MRDD - Revision history

Kirilas: Fixed broken links

2022-10-14T12:12:03Z

Fixed broken links

← Older revision		Revision as of 12:12, 14 October 2022
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	<br />		<br />

	This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD values were taken from the publication by Contrera J.F. et al. ''Regul Toxicol Pharmacol''. '''2004'''; 40(3):185-206 [~~http~~://~~www~~.~~sciencedirect~~.~~com~~/science?_ob=ArticleURL&_udi=B6WPT-4DFT374-2&_user=10&_coverDate=12%2F01%2F2004&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=df9eea39aab5d2dfbf86053d6bf8be1b] Prediction model of MRDD values is based on PLS and binomial regression analysis of Contrera et al. MRDD data set using fragmental descriptors. It also utilizes the Model Applicability Domain assessment methodology allowing the calculation of the Reliability Index for every prediction.		This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD values were taken from the publication by Contrera J.F. et al. ''Regul Toxicol Pharmacol''. '''2004'''; 40(3):185-206 [https://pubmed.ncbi.nlm.nih.gov/15546675] Prediction model of MRDD values is based on PLS and binomial regression analysis of Contrera et al. MRDD data set using fragmental descriptors. It also utilizes the Model Applicability Domain assessment methodology allowing the calculation of the Reliability Index for every prediction.

	'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.		'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.

Kirilas at 10:03, 15 June 2017

2017-06-15T10:03:44Z

← Older revision		Revision as of 10:03, 15 June 2017
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	<br />		<br />

	<div class="mw-collapsible ~~mw-collapsed~~">		<div class="mw-collapsible">

	==Technical information==		==Technical information==

Kirilas: /* Interface */

2016-06-20T10:44:27Z

Interface

← Older revision		Revision as of 10:44, 20 June 2016
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	# Text of the caution		# Text of the caution
	# Switch to the results of MRDD prediction		# Switch to the results of MRDD prediction
			# MRDD values for up to 5 similar drugs from Contrera et al. data set

	'''Note:''' Prediction reliability classification according to Reliability Index (RI) values:		'''Note:''' Prediction reliability classification according to Reliability Index (RI) values:

Kristina: /* Overview */

2012-05-29T09:53:43Z

Overview

← Older revision		Revision as of 09:53, 29 May 2012
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	<br />		<br />

	This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD values were taken from the publication by Contrera J.F. et al. ''Regul Toxicol Pharmacol''. '''2004'''; 40(3):185-206 [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WPT-4DFT374-2&_user=10&_coverDate=12%2F01%2F2004&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=df9eea39aab5d2dfbf86053d6bf8be1b] Prediction model of MRDD values is based on PLS and binomial regression analysis of Contrera et al. MRDD data set using fragmental descriptors. It also utilizes the Model Applicability Domain assessment methodology allowing the calculation of the Reliability Index for every prediction ~~(see more information about [[Trainable_Models#Overview\|Trainable Models]])~~.		This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD values were taken from the publication by Contrera J.F. et al. ''Regul Toxicol Pharmacol''. '''2004'''; 40(3):185-206 [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WPT-4DFT374-2&_user=10&_coverDate=12%2F01%2F2004&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=df9eea39aab5d2dfbf86053d6bf8be1b] Prediction model of MRDD values is based on PLS and binomial regression analysis of Contrera et al. MRDD data set using fragmental descriptors. It also utilizes the Model Applicability Domain assessment methodology allowing the calculation of the Reliability Index for every prediction.

	'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.		'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.

