to examine the effect of influencing factors inside and outside of the hotel context on hotel staff's low-carbon behaviors in star-rated hotels. A set of influencing factors were identified by using literature retrieval, ground theory and in-depth interviews. Structural equation modelling was then applied with 440 valid questionnaires collected from representative star-rated hotels in Eastern China. The results revealed that low-carbon managerial activities, strategic orientation, social norms, and perceived behavior control were four key factors affecting the low-carbon behavior adoption of staff from star-rated hotels. Among them, low-carbon managerial activities were found to be the strongest factor affecting hotel staff's low-carbon behaviors. Consumer attitude, however, exerted no significant impact. Targeted strategies were finally proposed for the improvement of hotel staff's low-carbon behavior from the perspectives of hoteliers and governments. This study contributes to the generation mechanism of low-carbon behavior among staff and, in practice, towards behavioral improvement by providing comprehensive insights about the attribution of factors belonging to multiple dimensions related to the low-carbon behavior of staff in the hotel industry.
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http://dx.doi.org/10.3390/ijerph17218222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664370PMC
November 2020

The ultralong-term comparison of osteogenic behavior of three scaffolds with different matrices and degradability between one and two years.

J Mater Chem B 2020 10;8(41):9524-9532

Research Center for Nano-Biomaterials, Analytical & Testing Center, Sichuan University, Chengdu 610064, China.

Attributed to their structure and composition manipulated to mimic natural bone tissue, porous scaffolds composed of inorganic nano-hydroxyapatite (n-HA) and organic polymers with different degrees of degradability have been proven to be a promising bone regeneration strategy. However, long-term and in-depth comparative research on the effects of scaffolds with different matrices and degrees of degradability on bone reconstruction is still lacking. In this study, the ultralong-term osteogenic performance of three polymeric composite scaffolds based on non-degradable polyamide 66 (PA66), slowly degradable polycaprolactone (PCL) and fast degradable poly (lactic-co-glycolic acid) (PLGA) were investigated comparatively after implanting the scaffolds into rabbit femoral defects for 12, 15, 18 and 21 months. The results demonstrated that the structural integrity of the scaffolds played a positive role in long-term bone reconstruction. Thus the n-HA/PA66 and n-HA/PCL scaffolds have a higher relative bone volume and bone density than the n-HA/PLGA scaffolds from 12 to 21 months. In addition, the favorable surface wettability and collagen-like molecular structure should endow the n-HA/PA66 scaffold with the best long-term osteogenic property among the three scaffolds. The ultralong-term comparative study reveals that a relatively stable scaffold integrity, together with favorable matrix molecular characteristics and hydrophilicity, may be more important for long-term osteogenesis besides the effect of scaffold pore structure, rather than the pursuit of fast scaffold degradation. The results also show that the space left by scaffold degradation is not easily occupied by new bone tissue, especially after bone tissue has formed a stable structure or the bone interface has become inert.
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http://dx.doi.org/10.1039/d0tb01987aDOI Listing
October 2020

Heparin conjugated PCL/Gel - PCL/Gel/n-HA bilayer fibrous membrane for potential regeneration of soft and hard tissues.

J Biomater Sci Polym Ed 2020 08 13;31(11):1421-1436. Epub 2020 May 13.

Research Center for Nano-Biomaterials, Analytical and Testing Center, Sichuan University, Chengdu, China.

A novel bilayer fibrous membrane for guided tissue regeneration (GTR) was prepared two-step electrospinning process, subsequent crosslinking and surface conjugation with heparin. The bilayer membrane consists of upper layer polycaprolactone/gelatin (PCL/Gel) membrane for soft tissue regeneration and lower layer PCL/Gel/nano-hydroxyapatite (PCL/Gel/n-HA) membrane for hard tissue regeneration. The results indicated that the physicochemical and biological properties of the membrane were strongly influenced by the crosslinking time and by the heparin conjugation. Crosslinking effectively prolonged the degradation time while maintaining the membrane barrier function, and the surface heparin conjugation obviously improved the biological performance of the membrane. An enhanced cell adhesion and proliferation were observed on the heparin-conjugated fibrous membranes, which also showed good histocompatibility and favorable degradability. The electrospun bilayer fibrous membrane may have promising prospect for modulation of cell response and simultaneous regeneration of soft and hard tissues.
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http://dx.doi.org/10.1080/09205063.2020.1760700DOI Listing
August 2020

The CRISPR-Associated Cas1 Involves Persistence and Tolerance to Anti-Tubercular Drugs.

Biomed Res Int 2019 2;2019:7861695. Epub 2019 Apr 2.

