整合生物标志物体系的建立及在疾病诊断和药物疗效评价中的应用
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摘要
近年来,研究人员越多来越多的关注生物标志物在疾病诊断、药物疗效评价中的作用,特别是一些临床棘手问题,例如糖尿病肾病的早期诊断等。本文结合临床信息和多层次的实验室数据建立整合生物标志物体系,并通过人工智能、显著性分析和ROC分析等方法进行生物标志物的筛选以解决临床难题。
1.定量测定技术在糖尿病肾病药物治疗和疾病诊断中的应用。针对糖肾方的疗效评价,本文利用正相HPLC-ESI-TOF/MS分析技术,测定了给药后不同时间的8种磷脂潜在生物标志物的含量。结果表明糖肾方可改善糖尿病肾病病人体内的磷脂代谢失调,并且与单独使用西医治疗相比有明显优势；但是对不同潜在生物标志物的调节作用和起效时间并不相同。针对现今生物标志物数量过多不利于临床应用,及存在数据非线性的情况,本文利用人工智能技术建立了一种标志物筛选和评价的方法,稳定性良好,总共筛选得到12个变量,预测准确率达到94.5%。并在糖肾方疗效评价中表现良好,可以作为疾病诊断及药物疗效评价指标筛选的一种新的数据挖掘方法。
2.整合生物标志物体系建立及在糖尿病肾病中的应用。目前,糖尿病肾病的诊断主要依赖于蛋白尿的测定,但在早期糖尿病肾病中(1期和2期)并不出现持续蛋白尿。针对这个问题,本文建立了一个包含6个临床生化指标、41个定量代谢潜在生物标志物和5个重要基因潜在生物标志物的整合生物标志物体系,预测准确率为98.9%；进一步采用显著性分析和ROC分析进行标志物筛选,所得的肌苷(0.086～0.162mg/L)结合肾小球滤过率估算值eGFR指标(120mL/min/1.73m2)可以很好的区分糖尿病、糖尿病肾病1期和2期,对临床风险评估和早期诊断有非常重要的意义。所得的指标群(包括肌苷、腺苷、S-腺苷同型半胱氨酸和亚油酸)可表征疾病的发生发展过程,可考虑作为未来临床联合用药的疗效评价指标。
3.定量代谢组学在药物联合应用疗效评价中的应用。针对异丙嗪治疗晕动症中存在的镇静副作用,本文提出了一个咖啡因和异丙嗪的联合用药方案,发现咖啡因+异丙嗪可以改善由异丙嗪镇静作用引起的认知功能下降;建立了同时测定咖啡因、异丙嗪及体内代谢物的HPLC-ESI-MS分析方法；然后利用这个方法对两个给药组中的重要化合物进行了测定,发现联合用药后异丙嗪体内代谢加快,其中表征异丙嗪体内代谢能力的异丙嗪/异丙嗪亚砜比值与咖啡因及其体内代谢物含量显著相关,这可能是联合用药后认知功能得到改善的原因之一；根据代谢组学数据建立OPLS-DA模型,得到了3个神经递质相关的代谢物,主要涉及多巴胺和肾上腺素的合成,这表明咖啡因可能通过调节多巴胺和肾上腺素相关的通路以改善认知功能下降的副作用。
Rencently, biomarkers become a hot topic in the study on disease diagnosis and drug effectiveness evaluation, especially in some thorny issues in clinic, like the early diagnosis of diabetic nephropathy, a renal complication of diabetes. In this dissertation, an integrated biomarker system was developed using clinical information and multilevel laboratory data. Then some screening methods, like artifical intelligence techniques, significance test and ROC analysis were applied to obtain the optimal biomarker for clinical challenges.
1. Drug effectiveness evaluation and disease diagnosis research of diabetic nephropathy based on quantitative techniques. First, a normal phase HPLC-ESI-TOF/MS method was used to determine the concentrations of eight phospholipid potential biomarkers during the treatment with Tangshen Formula. Results pointed out that when compared to single conventional western medicnie treatment, this traditional Chinese formula showed superiority in improving the phospholipid metabolism disorder in patients with diabetic nephropathy. However, the improvement and the onset time was not the same among all the potential biomarkers. Secondly, due to the large number of biomarkers and nonlinearity of data, a stable biomarker screening and evluation method was developed based on artificial intelligence technology.12variables were selected and the predictive accuracy was94.53%. In addition, these variables could also be used in the effectiveness evaluation of Tangshen Formula. Therefore, this method could be an alternative choice of data mining in disease diagnosis and drug effectiveness evaluation.
