105 results on '"Talloen, W."'
Search Results
2. Plasma levels of growth-related oncogene (CXCL1-3) associated with fibrosis and platelet counts in HCV-infected patients
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Johansson, S., Talloen, W., Tuefferd, M., Darling, J. M., Scholliers, A., Fanning, G., Fried, M. W., and Aerssens, J.
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- 2015
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3. Environmental stress and quantitative genetic variation in butterfly wing characteristics
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Talloen, W., Van Dongen, S., Van Dyck, H., and Lens, L.
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- 2009
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4. Fluctuating Asymmetry in Broiler Chickens: A Decision Protocol for Trait Selection in Seven Measuring Methods
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Van Nuffel, A., Tuyttens, F.A.M., Van Dongen, S., Talloen, W., Van Poucke, E., Sonck, B., and Lens, L.
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- 2007
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5. Spectral Map Analysis of Microarray Data
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Bijnens, L., primary, Verbeeck, R., additional, Göhlmann, H.W., additional, Talloen, W., additional, Ion, R.A., additional, Lewi, P.J., additional, and Wouters, L., additional
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- 2009
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6. Evaluation of fluctuating asymmetry as an indicator of broiler welfare.
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Nuffel, A. van, primary, Talloen, W., additional, Sonck, B., additional, Lens, L., additional, and Tuyttens, F., additional
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- 2004
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7. Safety, pharmakokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatmentnaive chronic hepatitis B (CHB) patients without cirrhosis
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Zoulim, F., primary, Yogaratnam, J.Z., additional, Vandenbossche, J.J., additional, Lenz, O., additional, Talloen, W., additional, Vistuer, C., additional, Moscalu, I., additional, Streinu-Cercel, A., additional, Bourgeois, S., additional, Buti, M., additional, Crespo, J., additional, Pascasio, J.M., additional, Sarrazin, C., additional, Vanwolleghem, T., additional, Blatt, L., additional, and Fry, J., additional
- Published
- 2018
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- View/download PDF
8. LBO-004 - Safety, pharmakokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatmentnaive chronic hepatitis B (CHB) patients without cirrhosis
- Author
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Zoulim, F., Yogaratnam, J.Z., Vandenbossche, J.J., Lenz, O., Talloen, W., Vistuer, C., Moscalu, I., Streinu-Cercel, A., Bourgeois, S., Buti, M., Crespo, J., Pascasio, J.M., Sarrazin, C., Vanwolleghem, T., Blatt, L., and Fry, J.
- Published
- 2018
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9. EEG Alpha Power as an Intermediate Measure between BDNF Val66Met and Depression Severity in Patients with Major Depressive Disorder
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zoon, H.F.A., Veth, C., Arns, M.W., Drinkenburg, W.H.I.M., Talloen, W., Peeters, P.J., Kenemans, J.L., and Beleid Economie & Organisatie vd Zorg
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Psychologie (PSYC) - Abstract
Major depressive disorder has a large impact on patients and society and is projected to be the second greatest global burden of disease by 2020. The brain-derived neurotrophic factor (BDNF) gene is considered to be one of the important factors in the etiology of major depressive disorder. In a recent study, alpha power was found to mediate between BDNF Met and subclinical depressed mood. The current study looked at a population of patients with major depressive disorder (N = 107) to examine the association between the BDNF Val66Met polymorphism, resting state EEG alpha power, and depression severity. For this purpose, repeated-measures analysis of variance, partial correlation, and multiple linear models were used. Results indicated a negative association between parietal-occipital alpha power in the eyes open resting state and depression severity. In addition, Met/Met patients showed lower global absolute alpha power in the eyes closed condition compared with Val-carriers. These findings are in accordance with the previously uncovered pathway between BDNF Val66Met, resting state EEG alpha power, and depression severity. Additional research is needed for the clarification of this tentative pathway and its implication in personalized treatment of major depressive disorder.
- Published
- 2013
10. Association between COMT Val158Met genotype and EEG alpha peak frequency tested in two independent cohorts
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Veth, C.P.M., Arns, M.W., Drinkenburg, W., Talloen, W., Peeters, P.J., Gordon, E., Buitelaar, J.K., Veth, C.P.M., Arns, M.W., Drinkenburg, W., Talloen, W., Peeters, P.J., Gordon, E., and Buitelaar, J.K.
- Abstract
Item does not contain fulltext, This study could not confirm the association between the Catechol-O-Methyltransferase Val158Met polymorphism (COMT) and electroencephalographic (EEG) alpha peak frequency (APF) in two independent cohorts of 187 (96 depressed and 91 healthy participants) and 413 healthy participants. If COMT and APF play a role in depression or antidepressant treatment response, they do not have a shared pathway. We emphasize the importance of publishing null-findings for obtaining more accurate overall estimates of genetic effects.
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- 2014
11. P1189 HIGH MIG (CXCL9) PLASMA LEVEL FAVORS RESPONSE TO PEGINTERFERON AND RIBAVIRIN IN HCV INFECTED PATIENTS BUT IS NOT LINKED TO DPP4 ACTIVITY
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Johansson, S., primary, Talloen, W., additional, Tuefferd, M., additional, Darling, J., additional, Fanning, G., additional, Fried, M.W., additional, and Aerssens, J., additional
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- 2014
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12. P767 PLASMA LEVELS OF GRO ASSOCIATE WITH FIBROSIS AND PLATELET COUNTS IN HCV INFECTED PATIENTS FROM THE VIRAHEP-C COHORT
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Johansson, S., primary, Talloen, W., additional, Tuefferd, M., additional, Darling, J., additional, Scholliers, A., additional, Fanning, G., additional, Fried, M.W., additional, and Aerssens, J., additional
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- 2014
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13. P1208 PREDICTION OF SEVERE CUTANEOUS REACTION DURING TRIPLE THERAPY IN HCV: VALIDATION OF A GWAS CANDIDATE GENETIC MARKER
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Palescandolo, E., primary, Vijgen, L., additional, Talloen, W., additional, Colombo, M., additional, Mangia, A., additional, Wedemeyer, H., additional, Demasi, R., additional, Lonjon-Domanec, I., additional, and Aerssens, J., additional
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- 2014
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14. Oviposition of a specialized myrmecophilous Maculinea butterfly: does the presence of ant nests matter ?
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van Dyck, H., Oostermeijer, J.G.B., Talloen, W., Feenstra, V., van der Hidde, A., and Experimental Plant Systematics (IBED, FNWI)
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- 2000
15. 1167 PRE-TREATMENT IP-10 LEVELS AND IL28B GENOTYPE IN PREDICTION OF SVR IN PRIOR TREATMENT-EXPERIENCED GENOTYPE 1 HCV PATIENTS TREATED WITH TELAPREVIR/PEGINTERFERON/RIBAVIRIN IN THE REALIZE STUDY
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Vijgen, L., primary, Talloen, W., additional, Scholliers, A., additional, Johansson, S., additional, Tuefferd, M., additional, De Meyer, S., additional, Witek, J., additional, Fanning, G., additional, Picchio, G., additional, Pol, S., additional, Zeuzem, S., additional, and Aerssens, J., additional
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- 2012
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16. PP 105 Multiple gene signatures: some putative answers on the why and the how
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Talloen, W., primary and Bijnens, L., additional
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- 2011
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17. cn.FARMS: a latent variable model to detect copy number variations in microarray data with a low false discovery rate
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Clevert, D.-A., primary, Mitterecker, A., additional, Mayr, A., additional, Klambauer, G., additional, Tuefferd, M., additional, Bondt, A. D., additional, Talloen, W., additional, Gohlmann, H., additional, and Hochreiter, S., additional
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- 2011
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18. Environmental stress and quantitative genetic variation in butterfly wing characteristics
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Talloen, W., primary, Van Dongen, S., additional, Van Dyck, H., additional, and Lens, L., additional
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- 2008
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19. THE COST OF MELANIZATION: BUTTERFLY WING COLORATION UNDERENVIRONMENTAL STRESS
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Talloen, W., primary, Dyck, H. Van, additional, and Lens, L., additional
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- 2004
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20. Probabilistic intake assessment and body burden estimation of dioxin-like substances in background conditions and during a short food contamination episode
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Vrijens, B., primary, De Henauw, S., additional, Dewettinck, K., additional, Talloen, W., additional, Goeyens, L., additional, Backer, G. De, additional, and Willems, J. L., additional
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- 2002
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21. Economics of education — A selected annoted bibliography
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Talloen, W., primary
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- 1973
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22. 4.07 - Spectral Map Analysis of Microarray Data
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Bijnens, L., Verbeeck, R., Göhlmann, H.W., Talloen, W., Ion, R.A., Lewi, P.J., and Wouters, L.