Chongqing Medical University, Chongqing 400016, China.

Tuberculosis remains one of the leading causes of death worldwide. Even if new antitubercular drugs are currently being developed, the rapid emergence and spread of drug-resistant strain remain a severe challenge. The CRISPR associated proteins 1 (Cas1), a most conserved endonuclease which is responsible for spacer integration into CRISPR arrays, was found deleted in many specific drug-resistant strains. The function of Cas1 is still unknown in type III-A CRISPR family. In this study, the Cas1 (Rv2817c) defect was found in 57.14% of clinical isolates. To investigate the function of Cas1 in new spacer acquisition, we challenged (BCG) with a mycobacteriophage D29. Newly acquired spacer sequence matches D29 genome was not found by spacer deep-sequencing. We further expressed Cas1 in recombinant . We found that Cas1 increased the sensitivity to multiple anti-tuberculosis drugs by reducing the persistence during drug treatment. We also showed that Cas1 impaired the repair of DNA damage and changed the stress response of . This study provides a further understanding of Cas1 in (MTBC) drug-resistance evolution and a new sight for the tuberculosis treatment.
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http://dx.doi.org/10.1155/2019/7861695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466960PMC
September 2019

Development of an Antibacterial Bone Graft by Immobilization of Levofloxacin Hydrochloride-Loaded Mesoporous Silica Microspheres on a Porous Scaffold Surface.

J Biomed Nanotechnol 2019 May;15(5):1097-1105

An effective local drug delivery system remains an urgently needed product for the treatment of chronic osteomyelitis in the clinic. In this study, we developed an antibacterial functionalization bone graft by immobilizing levofloxacin hydrochloride-loaded mesoporous silica microspheres (LFH @ MSNs) on the surface of a nanohydroxyapatite/polyurethane (-HA/PU) bioactive composite scaffold. Through pretreatment of the -HA/PU scaffold by chitosan solution and subsequent crosslinking by vanillin, LFH @ MSNs were uniformly and stably immobilized on the scaffold surface. The results of drug release experiments showed that the release of LFH from LFH @ MSN-modified -HA/PU scaffolds (LFH @ MSN/ HA/PU) lasted up to 42d. The antibacterial assays indicated that LFH @ MSN/-HA/PU offers satisfactory antibacterial activity against both gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria. The biosafety assays demonstrated that the LFH @ MSN/-HA/PU scaffold could satisfy the requirements of the biosafety standards. The constructed LFH @ MSN/-HA/PU porous scaffolds with an antibacterial surface and favorable biosafety are deemed a promising candidate for infectious bone defect repair.
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http://dx.doi.org/10.1166/jbn.2019.2743DOI Listing
May 2019

Multistate modeling and simulation of patient trajectories after allogeneic hematopoietic stem cell transplantation to inform drug development.

Biom J 2019 09 17;61(5):1303-1313. Epub 2018 Sep 17.

Biostatistical Sciences and Pharmacometrics, Novartis Pharma AG, Basel, Switzerland.

We present a case study for developing clinical trial scenarios in a complex progressive disease with multiple events of interest. The idea is to first capture the course of the disease in a multistate Markov model, and then to simulate clinical trials from this model, including a variety of hypothesized drug effects. This case study focuses on the prevention of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). The patient trajectory after HSCT is characterized by a complex interplay of various events of interest, and there is no established best method of measuring and/or analyzing treatment benefits. We characterized patient trajectories by means of multistate models that we fitted to a subset of the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Events of interest included acute GvHD of grade III or IV, severe chronic GvHD, relapse of the underlying disease, and death. The transition probability matrix was estimated using the Aalen-Johansen estimator, and patient characteristics were identified that were associated with different transition rates. In a second step, clinical trial scenarios were simulated from the model assuming various drug effects on the background transition rates, and the operating characteristics of different endpoints and analysis strategies were compared in these scenarios. This helped devise a drug development strategy in GvHD prevention after allogeneic HSCT. More generally, multistate models provide a rich framework for exploring complex progressive diseases, and the availability of a corresponding simulation machinery provides great flexibility for clinical trial planning.
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http://dx.doi.org/10.1002/bimj.201700285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074899PMC
September 2019

Nonpoint Pollution Source-Sink Landscape Pattern Change Analysis in a Coastal River Basin in Southeast China.

Int J Environ Res Public Health 2018 09 26;15(10). Epub 2018 Sep 26.

College of Geomatics Science and Technology, Nanjing Tech University, Nanjing 211816, China.