2. Development of integrated biomarker system and its application in diabetic nephropathy. The present method of diagnosing diabetic nephropathy mainly depends on the determination of proteinuria, however, it's very hard to perform the test in the early stage of this disease (stage1and2) for patients in this stage don't have persistent proteinuria. According to this, an integrated biomarker system incorporating six clinical biochemical indicators, forty-one metabolic potential biomarkers from quantitative metaoblomics and five key genes was estalished and was considered effective with a high total predictive accuracy (98.9%). Then significance test and ROC analysis were employed to select the most informative potential biomarkers. Inosine with a range of0.086-0.162mg/L combined with estimated glomerular filtration rate was selected to be a sufficient potential biomarker for early diagnosis. And the levels of inosine, adenosine, S-adenosylhomocysteine and linoleic acid showed significant changes during the process of diabetic nephropathy and may be used as possible evaluation indicators for future combination therapy.
3. Application of quantitative metabonomics in drug effectiveness evaluaiton of combination therapy. Promethazine is a effective drug against motion sickness, however, the sedative effects of promethazine can induce the decrease of cognitive funciton. In order to overcome this side effect, a combination therapy including caffeine and promethazine was proposed in this study. After the combination, the reduced cognitive function was improved. Then an HPLC-ESI-MS method was established to determine these two drugs and their metabolites simutaneously in all the subjects. The metabolism of promethazine was accelerated when combinaed with caffeine, and the concentraion ratio of promethazine to promethazine sulfoxide, a index of the metabolic capability, was significantly correlated with caffine and its metaoblites, which might be one of the reasons why cognitive function was improved after the combination. Besides, an OPLS-DA model was developed according to the metabonomic data, and3neurotransmitter metabolites involving dopamine and epinephrine synthesis were found significantly elevated after using caffine. Therefore, the improvement of decreased cogintive function induced by sedative effects of promethazine in combination therapy might be related with the changed endogenous metabolism including dopamine-, and epinephrine-associated pathways.
1.定量测定技术在糖尿病肾病药物治疗和疾病诊断中的应用。针对糖肾方的疗效评价,本文利用正相HPLC-ESI-TOF/MS分析技术,测定了给药后不同时间的8种磷脂潜在生物标志物的含量。结果表明糖肾方可改善糖尿病肾病病人体内的磷脂代谢失调,并且与单独使用西医治疗相比有明显优势；但是对不同潜在生物标志物的调节作用和起效时间并不相同。针对现今生物标志物数量过多不利于临床应用,及存在数据非线性的情况,本文利用人工智能技术建立了一种标志物筛选和评价的方法,稳定性良好,总共筛选得到12个变量,预测准确率达到94.5%。并在糖肾方疗效评价中表现良好,可以作为疾病诊断及药物疗效评价指标筛选的一种新的数据挖掘方法。
2.整合生物标志物体系建立及在糖尿病肾病中的应用。目前,糖尿病肾病的诊断主要依赖于蛋白尿的测定,但在早期糖尿病肾病中(1期和2期)并不出现持续蛋白尿。针对这个问题,本文建立了一个包含6个临床生化指标、41个定量代谢潜在生物标志物和5个重要基因潜在生物标志物的整合生物标志物体系,预测准确率为98.9%；进一步采用显著性分析和ROC分析进行标志物筛选,所得的肌苷(0.086～0.162mg/L)结合肾小球滤过率估算值eGFR指标(120mL/min/1.73m2)可以很好的区分糖尿病、糖尿病肾病1期和2期,对临床风险评估和早期诊断有非常重要的意义。所得的指标群(包括肌苷、腺苷、S-腺苷同型半胱氨酸和亚油酸)可表征疾病的发生发展过程,可考虑作为未来临床联合用药的疗效评价指标。
3.定量代谢组学在药物联合应用疗效评价中的应用。针对异丙嗪治疗晕动症中存在的镇静副作用,本文提出了一个咖啡因和异丙嗪的联合用药方案,发现咖啡因+异丙嗪可以改善由异丙嗪镇静作用引起的认知功能下降;建立了同时测定咖啡因、异丙嗪及体内代谢物的HPLC-ESI-MS分析方法；然后利用这个方法对两个给药组中的重要化合物进行了测定,发现联合用药后异丙嗪体内代谢加快,其中表征异丙嗪体内代谢能力的异丙嗪/异丙嗪亚砜比值与咖啡因及其体内代谢物含量显著相关,这可能是联合用药后认知功能得到改善的原因之一；根据代谢组学数据建立OPLS-DA模型,得到了3个神经递质相关的代谢物,主要涉及多巴胺和肾上腺素的合成,这表明咖啡因可能通过调节多巴胺和肾上腺素相关的通路以改善认知功能下降的副作用。
Rencently, biomarkers become a hot topic in the study on disease diagnosis and drug effectiveness evaluation, especially in some thorny issues in clinic, like the early diagnosis of diabetic nephropathy, a renal complication of diabetes. In this dissertation, an integrated biomarker system was developed using clinical information and multilevel laboratory data. Then some screening methods, like artifical intelligence techniques, significance test and ROC analysis were applied to obtain the optimal biomarker for clinical challenges.
