High-Throughput Toxicokinetics

Functions and data tables for simulation and statistical analysis of chemical toxicokinetics ("TK") using data obtained from relatively high throughput, in vitro studies. Both physiologically-based ("PBTK") and empirical (e.g., one compartment) "TK" models can be parameterized for several hundred chemicals and multiple species. These models are solved efficiently, often using compiled (C-based) code. A Monte Carlo sampler is included for simulating biological variability and measurement limitations. Functions are also provided for exporting "PBTK" models to "SBML" and "JARNAC" for use with other simulation software. These functions and data provide a set of tools for in vitro-in vivo extrapolation ("IVIVE") of high throughput screening data (e.g., ToxCast) to real-world exposures via reverse dosimetry (also known as "RTK").


News

��N�e�w�s� �f�o�r� �R� �p�a�c�k�a�g�e� �h�t�t�k� � � � �C�h�a�n�g�e�s� �i�n� �v�e�r�s�i�o�n� �1�.�8� � � � �T�h�i�s� �v�e�r�s�i�o�n� �i�s� �c�o�n�s�i�s�t�e�n�t� �w�i�t�h� �t�h�e� �p�u�b�l�i�s�h�e�d� �v�e�r�s�i�o�n� �o�f� �P�e�a�r�c�e� �e�t� �a�l�.� �"�E�v�a�l�u�a�t�i�o�n� �a�n�d� �c�a�l�i�b�r�a�t�i�o�n� �o�f� �h�i�g�h�-�t�h�r�o�u�g�h�p�u�t� �p�r�e�d�i�c�t�i�o�n�s� �o�f� �c�h�e�m�i�c�a�l� �d�i�s�t�r�i�b�u�t�i�o�n� �t�o� �t�i�s�s�u�e�s�"�,� � �t�h�u�s� �c�o�n�t�a�i�n�i�n�g� �n�e�w� �r�e�g�r�e�s�s�i�o�n�s� �a�d�d�e�d� �f�o�r� �p�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t� �c�a�l�i�b�r�a�t�i�o�n� �w�i�t�h�o�u�t� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �a�d�j�u�s�t�m�e�n�t� �w�i�t�h� � � �s�e�p�a�r�a�t�e� �a�r�g�u�m�e�n�t�s� �f�o�r� �u�s�i�n�g� �r�e�g�r�e�s�s�i�o�n�s� �(�r�e�g�r�e�s�s�i�o�n�)� �a�n�d� �a�d�j�u�s�t�e�d� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �(�a�d�j�u�s�t�e�d�.�F�u�n�b�o�u�n�d�.�p�l�a�s�m�a�)�.� � �D�a�t�a� �f�r�o�m� �A�D�M�E�T� �u�s�e�d� �i�n� �S�i�p�e�s� �e�t� �a�l�.� �(�2�0�1�7�)� �i�s� �n�o�w� �i�n�c�l�u�d�e�d� �a�s� �S�i�p�e�s�2�0�1�7� �a�n�d� �c�a�n� �b�e� �a�d�d�e�d� �w�i�t�h� �t�h�e� �n�e�w� �f�u�n�c�t�i�o�n�:� �l�o�a�d�_�s�i�p�e�s�2�0�1�7�(�)�.� � �S�e�p�a�r�a�t�e� �o�p�t�i�o�n�s� �h�a�v�e� �b�e�e�n� �a�d�d�e�d� �f�o�r� �t�h�e� �r�e�g�r�e�s�s�i�o�n�s� �a�n�d� �a�d�j�u�s�t�e�d� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a�.