Analyzing the spatiotemporal characteristics of source-sink landscape pattern change in river basins is crucial for managing and controlling nonpoint source pollution. This study investigated the landscape pattern changes in Jiulong River basin from 1990 to 2015. A random forest classifier combined with texture and spectral information was applied to interpret the multi-temporal Landsat images. Landscape metrics were calculated to quantify the landscape at the patch level. Transition matrixes were derived for analyzing the conversion among different landscape types. It is notable that the largest values of the number of patches and patch density of residential land appeared in 2005, indicating the highest degree of fragmentation over this time period. The percentage of landscape for forestland was always higher than 71%, and the percentage of residential land increased from 7.42% to 14.55% during the last three decades, while unused land decreased from 5.3% to 2.8%. The downward trend of DO and the upward trend of NH₃-N and TP indicate the deterioration of water quality during 2005⁻2015. The quantitative monitoring data of water quality indicators in Hua'an and Xiamen sites in Jiulong River basin are shown. The percentage of landscape of cultivated land increased during 2005⁻2010, which was consistent with the change tendency of NH₃-N. Transition matrixes showed that the main changes occurred when forestland and unused land were transformed to residential land and cultivated land over the last three decades. Analysis results demonstrated a higher extent of landscape fragmentation and an unsustainable transition among source-sink landscapes.
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http://dx.doi.org/10.3390/ijerph15102115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210854PMC
September 2018

Safety and efficacy of Qishen granules in patients with chronic heart failure: study protocol for a randomized controlled trial.

Trials 2017 Oct 10;18(1):468. Epub 2017 Oct 10.

Beijing Key Laboratory of Syndrome and Prescription Basic Research, Beijing University of Chinese Medicine, Beijing, 100029, China.

Background: Chronic heart failure (CHF), the final stage of various cardiovascular diseases, is a major public health problem resulting in significant hospitalization rates, mortality, and huge health care costs despite advances in the treatment and management of heart failure and heart failure-related risk factors. Qishen granules (QSG), a Chinese herbal formula, is widely used by traditional Chinese medicine (TCM) practitioners to treat CHF. Several animal experimental studies have showed that QSG can significantly relieve the heart failure symptoms in CHF rat models. However, there is as yet no standard clinical trial to confirm this. Thus, the investigators are conducting this study to evaluate the efficacy and safety of QSG in a large, and varied population.

Methods/design: This study is designed as a randomized, placebo-controlled, multi-center, double-blind clinical trial with parallel groups. A total of 200 patients with CHF will be recruited and randomly allocated to either the QSG treatment group or the placebo group (in a 1:1 ratio). The patients will receive QSG or placebo granules twice a day for 12 weeks. The primary outcome is the proportion of patients in the QSG group, compared with the placebo group, demonstrating a more than 30% decrease in NT-proBNP level during 12 weeks of treatment. The secondary outcomes consist of composite cardiac events, New York Heart Association functional classification, 6-minute walking distance, left ventricular ejection fraction, patient quality of life, and the TCM syndrome integral scale.

Discussion: On a background of standard treatment, QSG may further reduce the levels of NT-proBNP. This trial will provide high-quality evidence on the efficacy and safety of QSG in treating CHF, thus providing reference for clinical application of QSG.

Trial Registration: Clinical Trials.gov: NCT03027375 . Registered on 16 January 2017.
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http://dx.doi.org/10.1186/s13063-017-2193-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634880PMC
October 2017

A Note on Penalized Regression Spline Estimation in the Secondary Analysis of Case-Control Data.

Stat Biosci 2013 Nov;5(2):250-260

Department of Statistics, Texas A&M University, 3143 TAMU, College Station, TX 77843-3143.

Primary analysis of case-control studies focuses on the relationship between disease () and a set of covariates of interest (). A secondary application of the case-control study, often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated due to the case-control sampling, and to avoid the biased sampling that arises from the design, it is typical to use the control data only. In this paper, we develop penalized regression spline methodology that uses all the data, and improves precision of estimation compared to using only the controls. A simulation study and an empirical example are used to illustrate the methodology.
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http://dx.doi.org/10.1007/s12561-013-9094-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975606PMC
November 2013

Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial.

Lancet 2013 Nov 13;382(9906):1705-13. Epub 2013 Sep 13.

Department of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.

Background: Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis.

Methods: We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4:1 ratio) to either intravenous secukinumab (2×10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159.

Findings: 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group.

Interpretation: Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial.

Funding: Novartis.
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http://dx.doi.org/10.1016/S0140-6736(13)61134-4DOI Listing
November 2013

Robust estimation for homoscedastic regression in the secondary analysis of case-control data.

J R Stat Soc Series B Stat Methodol 2013 Jan;75(1):185-206

Texas A&M University, College Station, USA.