- Full Text
- View/download PDF
23. Automated Spot Counting in Microbiology.
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Lin CP, Duan Y, Sargsyan D, Cabrera J, Livingston CM, Vogel R, Hartman J, Das M, Talloen W, Geys H, Kanoulas ED, and Mohanty S
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- Cell Culture Techniques, Models, Statistical, Algorithms, Bacteria
- Abstract
Biological samples are routinely analyzed for microbe concentration. The samples are diluted, loaded onto established host cell cultures, and incubated. If infectious agents are present in the samples, they form circular spots that do not contain the host cells. Each spot is assumed to be originated from a single microbial unit such as a bacterial colony forming unit or viral plaque forming unit. The undiluted sample concentration is estimated by counting the spots and back-calculating. Counting the number of spots by trained technicians is currently the gold standard but it is laborious, subjective, and hard to scale. This paper presents a new automated algorithm for spot counting, Localized and Sequential Thresholding (LoST). Validation studies showed that LoST performance was comparable with manual counting and outperformed several existing tools on images with overlapping spots. The LoST algorithm employs sequential thresholding through a two-stage segmentation and borrows information across all images from the same dilution series to fine-tune the count and identify right censoring. The algorithm increases the efficiency of the spot counting and the quality of the downstream analysis, especially when coupled with an appropriate statistical serial dilution model to enhance the undiluted sample concentration estimation procedure.
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- 2023
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24. Viral sequence analysis of chronic hepatitis B patients treated with the capsid assembly modulator JNJ-56136379 in the JADE phase 2a study.
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Verbinnen T, Talloen W, Janssen HLA, Zoulim F, Shukla U, Vandenbossche JJ, Biermer M, De Meyer S, and Lenz O
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- Humans, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Capsid metabolism, DNA, Viral genetics, DNA, Viral metabolism, Treatment Outcome, Hepatitis B e Antigens metabolism, Hepatitis B virus genetics, Hepatitis B virus metabolism, Capsid Proteins metabolism, High-Throughput Nucleotide Sequencing, Drug Resistance, Viral genetics, Hepatitis B, Chronic
- Abstract
Background & Aims: In the monotherapy arms of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956) evaluating the safety and efficacy of JNJ-56136379 (capsid assembly modulator-class E) with/without nucleos(t)ide analogue (NA), viral breakthroughs (VBT) were observed, leading to JNJ-56136379 monotherapy discontinuation. We present the viral sequencing analysis of JNJ-56136379±NA-treated hepatitis B virus (HBV)-infected patients., Methods: The HBV full genome was sequenced using next generation sequencing. Baseline amino acid (aa) polymorphisms were defined as changes versus the universal HBV reference sequence (sequence read frequency >15%). Emerging mutations were defined as aa changes versus baseline sequence (frequency <1% at baseline and ≥15% post-baseline)., Results: 6/28 JNJ-56136379 75 mg monotherapy arm patients experienced VBT; all 6 had emerging JNJ-56136379-resistant variants T33N (n = 5; fold change [FC] = 85) or F23Y (n = 1; FC = 5.2). 1/32 JNJ-56136379 250 mg arm patients (genotype-E) had <1 log
10 IU/mL decline in HBV DNA at Week 4, experienced VBT at Week 8, and carried the I105T baseline polymorphism (FC = 7.9), but had no emerging variants. Eight additional monotherapy-treated patients had shallow second phases of their HBV DNA profile and emerging T33N (n = 7) or F23Y (n = 1) variants. NA initiation (switch [75 mg arm]; add-on [250 mg arm]) in all monotherapy patients with VBT resulted in HBV DNA decline in all patients. No VBT was observed during JNJ-56136379+NA combination therapy., Conclusions: JNJ-56136379 monotherapy resulted in VBT and was associated with the selection of JNJ-56136379-resistant variants. Efficacy of NA treatment (de novo combination or rescue therapy for VBT) was not impacted, confirming the lack of cross-resistance between these drug classes., Clinical Trial Number: NCT03361956., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TV, WT, US, JJV, MB, SDM, and OL are Janssen employees, and some may be Johnson & Johnson stockholders. HLAJ received grants from AbbVie, Arbutus, Gilead Sciences, Janssen, and Roche, and is a consultant for Arbutus, Arena, Enyo, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, Vir Biotechnology Inc., and Viroclinics. FZ has participated in advisory committees or review panels for Janssen, Gilead Sciences, GlaxoSmithKline, Arbutus, Aligos, Antios, Assembly., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
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25. Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection.
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Janssen HLA, Hou J, Asselah T, Chan HLY, Zoulim F, Tanaka Y, Janczewska E, Nahass RG, Bourgeois S, Buti M, Lampertico P, Lenz O, Verbinnen T, Vandenbossche J, Talloen W, Kalmeijer R, Beumont M, Biermer M, and Shukla U
- Subjects
- Humans, Hepatitis B virus genetics, Hepatitis B Surface Antigens, Antiviral Agents adverse effects, Hepatitis B e Antigens, Capsid chemistry, DNA, Viral analysis, Hepatitis B Core Antigens, Treatment Outcome, Hepatitis B, Chronic, Hepatitis B
- Abstract
Objective: We present the final analysis results of the phase 2 JADE study (ClinicalTrials.gov Identifier: NCT03361956)., Design: 232 patients with chronic hepatitis B (CHB) not currently treated at study start (NCT) at study start or virologically suppressed were randomised to receive 75 mg (part 1) or 250 mg (part 2) JNJ-56136379, a hepatitis B virus (HBV)-capsid assembly modulator, one time per day or placebo with nucleos(t)ide analogue (NA) (tenofovir disoproxil fumarate/entecavir) or JNJ-56136379 alone (NCT-only) for ≥24 and ≤48 weeks., Results: In patients who are NCT hepatitis B e-antigen (HBeAg) positive, JNJ-56136379 75 mg+NA and 250 mg+NA showed limited mean (SE) hepatitis B surface antigen (HBsAg) declines (0.14 (0.10) and 0.41 (0.15), respectively) from baseline at Week 24 (primary endpoint; placebo+NA: 0.25 (0.11) log
10 international unit (IU)/mL).In patients who are NCT HBeAg positive, mean (SE) HBV DNA declines at Week 24 were 5.53 (0.23) and 5.88 (0.34) for JNJ-56136379 75 mg+NA and 250 mg+NA, respectively, versus 5.21 (0.42) log10 IU/mL for placebo+NA. In NCT patients, mean (SE) HBV RNA declines were 2.96 (0.23) and 3.15 (0.33) versus 1.33 (0.32) log10 copies/mL, respectively.Patients with HBsAg declines had HBeAg and hepatitis B core-related antigen (HBcrAg) declines and some early on-treatment isolated alanine aminotransferase flares. Viral breakthrough occurred with JNJ-56136379 monotherapy with the emerging resistant-variant T33N, but not with JNJ-56136379+NA. JNJ-56136379 treatment beyond Week 24 had a generally small additional effect on viral markers.No study treatment-related serious adverse events or clinically significant changes in laboratory parameters occurred., Conclusions: In patients with non-cirrhotic CHB, JNJ-56136379+NA showed pronounced reductions in HBV DNA and HBV RNA, limited HBsAg or HBeAg declines in patients who are NCT HBeAg positive, and was well tolerated, but no clear benefit with regards to efficacy of JNJ-56136379 over NA was observed., Competing Interests: Competing interests: HLAJ received grants from AbbVie, Arbutus, Gilead Sciences, Janssen and Roche, and is a consultant for Arbutus, Arena, Enyo Pharma, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Roche, Vir Biotechnology and Viroclinics. JH declares no conflicts of interest. TA has received grants and served as a speaker and clinical investigator for AbbVie, Antios Therapeutics, Enyo Pharma, Eiger BioPharmaceuticals, Gilead Sciences, Janssen, Merck and Roche. HLYC is an advisor for AbbVie, Aligos, Arbutus, Gilead Sciences, Hepion, Janssen, Merck, Roche, Vir Biotechnology, Vaccitech and VenatoRx, and served as a speaker for Gilead Sciences, Mylan and Roche. FZ has participated in advisory committees or review panels for Janssen, Gilead Sciences, AbbVie, Arbutus, Transgene, Contravir, Myrpharma, Spring Bank, Aligos and Assembly, received grant/research support from Roche and Sanofi/Evotec, and speaking and teaching support from Gilead Sciences. YT received lecture fees from Fujirebio, Sysymex and Gilead Sciences, consigned/joint research expenses from Fujifilim, Janssen, Gilead Sciences, GlaxoSmithKline and Stanford Junior University, and has participated in advisory boards for Gilead Sciences and GlaxoSmithKline. EJ has served as a speaker and clinical investigator for AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck and Roche. RGN has received grant/clinical research support from Janssen, Assembly, AbbVie, Alkermes, Gilead Sciences, Merck and ViiV, and has participated in speaker panels for Gilead Sciences, Merck, Insemed and ViiV. SB has participated in advisory committees or review panels for AbbVie, Gilead Sciences and Merck, and has received speaking and teaching support from AbbVie, Bristol Myers Squibb and Gilead Sciences. MBu has participated in advisory committees or review panels for Arbutus, Gilead Sciences, Janssen, Merck, Roche and Spring Bank Board, board membership for AbbVie, received grant/research support from Gilead Sciences and Janssen, and speaking and teaching support from Gilead Sciences, Janssen and Bristol Myers Squibb. PL has participated in advisory boards/speaker bureaus for Bristol Myers Squibb, Roche, Gilead Sciences, GlaxoSmithKline, AbbVie, Merck, Arrowhead, Alnylam, Janssen, Spring Bank Board, Myrpharma and Eiger. OL, TV, JV, WT, MBe, RK, MBi and US are all employees of Janssen Pharmaceuticals and Johnson & Johnson stockholders., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2023
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26. Drug-Drug Interactions With the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379 (Bersacapavir).
