BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there ar...BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.展开更多
BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure...BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.展开更多
BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants signif...BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.展开更多
Background:Infliximab(IFX)is the first-line treatment for patients with Crohn’s disease(CD)and is noted for its relatively high cost.The therapeutic efficacy of IFX has noticeable individual differences.Known single-...Background:Infliximab(IFX)is the first-line treatment for patients with Crohn’s disease(CD)and is noted for its relatively high cost.The therapeutic efficacy of IFX has noticeable individual differences.Known single-gene polymorphisms(SNPs)are inadequate for predicting non-response to IFX.In this study,we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model.Methods:In this retrospective study,we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019.Primary non-response(PNR)and non-durable response(NDR)were evaluated using a simple endoscopic score for CD(SES-CD).A total of 125 SNPs within 44 genes were genotyped.A multivariate logistic-regression model was established to predict non-response to IFX.An area-under-the-receiver-operatingcharacteristics curve(AUROC)was applied to evaluate the predictive model performance.Results:Forty-two of 206(20.4%)patients experienced PNR and 15 of 159(9.4%)patients experienced NDR.Nine SNPs were associated with PNR(P<0.05).A PNR predictive model was established,incorporating 2-week high-sensitivity C-reactive protein(hs-CRP),rs61886887,rs61740234,rs357291,rs2269330,and rs111504845,and the AUROC on training and testing data sets were 0.818(P<0.001)and 0.888(P<0.001),respectively.At week 14,hs-CRP levels≥2.25 mg/L were significantly associated with NDR(AUROC=0.815,P<0.001).PNR-associated SNPs were not mutually associated with NDR,suggesting distinct mechanisms between PNR and NDR.Conclusion:Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.展开更多
Background:Trough levels of the post-induction serum infliximab(IFX)are associated with short-term and long-term responses of Crohn’s disease patients to IFX,but the inter-individual differences are large.We aimed to...Background:Trough levels of the post-induction serum infliximab(IFX)are associated with short-term and long-term responses of Crohn’s disease patients to IFX,but the inter-individual differences are large.We aimed to elucidate whether single gene polymorphisms(SNPs)within FCGR3A,ATG16L1,C1orf106,OSM,OSMR,NF-jB1,IL1RN,and IL10 partially account for these differences and employed a multivariate regression model to predict patients’post-induction IFX levels.Methods:The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy.Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped.Associations between SNPs and IFX levels were analysed.Then,a multivariate logistic-regression model was developed to predict whether the patients’IFX levels achieved the threshold of therapy(3 lg/mL).Results:Six SNPs(rs7587051,rs143063741,rs442905,rs59457695,rs3213448,and rs3021094)were significantly associated with the post-induction IFX trough level(P=0.015,P<0.001,P=0.046,P=0.022,P=0.011,P=0.013,respectively).A multivariate prediction model of the IFX level was established by baseline albumin(P=0.002),rs442905(P=0.025),rs59457695(P=0.049),rs3213448(P=0.056),and rs3021094(P=0.047).The area under the receiver operating characteristic curve(AUROC)of this prediction model in a representative training dataset was 0.758.This result was verified in a representative testing dataset,with an AUROC of 0.733.Conclusions:Polymorphisms in C1orf106,IL1RN,and IL10 play an important role in the variability of IFX post-induction levels,as indicated in this multivariate prediction model of IFX levels with fair performance.展开更多
Photoacoustic imaging （PAl）, as an emerging biomedicine diagnostic technique that has been aevelopea quickly in the past decade, inherits the high spatial resolution of ultrasonography in imaging deep tissue and the...Photoacoustic imaging （PAl）, as an emerging biomedicine diagnostic technique that has been aevelopea quickly in the past decade, inherits the high spatial resolution of ultrasonography in imaging deep tissue and the high sensitivity of optical imaging in evaluating tissue chemical and physiological information. In this paper, after introducing the basic principles of PAl including both photoacoustic tomography and photoacoustic microscopy, we will review some recent progress of PAl in biomedicine and demonstrate the capability of PAl in detecting the chemical compositions and in evaluating the histological microstructures in biological tissue.展开更多
基金Supported by the National Natural Science Foundation of China,No.82020108031,No.81973398,and No.82104290Guangdong Provincial Key Laboratory of Construction Foundation,No.2020B1212060034Guangdong Basic and Applied Basic Research Foundation,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines.Dose optimization guided by nudix hydrolase 15(NUDT15)has significantly reduced the early leucopenia rate,but there are no definitive biomarkers for late risk leucopenia prediction.AIM To determine the predictive value of early monitoring of DNA-thioguanine(DNATG)or 6-thioguanine nucleotides(6TGN)for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn’s disease(CD).METHODS Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations.Late leucopenia was defined as a leukocyte count<3.5×10^(9)/L over two months.RESULTS Of 148 patients studied,late leucopenia was observed in 15.6%(17/109)of NUDT15/thiopurine methyltransferase(TPMT)normal and 64.1%(25/39)of intermediate metabolizers.In patients suffering late leucopenia,early DNATG levels were significantly higher than in those who did not develop late leucopenia(P=4.9×10^(-13)).The DNATG threshold of 319.43 fmol/μg DNA could predict late leucopenia in the entire sample with an area under the curve(AUC)of 0.855(sensitivity 83%,specificity 81%),and in NUDT15/TPMT normal metabolizers,the predictive performance of a threshold of 315.72 fmol/μg DNA was much more remarkable with an AUC of 0.902(sensitivity 88%,specificity 85%).6TGN had a relatively poor correlation with late leucopenia whether in the entire sample(P=0.021)or NUDT15/TPMT normal or intermediate metabolizers(P=0.018,P=0.55,respectively).CONCLUSION Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD,especially the former.