Primary analysis of case-control studies focuses on the relationship between disease and a set of covariates of interest (, ). A secondary application of the case-control study, which is often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated owing to the case-control sampling, where the regression of on is different from what it is in the population. Previous work has assumed a parametric distribution for given and derived semiparametric efficient estimation and inference without any distributional assumptions about . We take up the issue of estimation of a regression function when given follows a homoscedastic regression model, but otherwise the distribution of is unspecified. The semiparametric efficient approaches can be used to construct semiparametric efficient estimates, but they suffer from a lack of robustness to the assumed model for given . We take an entirely different approach. We show how to estimate the regression parameters consistently even if the assumed model for given is incorrect, and thus the estimates are model robust. For this we make the assumption that the disease rate is known or well estimated. The assumption can be dropped when the disease is rare, which is typically so for most case-control studies, and the estimation algorithm simplifies. Simulations and empirical examples are used to illustrate the approach.
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http://dx.doi.org/10.1111/j.1467-9868.2012.01052.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639015PMC
January 2013

Testing for Constant Nonparametric Effects in General Semiparametric Regression Models with Interactions.

Stat Probab Lett 2011 Jul;81(7):717-723

Department of Statistics, 3143 TAMU, Texas A&M University, College Station, Texas 77843, USA.

We consider the problem of testing for a constant nonparametric effect in a general semi-parametric regression model when there is the potential for interaction between the parametrically and nonparametrically modeled variables. The work was originally motivated by a unique testing problem in genetic epidemiology (Chatterjee, et al., 2006) that involved a typical generalized linear model but with an additional term reminiscent of the Tukey one-degree-of-freedom formulation, and their interest was in testing for main effects of the genetic variables, while gaining statistical power by allowing for a possible interaction between genes and the environment. Later work (Maity, et al., 2009) involved the possibility of modeling the environmental variable nonparametrically, but they focused on whether there was a parametric main effect for the genetic variables. In this paper, we consider the complementary problem, where the interest is in testing for the main effect of the nonparametrically modeled environmental variable. We derive a generalized likelihood ratio test for this hypothesis, show how to implement it, and provide evidence that our method can improve statistical power when compared to standard partially linear models with main effects only. We use the method for the primary purpose of analyzing data from a case-control study of colorectal adenoma.
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http://dx.doi.org/10.1016/j.spl.2010.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124863PMC
July 2011

Comparisons of treatment means when factors do not interact in two-factorial studies.

Amino Acids 2012 May 6;42(5):2031-5. Epub 2011 May 6.

Department of Statistics, Texas A&M University, 3143 TAMU, College Station, TX 77843, USA.

Scientists in the fields of nutrition and other biological sciences often design factorial studies to test the hypotheses of interest and importance. In the case of two-factorial studies, it is widely recognized that the analysis of factor effects is generally based on treatment means when the interaction of the factors is statistically significant, and involves multiple comparisons of treatment means. However, when the two factors do not interact, a common understanding among biologists is that comparisons among treatment means cannot or should not be made. Here, we bring this misconception into the attention of researchers. Additionally, we indicate what kind of comparisons among the treatment means can be performed when there is a nonsignificant interaction among two factors. Such information should be useful in analyzing the experimental data and drawing meaningful conclusions.
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http://dx.doi.org/10.1007/s00726-011-0924-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199378PMC
May 2012

A chemoprotective fish oil- and pectin-containing diet temporally alters gene expression profiles in exfoliated rat colonocytes throughout oncogenesis.

J Nutr 2011 Jun 20;141(6):1029-35. Epub 2011 Apr 20.

Faculty of Nutrition Texas A&M University, College Station, TX 77843, USA.

We have demonstrated that fish oil- and pectin-containing (FO/P) diets protect against colon cancer compared with corn oil and cellulose (CO/C) by upregulating apoptosis and suppressing proliferation. To elucidate the mechanisms whereby FO/P diets induce apoptosis and suppress proliferation during the tumorigenic process, we analyzed the temporal gene expression profiles from exfoliated rat colonocytes. Rats consumed diets containing FO/P or CO/C and were injected with azoxymethane (AOM; 2 times, 15 mg/kg body weight, subcutaneously). Feces collected at initiation (24 h after AOM injection) and at aberrant crypt foci (ACF) (7 wk postinjection) and tumor (28 wk postinjection) stages of colon cancer were used for poly (A)+ RNA extraction. Gene expression signatures were determined using Codelink arrays. Changes in phenotypes (ACF, apoptosis, proliferation, and tumor incidence) were measured to establish the regulatory controls contributing to the chemoprotective effects of FO/P. At initiation, FO/P downregulated the expression of 3 genes involved with cell adhesion and enhanced apoptosis compared with CO/C. At the ACF stage, the expression of genes involved in cell cycle regulation was modulated by FO/P and the zone of proliferation was reduced in FO/P rats compared with CO/C rats. FO/P also increased apoptosis and the expression of genes that promote apoptosis at the tumor endpoint compared with CO/C. We conclude that the effects of chemotherapeutic diets on epithelial cell gene expression can be monitored noninvasively throughout the tumorigenic process and that a FO/P diet is chemoprotective in part due to its ability to affect expression of genes involved in apoptosis and cell cycle regulation throughout all stages of tumorigenesis.
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http://dx.doi.org/10.3945/jn.110.134973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095137PMC
June 2011