- Author
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Vandenbossche J, Yogaratnam J, Hillewaert V, Rasschaert F, Talloen W, Biewenga J, Snoeys J, Kakuda TN, Palmer M, Nangosyah J, and Biermer M
- Subjects
- Adult, Female, Humans, Antiviral Agents adverse effects, Capsid metabolism, Cytochrome P-450 CYP3A metabolism, Drug Interactions, Ethinyl Estradiol pharmacology, Itraconazole pharmacokinetics, Midazolam pharmacokinetics, Cytochrome P-450 CYP3A Inhibitors pharmacology, Hepatitis B virus metabolism
- Abstract
The capsid assembly modulator JNJ-56136379 (bersacapavir) disrupts hepatitis B virus replication. It is metabolized via cytochrome P450 (CYP) 3A, but little is known about the drug-drug interactions of JNJ-56136379 when combined with drugs that inhibit or are metabolized by CYP3A. In a phase 1, open-label trial (NCT03945539), healthy adults received 1 dose of JNJ-56136379 with and without 21 days of prior exposure to itraconazole 200 mg (CYP3A inhibitor). In a second phase 1, open-label trial (NCT03111511), healthy women received 1 dose of drospirenone/ethinyl estradiol and midazolam before and after 15 days of JNJ-56136379. Itraconazole increased the area under the plasma concentration-time curve (AUC) of JNJ-56136379 by 38%. JNJ-56136379 reduced the maximum observed concentration and AUC of midazolam (CYP3A substrate) by 42%-54%, increased AUC of ethinyl estradiol by 1.6-fold, but had no effect on drospirenone pharmacokinetics. Overall, these results demonstrated that a strong CYP3A inhibitor (itraconazole) modestly increased JNJ-56136379 exposure. Furthermore, JNJ-56136379 was a weak inducer of CYP3A (midazolam) and increased ethinyl estradiol exposure; coadministration of high-dose estrogen-based contraceptives and JNJ-56136379 is not recommended., (© 2022 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2022
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27. JNJ-73763989 pharmacokinetics and safety: Liver-targeted siRNAs against hepatitis B virus, in Japanese and non-Japanese healthy adults, and combined with JNJ-56136379 and a nucleos(t)ide analogue in patients with chronic hepatitis B.
- Author
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Gane E, Yuen MF, Kakuda TN, Ogawa T, Takahashi Y, Goeyvaerts N, Lonjon-Domanec I, Vaughan T, Schluep T, Hamilton J, Njumbe Ediage E, Hillewaert V, Snoeys J, Lenz O, Talloen W, and Biermer M
- Subjects
- Adult, Antiviral Agents adverse effects, Double-Blind Method, Hepatitis B virus genetics, Humans, Japan, Organic Chemicals, RNA, Small Interfering therapeutic use, Hepatitis B, Chronic drug therapy
- Abstract
Background: JNJ-73763989 comprises two hepatitis B virus (HBV)-specific, liver-targeted N-galactosamine-conjugated short interfering RNA triggers, JNJ-73763976 and JNJ-73763924. JNJ-73763989 pharmacokinetics, safety and tolerability were assessed in two phase 1 studies: Japanese (NCT04002752), and non-Japanese healthy participants and chronic hepatitis B (CHB) patients also receiving the HBV capsid assembly modulator JNJ-56136379 and a nucleos(t)ide analogue (NA) (NCT03365947)., Methods: Healthy participant cohorts were double-blind and randomized to receive a single subcutaneous JNJ-73763989 dose (non-Japanese participants, 35, 100, 200, 300 or 400 mg; Japanese participants, 25, 100 or 200 mg) or placebo. JNJ-73763976 and JNJ-73763924 plasma concentrations were assessed over 48 h. CHB patients received JNJ-73763989 200 mg every 4 weeks plus daily oral JNJ-56136379 250 mg and NA in an open-label fashion. Safety and tolerability were assessed through Day 28 (healthy participants) or Day 112 (patients)., Results: Thirty non-Japanese ( n = 4/dose; placebo, n = 10) and 24 Japanese healthy participants ( n = 6/dose; placebo, n = 6) were randomized. JNJ-73763976 and JNJ-73763924 exposure generally increased in a dose-proportional manner. Mean plasma half-life was 4-9 h. No differences between pharmacokinetic parameters were apparent between non-Japanese and Japanese healthy participants. In the 12 CHB patients, mean JNJ-73763976, JNJ-73763924 and JNJ-56136379 plasma concentrations 2 h post-dose on Day 29 were 663, 269 and 14,718 ng/mL, respectively. In both studies, all adverse events were mild/moderate., Conclusion: JNJ-73763976 and JNJ-73763924 had short plasma half-lives and exposure generally increased in a dose-proportional manner; there were no pharmacokinetic differences between Japanese and non-Japanese healthy adults. JNJ-73763989 with or without JNJ-56136379 and NA was generally safe and well tolerated.
- Published
- 2022
- Full Text
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28. Safety, antiviral activity and pharmacokinetics of JNJ-64530440, a novel capsid assembly modulator, as 4 week monotherapy in treatment-naive patients with chronic hepatitis B virus infection.