Kristina: /* Overview */

2012-05-29T09:53:03Z

Overview

← Older revision		Revision as of 09:53, 29 May 2012
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	'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.		'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.
	~~<br />~~

	~~===Features===~~
	* ...
	<br />		<br />

Kirilas: /* Interface */

2012-05-25T09:10:21Z

Interface

← Older revision		Revision as of 09:10, 25 May 2012
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	<br />		<br />

	# ~~Description~~		# Text of the caution
	# Switch to the results of MRDD prediction		# Switch to the results of MRDD prediction

Kristina: /* Interface */

2012-05-22T13:39:40Z

Interface

← Older revision		Revision as of 13:39, 22 May 2012
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	'''Results:'''		'''Results:'''
			<br />

	[[Image:MRDD_results.png\|center]]		[[Image:MRDD_results.png\|center]]
			<br />

	# Estimated maximum recommended daily dose in humans (mg/kg/day) after oral administration		# Estimated maximum recommended daily dose in humans (mg/kg/day) after oral administration
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	# The button appears in case of unreliable prediction. The unreliable results are for compounds that are dissimilar to training set, are used at very low doses and predicted to be toxic. Click the button to see more detail explanation of cautions for tested compound.		# The button appears in case of unreliable prediction. The unreliable results are for compounds that are dissimilar to training set, are used at very low doses and predicted to be toxic. Click the button to see more detail explanation of cautions for tested compound.
	# MRDD values for up to 5 similar drugs from Contrera et al. data set		# MRDD values for up to 5 similar drugs from Contrera et al. data set
			<br />

	'''Cautions:'''		'''Cautions:'''
			<br />

	[[Image:MRDD_Cautions.png\|center]]		[[Image:MRDD_Cautions.png\|center]]
			<br />

	# Description		# Description

Kristina: Created page with "==Overview==
This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD value..."

2012-05-22T13:35:41Z

Created page with "==Overview== This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD value..."

New page

==Overview==
 

This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD values were taken from the publication by Contrera J.F. et al. ''Regul Toxicol Pharmacol''. '''2004'''; 40(3):185-206 [http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WPT-4DFT374-2&_user=10&_coverDate=12%2F01%2F2004&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=df9eea39aab5d2dfbf86053d6bf8be1b] Prediction model of MRDD values is based on PLS and binomial regression analysis of Contrera et al. MRDD data set using fragmental descriptors. It also utilizes the Model Applicability Domain assessment methodology allowing the calculation of the Reliability Index for every prediction (see more information about [[Trainable_Models#Overview|Trainable Models]]).

'''Note:''' Estimation of MRDD is only approximate and can not be used for selection of starting dose in clinical trials.
 

===Features===
* ...
 

== Interface ==
 

'''Results:'''

[[Image:MRDD_results.png|center]]

# Estimated maximum recommended daily dose in humans (mg/kg/day) after oral administration
# Indication of the prediction reliability along with the Reliability Index value
# Estimated probability that drug candidate can be used only at low doses
# Displays possible explanation that restrict the use of drug at higher dose: predicted high acute toxicity (undesirable property is red) or high probability of health (adverse) effects on different organs
# The button appears in case of unreliable prediction. The unreliable results are for compounds that are dissimilar to training set, are used at very low doses and predicted to be toxic. Click the button to see more detail explanation of cautions for tested compound.
# MRDD values for up to 5 similar drugs from Contrera et al. data set

'''Cautions:'''

[[Image:MRDD_Cautions.png|center]]

# Description
# Switch to the results of MRDD prediction

'''Note:''' Prediction reliability classification according to Reliability Index (RI) values:
* RI < 0.3 – Not Reliable,
* RI in range 0.3-0.5 – Bordeline Reliability,
* RI in range 0.5-0.75 – Moderate Reliability,
* RI >= 0.75 – High Reliability
 

<div class="mw-collapsible mw-collapsed">

==Technical information==
 

<div class="mw-collapsible-content">
'''Training set size:''' 1,313 
'''Internal validation set size:''' 143 
'''Main sources of experimental data:'''
* Contrera, J.F. et al. Regul. Toxicol. Pharmacol. 2004, 40(3): 185-206
 