RFRCDB-siRNA: improved design of siRNAs by random forest regression model coupled with database searching.

Comput Methods Programs Biomed 2007 Sep 17;87(3):230-8. Epub 2007 Jul 17.

State Key Laboratory of Bioelectronics, Department of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, PR China.

Although the observations concerning the factors which influence the siRNA efficacy give clues to the mechanism of RNAi, the quantitative prediction of the siRNA efficacy is still a challenge task. In this paper, we introduced a novel non-linear regression method: random forest regression (RFR), to quantitatively estimate siRNAs efficacy values. Compared with an alternative machine learning regression algorithm, support vector machine regression (SVR) and four other score-based algorithms [A. Reynolds, D. Leake, Q. Boese, S. Scaringe, W.S. Marshall, A. Khvorova, Rational siRNA design for RNA interference, Nat. Biotechnol. 22 (2004) 326-330; K. Ui-Tei, Y. Naito, F. Takahashi, T. Haraguchi, H. Ohki-Hamazaki, A. Juni, R. Ueda, K. Saigo, Guidelines for the selection of highly effective siRNA sequences for mammalian and chick RNA interference, Nucleic Acids Res. 32 (2004) 936-948; A.C. Hsieh, R. Bo, J. Manola, F. Vazquez, O. Bare, A. Khvorova, S. Scaringe, W.R. Sellers, A library of siRNA duplexes targeting the phosphoinositide 3-kinase pathway: determinants of gene silencing for use in cell-based screens, Nucleic Acids Res. 32 (2004) 893-901; M. Amarzguioui, H. Prydz, An algorithm for selection of functional siRNA sequences, Biochem. Biophys. Res. Commun. 316 (2004) 1050-1058) our RFR model achieved the best performance of all. A web-server, RFRCDB-siRNA (http://www.bioinf.seu.edu.cn/siRNA/index.htm), has been developed. RFRCDB-siRNA consists of two modules: a siRNA-centric database and a RFR prediction system. RFRCDB-siRNA works as follows: (1) Instead of directly predicting the gene silencing activity of siRNAs, the service takes these siRNAs as queries to search against the siRNA-centric database. The matched sequences with the exceeding the user defined functionality value threshold are kept. (2) The mismatched sequences are then processed into the RFR prediction system for further analysis.
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http://dx.doi.org/10.1016/j.cmpb.2007.06.001DOI Listing
September 2007

RF-DYMHC: detecting the yeast meiotic recombination hotspots and coldspots by random forest model using gapped dinucleotide composition features.

Nucleic Acids Res 2007 Jul 3;35(Web Server issue):W47-51. Epub 2007 May 3.

State Key Laboratory of Bioelectronics, Department of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, PR China.

In the yeast, meiotic recombination is initiated by double-strand DNA breaks (DSBs) which occur at relatively high frequencies in some genomic regions (hotspots) and relatively low frequencies in others (coldspots). Although observations concerning individual hot/cold spots have given clues as to the mechanism of recombination initiation, the prediction of hot/cold spots from DNA sequence information is a challenging task. In this article, we introduce a random forest (RF) prediction model to detect recombination hot/cold spots from yeast genome. The out-of-bag (OOB) estimation of the model indicated that the RF classifier achieved high prediction performance with 82.05% total accuracy and 0.638 Mattew's correlation coefficient (MCC) value. Compared with an alternative machine-learning algorithm, support vector machine (SVM), the RF method outperforms it in both sensitivity and specificity. The prediction model is implemented as a web server (RF-DYMHC) and it is freely available at http://www.bioinf.seu.edu.cn/Recombination/rf_dymhc.htm. Given a yeast genome and prediction parameters (RI-value and non-overlapping window scan size), the program reports the predicted hot/cold spots and marks them in color.
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http://dx.doi.org/10.1093/nar/gkm217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1933199PMC
July 2007
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