- Author
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Gane EJ, Schwabe C, Berliba E, Tangkijvanich P, Jucov A, Ghicavii N, Verbinnen T, Lenz O, Talloen W, Kakuda TN, Westland C, Patel M, Yogaratnam JZ, Dragone L, and Van Remoortere P
- Subjects
- Adult, Antiviral Agents adverse effects, Capsid, DNA, Viral, Female, Hepatitis B e Antigens therapeutic use, Hepatitis B virus genetics, Humans, Male, Hepatitis B, Chronic drug therapy
- Abstract
Objectives: We investigated JNJ-64530440 (a hepatitis B virus capsid assembly modulator) safety, antiviral activity and pharmacokinetics in patients with chronic hepatitis B (CHB) (Phase 1b, NCT03439488)., Methods: Twenty treatment-naive, HBeAg-positive or -negative CHB patients were randomized 4:1 to JNJ-64530440 750 mg once or twice daily, or placebo for 28 days., Results: All patients (mean age 43.8 years; 85% male; 70% White; 20% HBeAg positive) completed dosing/28 day follow-up. Mild-to-moderate treatment-emergent adverse events occurred in 3/4 (placebo), 6/8 (once-daily) and 4/8 (twice-daily) patients; mostly fatigue, increased alanine aminotransferase, decreased neutrophil count, and headache. Hepatitis B virus (HBV) DNA was substantially reduced; mean (range) changes from baseline at day 29 were: -3.2 (-2.4 to -3.9) (once-daily) and -3.3 (-2.6 to -4.1) (twice-daily) log10 IU/mL; placebo 0.1 (0.7 to -0.6) log10 IU/mL. HBV DNA levels were below the lower limit of quantification (LLOQ) in 5/8 (once-daily) and 3/8 (twice-daily) patients. For patients with detectable baseline HBV RNA, mean (SE) changes versus baseline in HBV RNA at day 29 were: -2.65 (0.81) (once-daily) and -2.94 (0.33) (twice-daily) log10 copies/mL. HBV RNA levels were 'target not detected' in 4/6 (once-daily) and 3/7 (twice-daily) patients. JNJ-64530440 pharmacokinetics in CHB patients were comparable with those in healthy volunteers., Conclusions: JNJ-64530440 750 mg once-daily or twice-daily for 28 days was well tolerated and achieved potent antiviral activity in CHB patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
- Published
- 2022
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29. Mean HBsAg decline at week 24 of PEG-IFN-based treatment predicts subsequent rate of HBsAg clearance - suggesting a valuable endpoint for early development HBV trials.
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De Ridder F, Sonneveld MJ, Lenz O, Janssen HLA, Talloen W, and Hansen BE
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- Antiviral Agents therapeutic use, DNA, Viral, Hepatitis B e Antigens, Humans, Interferon-alpha therapeutic use, Polyethylene Glycols therapeutic use, Recombinant Proteins, Treatment Outcome, Hepatitis B Surface Antigens, Hepatitis B virus genetics
- Abstract
Earlier identification of potentially efficacious treatments in early development trials requires on-treatment response markers. We hypothesized that mean week 12 or 24 HBsAg decline could be a useful marker for subsequent off-treatment sustained HBsAg clearance at the treatment arm level in HBV trials. We used individual patient data from the studies HBV 9901 (peginterferon [PEG-IFN] versus PEG-IFN+lamivudine for HBeAg-positive CHB), PARC (PEG-IFN±ribavirin for HBeAg-negative CHB) and published data from 0149 (PEG-IFN±tenofovir for HBeAg-positive and HBeAg-negative CHB) and LIRA-B (PEG-IFN for HBeAg-positive CHB) to define the relationship between mean week HBsAg decline and HBsAg loss at 6 months post-treatment. A within-study comparison of HBsAg decline at weeks 12 and 24 between patients with or without HBsAg clearance was used to make projections beyond the observed HBsAg data. Across trials, a more pronounced mean HBsAg decline at week 24 was associated with higher rates of subsequent HBsAg loss. Mean HBsAg decline data at week 24 for patients with or without HBsAg clearance from HBV 9901 (4.3 vs 0.5), PARC (4.8 vs 0.3) and 0149 (PEG-IFN+TDF arm; 4.6 vs 0.6) were used to extrapolate this relationship beyond observed rates of HBsAg. An additional mean 1 log
10 decline at week 24 versus a comparator arm is expected to translate into a 20%-30% increase in subsequent HBsAg loss during off-treatment follow-up. Observations were similar for week 12 data, but the relationship was less strong. Mean week 24 HBsAg decline predicts subsequent HBsAg loss and could be a valuable and useful early endpoint in HBV-treatment trials., (© 2021 John Wiley & Sons Ltd.)- Published
- 2021
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30. Pharmacokinetics, safety and tolerability of single- and multiple-ascending doses of JNJ-64530440, a novel hepatitis B virus capsid assembly modulator, in healthy volunteers.
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Kakuda TN, Yogaratnam JZ, Westland C, Gane EJ, Schwabe C, Vuong J, Patel M, Snoeys J, Talloen W, Lenz O, Fry J, Chanda S, and van Remoortere P
- Subjects
- Adult, Antiviral Agents pharmacokinetics, Area Under Curve, Healthy Volunteers, Humans, Capsid, Hepatitis B virus
- Abstract
Background: Pharmacokinetics and safety of JNJ-64530440, a hepatitis B virus capsid assembly modulator producing normal empty capsids (CAM-N), in healthy volunteers were evaluated., Methods: This Phase I study (NCT03439488) was a double-blind, randomised, placebo-controlled study. Adults ( n = 10/cohort, five Asian/five non-Asian), randomised 4:1, received single-ascending doses of oral JNJ-64530440 (first- and second-generation formulations) or placebo under fasted (50, 150, 300 and 900 mg) or fed (300, 750, 1,000, 2000 and 4000 mg) conditions. Multiple-ascending doses of 750 or 2000 mg once daily and 750 mg twice daily JNJ-64530440 (second-generation formulation) for 7 days were evaluated. Pharmacokinetic parameters were estimated from plasma concentrations. Safety was assessed throughout., Results: Less than dose-proportional increases in maximum plasma concentrations (C
max ) and area under the plasma concentration-time curves (AUCs) were observed across the doses. Mean plasma half-lives ranged from 9.3 to 14.5 h. Cmax and AUC were ∼two fold higher under fed versus fasting conditions and slightly higher in Asians versus Caucasians. JNJ-64530440 doses ≥750 mg achieved plasma levels higher than protein-binding adjusted concentrations demonstrating in vitro antiviral activity. No serious adverse events (AEs), treatment discontinuations or dose-limiting toxicities were seen. AE frequency/severity did not increase with dose., Conclusions: Single (up to 4000 mg) and multiple doses (up to 2000 mg for 7 days) of JNJ-64530440 were well tolerated in healthy volunteers. Multiple doses ≥750 mg/day achieved plasma concentrations expected to have antiviral activity that may lower hepatitis B surface antigen. No clinically relevant differences in tolerability or pharmacokinetic parameters were seen between Asians versus Caucasians.- Published
- 2021
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31. Virology analysis of chronic hepatitis B virus-infected patients treated for 28 days with JNJ-56136379 monotherapy.
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Verbinnen T, Hodari M, Talloen W, Berke JM, Blue D, Yogaratnam J, Vandenbossche J, Shukla U, De Meyer S, and Lenz O
- Subjects
- Antiviral Agents therapeutic use, Capsid, DNA, Viral, Hepatitis B e Antigens, Humans, Treatment Outcome, Hepatitis B virus genetics, Hepatitis B, Chronic drug therapy, Hepatitis B, Chronic virology
- Abstract
Four weeks of once-daily oral JNJ-56136379 (JNJ-6379; 25, 75, 150 or 250 mg), a class-N capsid assembly modulator (CAM-N), was well tolerated with potent antiviral activity in treatment-naïve, chronic hepatitis B e antigen-positive and hepatitis B e antigen-negative patients (NCT02662712). Hepatitis B virus (HBV) genome sequence analysis, using HBV DNA next-generation sequence technology, was performed, and impact of substitutions on efficacy was assessed. Analyses focused on HBV core protein amino acid positions associated with JNJ-6379 and/or other CAMs in vitro resistance, and those within the CAM-binding pocket. 31/57 patients had ≥ 1 polymorphism at any of the core amino acid positions of interest, most frequently at positions 38 (32%), 105 (23%) and 109 (14%). None of these polymorphisms are known to reduce JNJ-6379 in vitro activity (fold change [FC] in 50% effective concentration <3.0). Two JNJ-6379-treated patients carried a Y118F baseline core polymorphism known to reduce JNJ-6379 activity in vitro (FC = 6.6) and had HBV DNA declines of 2.77 (75 mg) and 2.19 log
10 IU/mL (150 mg) at the end of treatment. One 75 mg JNJ-6379-treated patient had an emerging T109S substitution (FC = 1.8; HBV DNA decline 3.18 log10 IU/mL). A 25 mg JNJ-6379-treated patient had on-treatment enrichment of Y118F variant (HBV DNA decline 2.13 log10 IU/mL). In conclusion, baseline polymorphisms and enrichment of substitutions reducing JNJ-6379 in vitro activity were rare, with no consistent impact on virological response during a 4-week phase 1b study. Emergence of resistance to longer treatments of JNJ-6379 will be evaluated in phase 2 studies., (© 2020 John Wiley & Sons Ltd.)- Published
- 2020
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32. JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection.