� � �N�e�w� �d�a�t�a� �h�a�s� �b�e�e�n� �a�d�d�e�d� �f�r�o�m� �a�n� �I�V�I�V�E� �e�v�a�l�u�a�t�i�o�n� �o�f� �t�o�x�i�c�o�k�i�n�e�t�i�c�s� �(�W�a�m�b�a�u�g�h� �e�t� �a�l�.� �2�0�1�8�)�.� � �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �v�a�l�u�e�s� �f�r�o�m� �W�e�t�m�o�r�e� �2�0�1�2� �a�n�d� �2�0�1�3� �t�h�a�t� �w�e�r�e� �p�r�e�v�i�o�u�s�l�y� �r�o�u�n�d�e�d� �t�o� �2� �d�e�c�i�m�a�l� �p�l�a�c�e�s� �a�r�e� �n�o�w� �r�o�u�n�d�e�d� �t�o� �3�,� � �a�d�d�i�n�g� �a�d�d�i�t�i�o�n�a�l� �c�o�m�p�o�u�n�d�s� �t�h�a�t� �w�e�r�e� �o�t�h�e�r�w�i�s�e� �a�s�s�u�m�e�d� �t�o� �b�e� �b�e�l�o�w� �t�h�e� �l�i�m�i�t� �o�f� �d�e�t�e�c�t�i�o�n�.� � �p�K�a� �d�a�t�a� �i�s� �n�o�w� �r�e�a�d�a�b�l�e� �w�h�e�n� �v�a�l�u�e�s� �a�r�e� �s�e�p�a�r�a�t�e�d� �b�y� �a� �s�e�m�i�c�o�l�o�n� �r�a�t�h�e�r� �t�h�a�n� �a� �c�o�m�m�a�.� �T�h�e�s�e� �v�a�l�u�e�s� �w�e�r�e� �p�r�e�v�i�o�u�s�l�y� � �m�i�s�r�e�a�d� �a�s� �n�e�u�t�r�a�l�.� � �P�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t�s� �c�a�n� �n�o�w� �b�e� �p�r�e�d�i�c�t�e�d� �w�i�t�h�o�u�t� �c�a�l�c�u�l�a�t�i�n�g� �a�l�l� �o�f� �t�h�e�m�,� �u�s�i�n�g� �t�h�e� �t�i�s�s�u�e�s� �a�r�g�u�m�e�n�t�.� � �C�a�l�c�_�m�c�_�c�s�s� �r�u�n�s� �f�a�s�t�e�r� �w�h�e�n� �n�o�t� �u�s�i�n�g� �h�t�t�k�p�o�p� �a�n�d� �c�a�l�c�u�l�a�t�i�n�g� �R�b�l�o�o�d�2�p�l�a�s�m�a�,� �n�o�w� �o�n�l�y� �c�a�l�c�u�l�a�t�e�d� �o�n�c�e�.� � �N�e�w� �d�a�t�a� �a�r�e� �a�d�d�e�d� �t�o� �c�h�e�m�.�i�n�v�i�v�o�.�P�K�.�d�a�t�a� �a�n�d� �c�h�e�m�.�i�n�v�i�v�o�.�P�K�.�s�u�m�m�a�r�y�.�d�a�t�a�.� � �c�h�e�m�.�l�i�s�t�s� �i�s� �u�p�d�a�t�e�d�,� �a�n�d� �i�s�.�p�h�a�r�m�a� �h�a�s� �b�e�e�n� �a�d�d�e�d� �a�s� �a� �f�u�n�c�t�i�o�n�.� � �A� �n�e�w� �t�a�b�l�e� �i�s� �i�n�c�l�u�d�e�d�:� �c�h�e�m�.�i�n�v�i�v�o�.�P�K�.�a�g�g�r�e�g�a�t�e� �d�a�t�a� � �c�a�l�c�_�m�c�_�c�s�s� �b�u�g� �f�i�x�:� �d�a�i�l�y�.�d�o�s�e� �n�o�w� �w�o�r�k�i�n�g� �a�s� �a�n� �a�r�g�u�m�e�n�t� �(�p�r�e�v�i�o�u�s�l�y� �o�n�l�y� �r�u�n�n�i�n�g� �a�s� �1�)�.� � �c�a�l�c�_�a�n�a�l�y�t�i�c�_�c�s�s� �d�o�e�s� �n�o�t� �r�e�c�a�l�c�u�l�a�t�e� �a�l�l� �p�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t�s� �w�h�e�n� �s�p�e�c�i�f�y�i�n�g� �a� �t�i�s�s�u�e�.� � �l�o�g�P� �v�a�l�u�e�s� �f�r�o�m� �E�P�I�S�u�i�t�e� �o�r� �v�a�l�u�e�d� �N�A� �h�a�v�e� �b�e�e�n� �r�e�p�l�a�c�e�d� �w�i�t�h� �p�r�e�d�i�c�t�i�o�n�s� �f�r�o�m� �O�P�E�R�A� �w�h�e�r�e� �a�v�a�i�l�a�b�l�e�.� � � �h�e�p�a�t�i�c�.