1. Drug effectiveness evaluation and disease diagnosis research of diabetic nephropathy based on quantitative techniques. First, a normal phase HPLC-ESI-TOF/MS method was used to determine the concentrations of eight phospholipid potential biomarkers during the treatment with Tangshen Formula. Results pointed out that when compared to single conventional western medicnie treatment, this traditional Chinese formula showed superiority in improving the phospholipid metabolism disorder in patients with diabetic nephropathy. However, the improvement and the onset time was not the same among all the potential biomarkers. Secondly, due to the large number of biomarkers and nonlinearity of data, a stable biomarker screening and evluation method was developed based on artificial intelligence technology.12variables were selected and the predictive accuracy was94.53%. In addition, these variables could also be used in the effectiveness evaluation of Tangshen Formula. Therefore, this method could be an alternative choice of data mining in disease diagnosis and drug effectiveness evaluation.
2. Development of integrated biomarker system and its application in diabetic nephropathy. The present method of diagnosing diabetic nephropathy mainly depends on the determination of proteinuria, however, it's very hard to perform the test in the early stage of this disease (stage1and2) for patients in this stage don't have persistent proteinuria. According to this, an integrated biomarker system incorporating six clinical biochemical indicators, forty-one metabolic potential biomarkers from quantitative metaoblomics and five key genes was estalished and was considered effective with a high total predictive accuracy (98.9%). Then significance test and ROC analysis were employed to select the most informative potential biomarkers. Inosine with a range of0.086-0.162mg/L combined with estimated glomerular filtration rate was selected to be a sufficient potential biomarker for early diagnosis. And the levels of inosine, adenosine, S-adenosylhomocysteine and linoleic acid showed significant changes during the process of diabetic nephropathy and may be used as possible evaluation indicators for future combination therapy.
3. Application of quantitative metabonomics in drug effectiveness evaluaiton of combination therapy. Promethazine is a effective drug against motion sickness, however, the sedative effects of promethazine can induce the decrease of cognitive funciton. In order to overcome this side effect, a combination therapy including caffeine and promethazine was proposed in this study. After the combination, the reduced cognitive function was improved. Then an HPLC-ESI-MS method was established to determine these two drugs and their metabolites simutaneously in all the subjects. The metabolism of promethazine was accelerated when combinaed with caffeine, and the concentraion ratio of promethazine to promethazine sulfoxide, a index of the metabolic capability, was significantly correlated with caffine and its metaoblites, which might be one of the reasons why cognitive function was improved after the combination. Besides, an OPLS-DA model was developed according to the metabonomic data, and3neurotransmitter metabolites involving dopamine and epinephrine synthesis were found significantly elevated after using caffine. Therefore, the improvement of decreased cogintive function induced by sedative effects of promethazine in combination therapy might be related with the changed endogenous metabolism including dopamine-, and epinephrine-associated pathways.
引文
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