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Zoulim F, Lenz O, Vandenbossche JJ, Talloen W, Verbinnen T, Moscalu I, Streinu-Cercel A, Bourgeois S, Buti M, Crespo J, Manuel Pascasio J, Sarrazin C, Vanwolleghem T, Shukla U, Fry J, and Yogaratnam JZ
- Subjects
- Administration, Oral, Antiviral Agents administration & dosage, Antiviral Agents pharmacokinetics, Capsid drug effects, DNA, Viral blood, DNA, Viral isolation & purification, Dose-Response Relationship, Drug, Double-Blind Method, Female, Hepatitis B virus drug effects, Hepatitis B virus genetics, Hepatitis B, Chronic blood, Hepatitis B, Chronic diagnosis, Hepatitis B, Chronic virology, Humans, Male, Middle Aged, Organic Chemicals administration & dosage, Organic Chemicals pharmacokinetics, Treatment Outcome, Virus Assembly drug effects, Young Adult, Antiviral Agents adverse effects, Hepatitis B virus isolation & purification, Hepatitis B, Chronic drug therapy, Organic Chemicals adverse effects
- Abstract
Background & Aims: JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection., Methods: We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period., Results: Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed., Conclusions: In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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33. Correction to: Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects.
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Vandenbossche J, Jessner W, van den Boer M, Biewenga J, Berke JM, Talloen W, De Zwart L, Snoeys J, Vandyck K, Fry J, and Yogaratnam J
- Abstract
In the original article Ninth and Tenth authors were incorrectly omitted from the author group. The correct author group is Joris Vandenbossche, Wolfgang Jessner, Maarten van den Boer, Jeike Biewenga, Jan Martin Berke, Willem Talloen, Loeckie De Zwart, Jan Snoeys, Koen Vandyck, John Fry, Jeysen Yogaratnam.
- Published
- 2020
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34. New Developments in Factor Score Regression: Fit Indices and a Model Comparison Test.
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Devlieger I, Talloen W, and Rosseel Y
- Abstract
Factor score regression (FSR) is a popular alternative for structural equation modeling. Naively applying FSR induces bias for the estimators of the regression coefficients. Croon proposed a method to correct for this bias. Next to estimating effects without bias, interest often lies in inference of regression coefficients or in the fit of the model. In this article, we propose fit indices for FSR that can be used to inspect the model fit. We also introduce a model comparison test based on one of these newly proposed fit indices that can be used for inference of the estimators on the regression coefficients. In a simulation study we compare FSR with Croon's corrections and structural equation modeling in terms of bias of the regression coefficients, Type I error rate and power., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)
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- 2019
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35. Pharmacokinetics, Safety and Tolerability of JNJ-56136379, a Novel Hepatitis B Virus Capsid Assembly Modulator, in Healthy Subjects.
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Vandenbossche J, Jessner W, van den Boer M, Biewenga J, Berke JM, Talloen W, De Zwart L, Snoeys J, and Yogaratnam J
- Subjects
- Adult, Area Under Curve, Azepines administration & dosage, Azepines adverse effects, Dose-Response Relationship, Drug, Double-Blind Method, Female, Healthy Volunteers, Hepatitis B virus drug effects, Humans, Male, Middle Aged, Piperidines administration & dosage, Piperidines adverse effects, Antiviral Agents administration & dosage, Azepines pharmacology, Capsid drug effects, Hepatitis B, Chronic drug therapy, Piperidines pharmacology
- Abstract
Introduction: Hepatitis B viral capsid assembly is an attractive target for new antiviral treatments. JNJ-56136379 (JNJ-6379) is a potent capsid assembly modulator in vitro with a dual mode of action. In Part 1 of this first-in-human study in healthy adults, the pharmacokinetics (PK), safety and tolerability of JNJ-6379 were evaluated following single ascending and multiple oral doses., Methods: This was a double-blind, randomized, placebo-controlled study in 30 healthy adults. Eighteen subjects were randomized to receive single doses of JNJ-6379 (25 to 600 mg) or placebo. Twelve subjects were randomized to receive 150 mg JNJ-6379 or placebo twice daily for 2 days, followed by 100 mg JNJ-6379 or placebo daily for 10 days., Results: The maximum observed plasma concentration and the area under the curve increased dose proportionally from 25 to 300 mg JNJ-6379. Following multiple dosing, steady-state conditions were achieved on day 8. Steady-state clearance was similar following single and multiple dosing, suggesting time-linear PK. All adverse events (AEs) reported were mild to moderate in severity. There were no serious AEs or dose-limiting toxicities and no apparent relationship to dose for any AE., Conclusion: JNJ-6379 was well tolerated in this study. Based on the safety profile and plasma exposures of JNJ-6379 in healthy subjects, a dosing regimen was selected for Part 2 of this study in patients with chronic hepatitis B. This is anticipated to achieve trough plasma exposures of JNJ-6379 at steady state of more than three times the 90% effective concentration of viral replication determined in vitro., Trial Registration: Clinicaltrials.gov identifier, NCT02662712., Funding: Janssen Pharmaceutica.
- Published
- 2019
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36. Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection.
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Yuen MF, Gane EJ, Kim DJ, Weilert F, Yuen Chan HL, Lalezari J, Hwang SG, Nguyen T, Flores O, Hartman G, Liaw S, Lenz O, Kakuda TN, Talloen W, Schwabe C, Klumpp K, and Brown N
- Subjects
- Administration, Oral, Adult, Antiviral Agents administration & dosage, Antiviral Agents adverse effects, Asia, Benzamides administration & dosage, Benzamides adverse effects, DNA, Viral blood, DNA, Viral genetics, Drug Administration Schedule, Drug Therapy, Combination, Female, Hepatitis B e Antigens blood, Hepatitis B e Antigens immunology, Hepatitis B virus genetics, Hepatitis B virus growth & development, Hepatitis B virus immunology, Hepatitis B, Chronic diagnosis, Hepatitis B, Chronic virology, Humans, Interferon-alpha administration & dosage, Male, Middle Aged, New Zealand, Piperidines administration & dosage, Piperidines adverse effects, Polyethylene Glycols administration & dosage, RNA, Viral blood, RNA, Viral genetics, Recombinant Proteins administration & dosage, Treatment Outcome, United States, Viral Load, Young Adult, Antiviral Agents pharmacokinetics, Benzamides pharmacokinetics, Hepatitis B virus drug effects, Hepatitis B, Chronic drug therapy, Piperidines pharmacokinetics, Virus Replication drug effects
- Abstract
Background & Aims: NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic HBV infection., Methods: We performed a phase 1 study in 73 hepatitis B envelope antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo., Results: Reductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/d NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log
10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778., Conclusions: In a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA, to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778. Clinicaltrials.gov no. NCT02112799 (single-center) and NCT02401737 (multicenter)., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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37. A bootstrap version of the Hausman test to assess the impact of cluster-level endogeneity beyond the random intercept model.