====Internal Validation====
MRDD is one of the many parameters evaluating the potential of a compound to cause acute toxicity or long-term adverse effects, i.e., it is a very complex property depending on a variety of complicated mechanisms. As a result, the only available MRDD dataset published by Contrera and coauthors is nowhere near enough for the development of a robust global quantitative model. As a result this model should be treated only as a very rough estimation, and therefore its validation wasn't emphasized as the results can hardly lead to any relevant conclusions. In this respect the qualitative model indicating the probability that compound's MRDD does not exceed 3 mg/kg/day can be of greater practical value as it can be indicative of potential safety problems associated with the query compound. Internal validation results for this model are provided in the below table. In any case it should be stressed that any estimations provided within ACD/MRDD module are only approximate and can not be used for selection of starting dose in clinical trials.


{| cellpadding="2" cellspacing="0" style="border-top:2px solid black; border-bottom:2px solid black"
|+ Table 1. Classification accuracy of the qualitative MRDD model on the internal validation set.
|-
! style="border-bottom:1px solid black; background:#EAEAEA" width="120" rowspan="2" | Subset
! style="border-bottom:1px solid black; background:#EAEAEA" width="200" rowspan="2" | Coverage of the entire internal validation set (N=143)
! style="border-bottom:1px solid black; background:#EAEAEA" width="100" rowspan="2" | Observed*
! style="border-bottom:1px solid black; background:#EAEAEA" width="200" colspan="2" | Calculated probability (p)
|-
! style="border-bottom:1px solid black; background:#EAEAEA" width="100" | >0.5
! style="border-bottom:1px solid black; background:#EAEAEA" width="100" | <0.5
|-
| style="border-bottom:1px solid black" align="center" rowspan="2" | RI > 0.3 N = 143

| rowspan="2" align="center" style="border-bottom:1px solid black" |
{| cellpadding="0" cellspacing="0" style="width:80%; height:40px"
| style="color:white; background:#B9CDE5" align="right" width="100%" | 100.0% 
|}

| style="border-bottom:1px solid black" | True || align="center" style="border-bottom:1px solid black; background:#E1FFE1" | 17 (11.9%) || align="center" style="border-bottom:1px solid black; background:#FFE1E1" | 9 (6.3%)
|-
| style="border-bottom:1px solid black" | False || align="center" style="border-bottom:1px solid black; background:#FFE1E1" | 41 (28.7%) || align="center" style="border-bottom:1px solid black; background:#E1FFE1" | 76 (53.1%)
|-
| style="height:30px" colspan="2" |   || Accuracy
| colspan="2" align="center" |
{| cellpadding="0" cellspacing="0" style="width:80%; height:20px"
| style="color:white; background:#B9CDE5" align="right" width="65.0%" | 65.0%  || style="background:#EDF2F9" width="35.0%" |  
|}

|-
| style="height:30px" colspan="2" |   || Sensitivity
| colspan="2" align="center" |
{| cellpadding="0" cellspacing="0" style="width:80%; height:20px"
| style="color:white; background:#B9CDE5" align="right" width="65.4%" | 65.4%  || style="background:#EDF2F9" width="34.6%" |  
|}

|-
| style="height:30px" colspan="2" |   || Specificity
| colspan="2" align="center" |
{| cellpadding="0" cellspacing="0" style="width:80%; height:20px"
| style="color:white; background:#B9CDE5" align="right" width="65.0%" | 65.0%  || style="background:#EDF2F9" width="35.0%" |  
|}

|}
* - True means that the compound is recommended to be used only at very low doses (MRDD < 3 mg/kg/day).
</div>
</div>

MRDD - Revision history

Kirilas: Fixed broken links

Kirilas at 10:03, 15 June 2017

Kirilas: /* Interface */

Kristina: /* Overview */

Kristina: /* Overview */

Kirilas: /* Interface */

Kristina: /* Interface */

Kristina: Created page with "==Overview== This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD value..."

Kristina: Created page with "==Overview==
This module estimates maximum recommended daily dose (MRDD) that can be used for humans in clinical trials. Description and data compilation of MRDD value..."