基金National Natural Science Foundation of China,No.81973398,No.81730103,No.81573507 and No.82020108031The National Key Research and Development Program,No.2017YFC0909300 and No.2016YFC0905001+5 种基金Guangdong Provincial Key Laboratory of Construction Foundation,No.2017B030314030 and No.2020B1212060034Science and Technology Program of Guangzhou,No.201607020031National Engineering and Technology Research Center for New Drug Druggability Evaluation(Seed Program of Guangdong Province),No.2017B090903004The 111 Project,No.B16047China Postdoctoral Science Foundation,No.2019M66324,No.2020M683140 and No.2020M683139Natural Science Foundation of Guangdong Province,No.2022A1515012549 and No.2023A1515012667.
文摘BACKGROUND Thalidomide is an effective treatment for refractory Crohn’s disease(CD).However,thalidomide-induced peripheral neuropathy(TiPN),which has a large individual variation,is a major cause of treatment failure.TiPN is rarely predictable and recognized,especially in CD.It is necessary to develop a risk model to predict TiPN occurrence.AIM To develop and compare a predictive model of TiPN using machine learning based on comprehensive clinical and genetic variables.METHODS A retrospective cohort of 164 CD patients from January 2016 to June 2022 was used to establish the model.The National Cancer Institute Common Toxicity Criteria Sensory Scale(version 4.0)was used to assess TiPN.With 18 clinical features and 150 genetic variables,five predictive models were established and evaluated by the confusion matrix receiver operating characteristic curve(AUROC),area under the precision-recall curve(AUPRC),specificity,sensitivity(recall rate),precision,accuracy,and F1 score.RESULTS The top-ranking five risk variables associated with TiPN were interleukin-12 rs1353248[P=0.0004,odds ratio(OR):8.983,95%confidence interval(CI):2.497-30.90],dose(mg/d,P=0.002),brainderived neurotrophic factor(BDNF)rs2030324(P=0.001,OR:3.164,95%CI:1.561-6.434),BDNF rs6265(P=0.001,OR:3.150,95%CI:1.546-6.073)and BDNF rs11030104(P=0.001,OR:3.091,95%CI:1.525-5.960).In the training set,gradient boosting decision tree(GBDT),extremely random trees(ET),random forest,logistic regression and extreme gradient boosting(XGBoost)obtained AUROC values>0.90 and AUPRC>0.87.Among these models,XGBoost and GBDT obtained the first two highest AUROC(0.90 and 1),AUPRC(0.98 and 1),accuracy(0.96 and 0.98),precision(0.90 and 0.95),F1 score(0.95 and 0.98),specificity(0.94 and 0.97),and sensitivity(1).In the validation set,XGBoost algorithm exhibited the best predictive performance with the highest specificity(0.857),accuracy(0.818),AUPRC(0.86)and AUROC(0.89).ET and GBDT obtained the highest sensitivity(1)and F1 score(0.8).Overall,compared with other state-of-the-art classifiers such as ET,GBDT and RF,XGBoost algorithm not only showed a more stable performance,but also yielded higher ROC-AUC and PRC-AUC scores,demonstrating its high accuracy in prediction of TiPN occurrence.CONCLUSION The powerful XGBoost algorithm accurately predicts TiPN using 18 clinical features and 14 genetic variables.With the ability to identify high-risk patients using single nucleotide polymorphisms,it offers a feasible option for improving thalidomide efficacy in CD patients.