- Author
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Talloen W, Loeys T, and Moerkerke B
- Subjects
- Data Interpretation, Statistical, Humans, Multilevel Analysis, Multivariate Analysis, Cluster Analysis, Models, Statistical
- Abstract
In the random intercept model for clustered data, the random effect is typically assumed to be independent of predictors. Violation of this assumption due to unmeasured cluster-level confounding (endogeneity) induces bias in the estimates of effects of within-cluster predictors. Treating cluster-specific intercepts as fixed rather than random avoids this bias. The Hausman test contrasts the fixed effect estimator with the traditional random effect estimator in the random intercept model to test for the presence of cluster-level endogeneity and has a known asymptotic χ 2 -distribution under correct model specification. Unmeasured cluster-level heterogeneity may, however, interact with predictors as well, necessitating random slope models. Relying on either cluster or residual resampling in a bootstrap procedure, we propose two extensions of the Hausman test that can easily be used beyond the random intercept model. We compare the original Hausman test and its robust version to the newly proposed bootstrap tests in terms of empirical type I error rate and power. Under additive unmeasured heterogeneity, all methods perform equally well, whereas the original and robust Hausman tests are too liberal or too conservative under additional slope heterogeneity, both bootstrap Hausman tests maintain appropriate performance. Moreover, both bootstrap tests show robustness against misspecification in the presence of unit-level heteroscedasticity and temporal correlation.
- Published
- 2019
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38. A random effects model for the identification of differential splicing (REIDS) using exon and HTA arrays.
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Van Moerbeke M, Kasim A, Talloen W, Reumers J, Göhlmann HWH, and Shkedy Z
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- Area Under Curve, Colonic Neoplasms genetics, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Exons, Humans, LIM Domain Proteins genetics, Microfilament Proteins genetics, Protein Isoforms genetics, ROC Curve, Alternative Splicing, Models, Genetic, Oligonucleotide Array Sequence Analysis methods, Transcriptome
- Abstract
Background: Alternative gene splicing is a common phenomenon in which a single gene gives rise to multiple transcript isoforms. The process is strictly guided and involves a multitude of proteins and regulatory complexes. Unfortunately, aberrant splicing events do occur which have been linked to genetic disorders, such as several types of cancer and neurodegenerative diseases (Fan et al., Theor Biol Med Model 3:19, 2006). Therefore, understanding the mechanism of alternative splicing and identifying the difference in splicing events between diseased and healthy tissue is crucial in biomedical research with the potential of applications in personalized medicine as well as in drug development., Results: We propose a linear mixed model, Random Effects for the Identification of Differential Splicing (REIDS), for the identification of alternative splicing events. Based on a set of scores, an exon score and an array score, a decision regarding alternative splicing can be made. The model enables the ability to distinguish a differential expressed gene from a differential spliced exon. The proposed model was applied to three case studies concerning both exon and HTA arrays., Conclusion: The REIDS model provides a work flow for the identification of alternative splicing events relying on the established linear mixed model. The model can be applied to different types of arrays.
- Published
- 2017
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39. Identification of the minimum effective dose for normally distributed data using a Bayesian variable selection approach.
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Otava M, Shkedy Z, Hothorn LA, Talloen W, Gerhard D, and Kasim A
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- Dose-Response Relationship, Drug, Humans, Normal Distribution, Bayes Theorem, Data Interpretation, Statistical, Uncertainty
- Abstract
The identification of the minimum effective dose is of high importance in the drug development process. In early stage screening experiments, establishing the minimum effective dose can be translated into a model selection based on information criteria. The presented alternative, Bayesian variable selection approach, allows for selection of the minimum effective dose, while taking into account model uncertainty. The performance of Bayesian variable selection is compared with the generalized order restricted information criterion on two dose-response experiments and through the simulations study. Which method has performed better depends on the complexity of the underlying model and the effect size relative to noise.
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- 2017
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40. Gait characteristics and spatio-temporal variables of climbing in bonobos (Pan paniscus).
- Author
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Schoonaert K, D'Août K, Samuel D, Talloen W, Nauwelaerts S, Kivell TL, and Aerts P
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- Animals, Biomechanical Phenomena, Foot, Gait, Locomotion, Pan paniscus
- Abstract
Although much is known about the terrestrial locomotion of great apes, their arboreal locomotion has been studied less extensively. This study investigates arboreal locomotion in bonobos (Pan paniscus), focusing on the gait characteristics and spatio-temporal variables associated with locomotion on a pole. These features are compared across different substrate inclinations (0°, 30°, 45°, 60°, and 90°), and horizontal quadrupedal walking is compared between an arboreal and a terrestrial substrate. Our results show greater variation in footfall patterns with increasing incline, resulting in more lateral gait sequences. During climbing on arboreal inclines, smaller steps and strides but higher stride frequencies and duty factors are found compared to horizontal arboreal walking. This may facilitate better balance control and dynamic stability on the arboreal substrate. We found no gradual change in spatio-temporal variables with increasing incline; instead, the results for all inclines were clustered together. Bonobos take larger strides at lower stride frequencies and lower duty factors on a horizontal arboreal substrate than on a flat terrestrial substrate. We suggest that these changes are the result of the better grip of the grasping feet on an arboreal substrate. Speed modulation of the spatio-temporal variables is similar across substrate inclinations and between substrate types, suggesting a comparable underlying motor control. Finally, we contrast these variables of arboreal inclined climbing with those of terrestrial bipedal locomotion, and briefly discuss the results with respect to the origin of habitual bipedalism. Am. J. Primatol. 78:1165-1177, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
- Published
- 2016
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41. Assessing moderated mediation in linear models requires fewer confounding assumptions than assessing mediation.
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Loeys T, Talloen W, Goubert L, Moerkerke B, and Vansteelandt S
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- Computer Simulation, Humans, Confounding Factors, Epidemiologic, Data Interpretation, Statistical, Effect Modifier, Epidemiologic, Linear Models, Regression Analysis
- Abstract
It is well known from the mediation analysis literature that the identification of direct and indirect effects relies on strong no unmeasured confounding assumptions of no unmeasured confounding. Even in randomized studies the mediator may still be correlated with unobserved prognostic variables that affect the outcome, in which case the mediator's role in the causal process may not be inferred without bias. In the behavioural and social science literature very little attention has been given so far to the causal assumptions required for moderated mediation analysis. In this paper we focus on the index for moderated mediation, which measures by how much the mediated effect is larger or smaller for varying levels of the moderator. We show that in linear models this index can be estimated without bias in the presence of unmeasured common causes of the moderator, mediator and outcome under certain conditions. Importantly, one can thus use the test for moderated mediation to support evidence for mediation under less stringent confounding conditions. We illustrate our findings with data from a randomized experiment assessing the impact of being primed with social deception upon observer responses to others' pain, and from an observational study of individuals who ended a romantic relationship assessing the effect of attachment anxiety during the relationship on mental distress 2 years after the break-up., (© 2016 The British Psychological Society.)
- Published
- 2016
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42. Weighted similarity-based clustering of chemical structures and bioactivity data in early drug discovery.
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Perualila-Tan NJ, Shkedy Z, Talloen W, Göhlmann HW, Moerbeke MV, and Kasim A
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- Drug Screening Assays, Antitumor, Humans, Information Storage and Retrieval, Algorithms, Cluster Analysis, Databases, Factual, Drug Discovery methods, ErbB Receptors
- Abstract
The modern process of discovering candidate molecules in early drug discovery phase includes a wide range of approaches to extract vital information from the intersection of biology and chemistry. A typical strategy in compound selection involves compound clustering based on chemical similarity to obtain representative chemically diverse compounds (not incorporating potency information). In this paper, we propose an integrative clustering approach that makes use of both biological (compound efficacy) and chemical (structural features) data sources for the purpose of discovering a subset of compounds with aligned structural and biological properties. The datasets are integrated at the similarity level by assigning complementary weights to produce a weighted similarity matrix, serving as a generic input in any clustering algorithm. This new analysis work flow is semi-supervised method since, after the determination of clusters, a secondary analysis is performed wherein it finds differentially expressed genes associated to the derived integrated cluster(s) to further explain the compound-induced biological effects inside the cell. In this paper, datasets from two drug development oncology projects are used to illustrate the usefulness of the weighted similarity-based clustering approach to integrate multi-source high-dimensional information to aid drug discovery. Compounds that are structurally and biologically similar to the reference compounds are discovered using this proposed integrative approach.
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- 2016
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43. A joint modeling approach for uncovering associations between gene expression, bioactivity and chemical structure in early drug discovery to guide lead selection and genomic biomarker development.
- Author
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Perualila-Tan N, Kasim A, Talloen W, Verbist B, Göhlmann HW, and Shkedy Z
- Subjects
- Genomics, Molecular Structure, Biomarkers chemistry, Chemistry, Pharmaceutical methods, Drug Discovery, Gene Expression, Models, Genetic
- Abstract
The modern drug discovery process involves multiple sources of high-dimensional data. This imposes the challenge of data integration. A typical example is the integration of chemical structure (fingerprint features), phenotypic bioactivity (bioassay read-outs) data for targets of interest, and transcriptomic (gene expression) data in early drug discovery to better understand the chemical and biological mechanisms of candidate drugs, and to facilitate early detection of safety issues prior to later and expensive phases of drug development cycles. In this paper, we discuss a joint model for the transcriptomic and the phenotypic variables conditioned on the chemical structure. This modeling approach can be used to uncover, for a given set of compounds, the association between gene expression and biological activity taking into account the influence of the chemical structure of the compound on both variables. The model allows to detect genes that are associated with the bioactivity data facilitating the identification of potential genomic biomarkers for compounds efficacy. In addition, the effect of every structural feature on both genes and pIC50 and their associations can be simultaneously investigated. Two oncology projects are used to illustrate the applicability and usefulness of the joint model to integrate multi-source high-dimensional information to aid drug discovery.
- Published
- 2016
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44. High MIG (CXCL9) plasma levels favours response to peginterferon and ribavirin in HCV-infected patients regardless of DPP4 activity.
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Johansson S, Talloen W, Tuefferd M, Darling J, Fanning G, Fried MW, and Aerssens J
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- Adult, Black or African American genetics, Aged, Antiviral Agents adverse effects, Biomarkers blood, Drug Therapy, Combination, Female, Genotype, Hepatitis C blood, Hepatitis C diagnosis, Hepatitis C enzymology, Humans, Interferon-alpha adverse effects, Interferons, Interleukin-10 blood, Interleukins genetics, Male, Middle Aged, Phenotype, Polyethylene Glycols adverse effects, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Ribavirin adverse effects, Time Factors, Treatment Outcome, United States, Up-Regulation, White People genetics, Young Adult, Antiviral Agents therapeutic use, Chemokine CXCL9 blood, Dipeptidyl Peptidase 4 blood, Hepatitis C drug therapy, Interferon-alpha therapeutic use, Polyethylene Glycols therapeutic use, Ribavirin therapeutic use
- Abstract
Background & Aims: Sustained virological response (SVR) following peginterferon (pegIFN) and ribavirin (RBV) treatment in hepatitis C virus (HCV)-infected patients has been linked with the IL28B genotype and lower peripheral levels of the CXCR3-binding chemokine IP-10 (CXCL10). To further improve the understanding of these biomarkers we investigated plasma levels of the other CXCR3-binding chemokines and activity of the dipeptidyl peptidase IV (DPP4, CD26) protease, which cleaves IP-10, in relation to treatment response., Methods: African-American and Caucasian HCV genotype 1-infected patients (n = 401) were treated with pegIFN/RBV for 48 weeks (ViraHep-C cohort). Pretreatment plasma levels of MIG (CXCL9), I-TAC (CXCL11) and the type III interferon IL29 were investigated by Luminex and DPP4 activity by using a luciferase assay., Results: Patients achieving SVR had higher baseline MIG plasma levels and lower DPP4 activity than non-SVR patients. MIG was higher in Caucasians, IL28B CC (rs1297860) genotype carriers and patients with higher ALT levels. MIG correlated with IP-10 in SVR patients, but not in non-SVRs. A high DPP4 activity correlated with higher IP-10 levels, while DPP4 activity was not associated with MIG or I-TAC levels., Conclusions: The associations of MIG with SVR status and IL28B genotype imply that higher MIG plasma levels could reflect a beneficial immunological state for response to pegIFN/RBV treatment. The correlation between MIG and IP-10 observed only in SVR patients may contribute to a better treatment response, whereas this MIG/IP-10 balance might be disrupted in non-SVR patients because of the increased DPP4 cleavage of IP-10 into a dysfunctional form., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2016
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45. Integrating High-Dimensional Transcriptomics and Image Analysis Tools into Early Safety Screening: Proof of Concept for a New Early Drug Development Strategy.
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Verbist BM, Verheyen GR, Vervoort L, Crabbe M, Beerens D, Bosmans C, Jaensch S, Osselaer S, Talloen W, Van den Wyngaert I, Van Hecke G, Wuyts D, Van Goethem F, and Göhlmann HW
- Subjects
- Animals, Cell Line, Tumor, HEK293 Cells, Humans, Microscopy, Confocal, Phosphodiesterase Inhibitors chemistry, Phosphodiesterase Inhibitors metabolism, Phosphodiesterase Inhibitors toxicity, Phosphoric Diester Hydrolases chemistry, Phosphoric Diester Hydrolases metabolism, Pyrrolidines chemistry, Pyrrolidines metabolism, Pyrrolidines toxicity, Structure-Activity Relationship, Transcriptome drug effects, Tubulin metabolism, Drug Discovery, Gene Expression Profiling
- Abstract
During drug discovery and development, the early identification of adverse effects is expected to reduce costly late-stage failures of candidate drugs. As risk/safety assessment takes place rather late during the development process and due to the limited ability of animal models to predict the human situation, modern unbiased high-dimensional biology readouts are sought, such as molecular signatures predictive for in vivo response using high-throughput cell-based assays. In this theoretical proof of concept, we provide findings of an in-depth exploration of a single chemical core structure. Via transcriptional profiling, we identified a subset of close analogues that commonly downregulate multiple tubulin genes across cellular contexts, suggesting possible spindle poison effects. Confirmation via a qualified toxicity assay (in vitro micronucleus test) and the identification of a characteristic aggregate-formation phenotype via exploratory high-content imaging validated the initial findings. SAR analysis triggered the synthesis of a new set of compounds and allowed us to extend the series showing the genotoxic effect. We demonstrate the potential to flag toxicity issues by utilizing data from exploratory experiments that are typically generated for target evaluation purposes during early drug discovery. We share our thoughts on how this approach may be incorporated into drug development strategies.
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- 2015
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46. Identification of in vitro and in vivo disconnects using transcriptomic data.
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Otava M, Shkedy Z, Talloen W, Verheyen GR, and Kasim A
- Subjects
- Algorithms, Animals, Cluster Analysis, Dose-Response Relationship, Drug, Drug-Related Side Effects and Adverse Reactions, In Vitro Techniques, Models, Chemical, Rats, Drug Evaluation, Preclinical, Toxicogenetics methods, Transcriptome
- Abstract
Background: Integrating transcriptomic experiments within drug development is increasingly advocated for the early detection of toxicity. This is partly to reduce costs related to drug failures in the late, and expensive phases of clinical trials. Such an approach has proven useful both in the study of toxicology and carcinogenicity. However, general lack of translation of in vitro findings to in vivo systems remains one of the bottle necks in drug development. This paper proposes a method for identifying disconnected genes between in vitro and in vivo toxicogenomic rat experiments. The analytical framework is based on the joint modeling of dose-dependent in vitro and in vivo data using a fractional polynomial framework and biclustering algorithm., Results: Most disconnected genes identified belonged to known pathways, such as drug metabolism and oxidative stress due to reactive metabolites, bilirubin increase, glutathion depletion and phospholipidosis. We also identified compounds that were likely to induce disconnect in gene expression between in vitro and in vivo toxicogenomic rat experiments. These compounds include: sulindac and diclofenac (both linked to liver damage), naphtyl isothiocyanate (linked to hepatoxocity), indomethacin and naproxen (linked to gastrointestinal problem and damage of intestines)., Conclusion: The results confirmed that there are important discrepancies between in vitro and in vivo toxicogenomic experiments. However, the contribution of this paper is to provide a tool to identify genes that are disconnected between the two systems. Pathway analysis of disconnected genes may improve our understanding of uncertainties in the mechanism of actions of drug candidates in humans, especially concerning the early detection of toxicity.
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- 2015
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47. Using transcriptomics to guide lead optimization in drug discovery projects: Lessons learned from the QSTAR project.