基金Supported by the National Natural Science Foundation of China,No.81573507,No.81473283,No.81173131,and No.81320108027Guangdong Provincial Key Laboratory Construction Foundation,No.2017B030314030+1 种基金The National Key Research and Development Program,No.2016YFC0905003the 111 Project,No.B16047
文摘BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
基金supported by the National Natural Science Foundation of China[Grant No.81573507,81473283,81173131,and 81320108027]the Natural Major Projects for science and technology development from Science and Technology Ministry of China[Grant No.2012ZX09506001-004]+1 种基金the Major Scientific and Technological Project of Guangdong Province[Grant No.2011A080300001]the Medical Scientific Research Foundation of Guangdong Province of China[Grant No.A2020123].
文摘Background:Infliximab(IFX)is the first-line treatment for patients with Crohn’s disease(CD)and is noted for its relatively high cost.The therapeutic efficacy of IFX has noticeable individual differences.Known single-gene polymorphisms(SNPs)are inadequate for predicting non-response to IFX.In this study,we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model.Methods:In this retrospective study,we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019.Primary non-response(PNR)and non-durable response(NDR)were evaluated using a simple endoscopic score for CD(SES-CD).A total of 125 SNPs within 44 genes were genotyped.A multivariate logistic-regression model was established to predict non-response to IFX.An area-under-the-receiver-operatingcharacteristics curve(AUROC)was applied to evaluate the predictive model performance.Results:Forty-two of 206(20.4%)patients experienced PNR and 15 of 159(9.4%)patients experienced NDR.Nine SNPs were associated with PNR(P<0.05).A PNR predictive model was established,incorporating 2-week high-sensitivity C-reactive protein(hs-CRP),rs61886887,rs61740234,rs357291,rs2269330,and rs111504845,and the AUROC on training and testing data sets were 0.818(P<0.001)and 0.888(P<0.001),respectively.At week 14,hs-CRP levels≥2.25 mg/L were significantly associated with NDR(AUROC=0.815,P<0.001).PNR-associated SNPs were not mutually associated with NDR,suggesting distinct mechanisms between PNR and NDR.Conclusion:Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.
基金funded by grants from the National Natural Science Foundation of China[Grant No.81573507]the National Natural Science Foundation of China[Grant No.81473283]+3 种基金the National Natural Science Foundation of China[Grant No.81173131]the National Natural Science Foundation of China[Grant No.81320108027]the Natural Major Projects for Science and Technology Development from Science and Technology Ministry of China[Grant No.2012ZX09506001-004]the Major Scientific and Technological Project of Guangdong Province,China[Grant No.2011A080300001].
文摘Background:Trough levels of the post-induction serum infliximab(IFX)are associated with short-term and long-term responses of Crohn’s disease patients to IFX,but the inter-individual differences are large.We aimed to elucidate whether single gene polymorphisms(SNPs)within FCGR3A,ATG16L1,C1orf106,OSM,OSMR,NF-jB1,IL1RN,and IL10 partially account for these differences and employed a multivariate regression model to predict patients’post-induction IFX levels.Methods:The retrospective study included 189 Crohn’s disease patients undergoing IFX therapy.Post-induction IFX levels were measured and 41 tag SNPs within eight genes were genotyped.Associations between SNPs and IFX levels were analysed.Then,a multivariate logistic-regression model was developed to predict whether the patients’IFX levels achieved the threshold of therapy(3 lg/mL).Results:Six SNPs(rs7587051,rs143063741,rs442905,rs59457695,rs3213448,and rs3021094)were significantly associated with the post-induction IFX trough level(P=0.015,P<0.001,P=0.046,P=0.022,P=0.011,P=0.013,respectively).A multivariate prediction model of the IFX level was established by baseline albumin(P=0.002),rs442905(P=0.025),rs59457695(P=0.049),rs3213448(P=0.056),and rs3021094(P=0.047).The area under the receiver operating characteristic curve(AUROC)of this prediction model in a representative training dataset was 0.758.This result was verified in a representative testing dataset,with an AUROC of 0.733.Conclusions:Polymorphisms in C1orf106,IL1RN,and IL10 play an important role in the variability of IFX post-induction levels,as indicated in this multivariate prediction model of IFX levels with fair performance.
基金supported by the National Basic Research Program of China (No.2012CB921504)the National Natural Science Foundation of China (Nos.11422439,11274167,11274171,and 11028408)SRFDP (No.20120091110001)
文摘Photoacoustic imaging （PAl）, as an emerging biomedicine diagnostic technique that has been aevelopea quickly in the past decade, inherits the high spatial resolution of ultrasonography in imaging deep tissue and the high sensitivity of optical imaging in evaluating tissue chemical and physiological information. In this paper, after introducing the basic principles of PAl including both photoacoustic tomography and photoacoustic microscopy, we will review some recent progress of PAl in biomedicine and demonstrate the capability of PAl in detecting the chemical compositions and in evaluating the histological microstructures in biological tissue.