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Verbist B, Klambauer G, Vervoort L, Talloen W, Shkedy Z, Thas O, Bender A, Göhlmann HW, and Hochreiter S
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- Animals, Databases, Genetic, Decision Support Techniques, Gene Expression Regulation drug effects, Humans, Molecular Structure, Program Evaluation, Quantitative Structure-Activity Relationship, Risk Assessment, Drug Approval, Drug Discovery methods, Drug-Related Side Effects and Adverse Reactions genetics, Gene Expression Profiling, Transcription, Genetic drug effects
- Abstract
The pharmaceutical industry is faced with steadily declining R&D efficiency which results in fewer drugs reaching the market despite increased investment. A major cause for this low efficiency is the failure of drug candidates in late-stage development owing to safety issues or previously undiscovered side-effects. We analyzed to what extent gene expression data can help to de-risk drug development in early phases by detecting the biological effects of compounds across disease areas, targets and scaffolds. For eight drug discovery projects within a global pharmaceutical company, gene expression data were informative and able to support go/no-go decisions. Our studies show that gene expression profiling can detect adverse effects of compounds, and is a valuable tool in early-stage drug discovery decision making., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2015
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48. ViVaMBC: estimating viral sequence variation in complex populations from illumina deep-sequencing data using model-based clustering.
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Verbist B, Clement L, Reumers J, Thys K, Vapirev A, Talloen W, Wetzels Y, Meys J, Aerssens J, Bijnens L, and Thas O
- Subjects
- Cluster Analysis, Genome, Viral, Genomics methods, Hepatitis C virology, Humans, Sensitivity and Specificity, Sequence Analysis, DNA methods, Algorithms, Genetic Variation genetics, Hepacivirus genetics, Hepatitis C genetics, High-Throughput Nucleotide Sequencing methods, Mutation genetics, Software
- Abstract
Background: Deep-sequencing allows for an in-depth characterization of sequence variation in complex populations. However, technology associated errors may impede a powerful assessment of low-frequency mutations. Fortunately, base calls are complemented with quality scores which are derived from a quadruplet of intensities, one channel for each nucleotide type for Illumina sequencing. The highest intensity of the four channels determines the base that is called. Mismatch bases can often be corrected by the second best base, i.e. the base with the second highest intensity in the quadruplet. A virus variant model-based clustering method, ViVaMBC, is presented that explores quality scores and second best base calls for identifying and quantifying viral variants. ViVaMBC is optimized to call variants at the codon level (nucleotide triplets) which enables immediate biological interpretation of the variants with respect to their antiviral drug responses., Results: Using mixtures of HCV plasmids we show that our method accurately estimates frequencies down to 0.5%. The estimates are unbiased when average coverages of 25,000 are reached. A comparison with the SNP-callers V-Phaser2, ShoRAH, and LoFreq shows that ViVaMBC has a superb sensitivity and specificity for variants with frequencies above 0.4%. Unlike the competitors, ViVaMBC reports a higher number of false-positive findings with frequencies below 0.4% which might partially originate from picking up artificial variants introduced by errors in the sample and library preparation step., Conclusions: ViVaMBC is the first method to call viral variants directly at the codon level. The strength of the approach lies in modeling the error probabilities based on the quality scores. Although the use of second best base calls appeared very promising in our data exploration phase, their utility was limited. They provided a slight increase in sensitivity, which however does not warrant the additional computational cost of running the offline base caller. Apparently a lot of information is already contained in the quality scores enabling the model based clustering procedure to adjust the majority of the sequencing errors. Overall the sensitivity of ViVaMBC is such that technical constraints like PCR errors start to form the bottleneck for low frequency variant detection.
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- 2015
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49. Connecting gene expression data from connectivity map and in silico target predictions for small molecule mechanism-of-action analysis.
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Ravindranath AC, Perualila-Tan N, Kasim A, Drakakis G, Liggi S, Brewerton SC, Mason D, Bodkin MJ, Evans DA, Bhagwat A, Talloen W, Göhlmann HW, Shkedy Z, and Bender A
- Subjects
- Algorithms, Anti-Inflammatory Agents pharmacology, Antineoplastic Agents pharmacology, Antipsychotic Agents pharmacology, Cell Line, Tumor, Cluster Analysis, Databases, Genetic, Humans, Hypoglycemic Agents pharmacology, Signal Transduction, Computational Biology methods, Computer Simulation, Drug Discovery methods, Gene Expression Regulation drug effects, Gene Regulatory Networks, Transcriptome
- Abstract
Integrating gene expression profiles with certain proteins can improve our understanding of the fundamental mechanisms in protein-ligand binding. This paper spotlights the integration of gene expression data and target prediction scores, providing insight into mechanism of action (MoA). Compounds are clustered based upon the similarity of their predicted protein targets and each cluster is linked to gene sets using Linear Models for Microarray Data. MLP analysis is used to generate gene sets based upon their biological processes and a qualitative search is performed on the homogeneous target-based compound clusters to identify pathways. Genes and proteins were linked through pathways for 6 of the 8 MCF7 and 6 of the 11 PC3 clusters. Three compound clusters are studied; (i) the target-driven cluster involving HSP90 inhibitors, geldanamycin and tanespimycin induces differential expression for HSP90-related genes and overlap with pathway response to unfolded protein. Gene expression results are in agreement with target prediction and pathway annotations add information to enable understanding of MoA. (ii) The antipsychotic cluster shows differential expression for genes LDLR and INSIG-1 and is predicted to target CYP2D6. Pathway steroid metabolic process links the protein and respective genes, hypothesizing the MoA for antipsychotics. A sub-cluster (verepamil and dexverepamil), although sharing similar protein targets with the antipsychotic drug cluster, has a lower intensity of expression profile on related genes, indicating that this method distinguishes close sub-clusters and suggests differences in their MoA. Lastly, (iii) the thiazolidinediones drug cluster predicted peroxisome proliferator activated receptor (PPAR) PPAR-alpha, PPAR-gamma, acyl CoA desaturase and significant differential expression of genes ANGPTL4, FABP4 and PRKCD. The targets and genes are linked via PPAR signalling pathway and induction of apoptosis, generating a hypothesis for the MoA of thiazolidinediones. Our analysis show one or more underlying MoA for compounds and were well-substantiated with literature.
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- 2015
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50. VirVarSeq: a low-frequency virus variant detection pipeline for Illumina sequencing using adaptive base-calling accuracy filtering.
- Author
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Verbist BM, Thys K, Reumers J, Wetzels Y, Van der Borght K, Talloen W, Aerssens J, Clement L, and Thas O
- Subjects
- Genome, Viral, Hepatitis C virology, Humans, Algorithms, Genetic Variation genetics, Genomics methods, Hepacivirus genetics, Hepatitis C genetics, High-Throughput Nucleotide Sequencing methods, Software
- Abstract
Motivation: In virology, massively parallel sequencing (MPS) opens many opportunities for studying viral quasi-species, e.g. in HIV-1- and HCV-infected patients. This is essential for understanding pathways to resistance, which can substantially improve treatment. Although MPS platforms allow in-depth characterization of sequence variation, their measurements still involve substantial technical noise. For Illumina sequencing, single base substitutions are the main error source and impede powerful assessment of low-frequency mutations. Fortunately, base calls are complemented with quality scores (Qs) that are useful for differentiating errors from the real low-frequency mutations., Results: A variant calling tool, Q-cpileup, is proposed, which exploits the Qs of nucleotides in a filtering strategy to increase specificity. The tool is imbedded in an open-source pipeline, VirVarSeq, which allows variant calling starting from fastq files. Using both plasmid mixtures and clinical samples, we show that Q-cpileup is able to reduce the number of false-positive findings. The filtering strategy is adaptive and provides an optimized threshold for individual samples in each sequencing run. Additionally, linkage information is kept between single-nucleotide polymorphisms as variants are called at the codon level. This enables virologists to have an immediate biological interpretation of the reported variants with respect to their antiviral drug responses. A comparison with existing SNP caller tools reveals that calling variants at the codon level with Q-cpileup results in an outstanding sensitivity while maintaining a good specificity for variants with frequencies down to 0.5%., Availability: The VirVarSeq is available, together with a user's guide and test data, at sourceforge: http://sourceforge.net/projects/virtools/?source=directory., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2015
- Full Text
- View/download PDF
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