�b�i�o�a�v�a�i�l�a�b�i�l�i�t�y� �i�s� �a�d�d�e�d� �a�s� �a� �p�a�r�a�m�e�t�e�r� �t�o� �t�h�e� �m�o�d�e�l�s� �1�c�o�m�p�a�r�t�m�e�n�t� �(�p�a�r�a�m�e�t�e�r�i�z�e�_�1�c�o�m�p�)� �a�n�d� �3�c�o�m�p�a�r�t�m�e�n�t�s�s� �(�p�a�r�a�m�e�t�e�r�i�z�e�_�s�t�e�a�d�y�s�t�a�t�e�)� � �a�n�d� �n�o�w� �u�s�e�d� �w�i�t�h� �t�h�e�s�e� �m�o�d�e�l�s� �(�m�u�l�t�i�p�l�i�e�d� �b�y� �t�h�e� �d�o�s�e� �a�n�d� �F�g�u�t�a�b�s�)�.� � �k�i�n�h�a�b�s� �a�n�d� �k�d�e�r�m�a�b�s�,� �b�o�t�h� �o�f� �w�h�i�c�h� �w�e�r�e� �u�n�u�s�e�d� �i�n� �t�h�e� �m�o�d�e�l�s�,� �a�r�e� �r�e�m�o�v�e�d�.� � �v�L�i�v�e�r�P�B�P�K�.�c�,� �t�h�e� �s�o�u�r�c�e� �f�i�l�e� �f�o�r� �t�h�e� �p�b�t�k� �m�o�d�e�l�,� �n�o�w� �h�a�s� �u�p�d�a�t�e�d� �v�a�r�i�a�b�l�e� �n�a�m�e�s�,� �a�n�d� �c�o�r�r�e�s�p�o�n�d�i�n�g� �c�h�a�n�g�e�s� �a�r�e� �m�a�d�e� �i�n� �s�o�l�v�e�_�p�b�t�k�.� � �T�h�e� �t�i�m�e� �s�t�e�p� �i�m�m�e�d�i�a�t�e�l�y� �a�f�t�e�r� �a�d�d�i�t�i�o�n� �o�f� �d�o�s�e� �i�s� �a�d�d�e�d� �t�o� �b�e�t�t�e�r� �c�a�p�t�u�r�e� �p�e�a�k� �c�o�n�c�e�n�t�r�a�t�i�o�n� �f�o�r� �i�v� �d�o�s�i�n�g�.� � �k�g�u�t�a�b�s� �d�e�f�a�u�l�t� �c�h�a�n�g�e�d� �t�o� �2�.�1�8�.� � � � � � � � �C�h�a�n�g�e�s� �i�n� �v�e�r�s�i�o�n� �1�.�7� � � � �T�h�i�s� �r�e�v�i�s�i�o�n� �i�s� �c�o�n�s�i�s�t�e�n�t� �w�i�t�h� �t�h�e� �J�S�S� �p�u�b�l�i�c�a�t�i�o�n� �o�f� �P�e�a�r�c�e� �e�t� �a�l�.� �"�h�t�t�k�:� �R� �P�a�c�k�a�g�e� �f�o�r� �H�i�g�h�-�T�h�r�o�u�g�h�p�u�t� �T�o�x�i�c�o�k�i�n�e�t�i�c�s�"�.� � �M�i�n�o�r� �b�u�g� �f�i�x�e�s� �i�n�c�l�u�d�e�:� �c�o�r�r�e�c�t�e�d� �i�n�t�r�i�n�s�i�c� �c�l�e�a�r�a�n�c�e�s� �f�o�r� �(�a�b�o�u�t� �1�0�)� �c�o�m�p�o�u�n�d�s� �f�r�o�m� �B�r�o�w�n� �2�0�0�7�,� �f�i�x�e�d� �o�u�t�p�u�t� �m�e�s�s�a�g�e� �f�r�o�m� �c�a�l�c�_�m�c�_�c�s�s� � �C�o�r�r�e�c�t�e�d� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �u�s�e�d� �f�o�r� �p�r�e�d�i�c�t�i�n�g� �p�a�r�t�i�t�i�o�n�i�n�g� �i�n�t�o� �i�n�t�e�r�s�t�i�t�i�a�l� �p�r�o�t�e�i�n� �(�n�e�g�l�i�g�i�b�l�e� �d�i�f�f�e�r�e�n�c�e� �i�n� �p�r�e�d�i�c�t�i�o�n�s�)� � �F�i�x�e�d� �b�u�g� �i�n� �c�a�l�c�u�l�a�t�i�n�g� �R�b�l�o�o�d�2�p�l�a�s�m�a� �i�n� �c�a�l�c�_�m�c�_�c�s�s�,� �a�n�d� �a�d�d�e�d� �f�a�s�t�e�r� �m�e�t�h�o�d� �f�o�r� �c�a�l�c�u�l�a�t�i�n�g� �R�b�l�o�o�d�2�p�l�a�s�m�a� �f�o�r� �3�c�o�m�p�a�r�t�m�e�n�t�s�s�.� � � � �c�h�a�n�g�e�s� �i�n� �v�e�r�s�i�o�n� �1�.�6� � � � �T�h�i�s� �r�e�v�i�s�i�o�n� �i�n�c�l�u�d�e�s� �d�a�t�a� �a�n�d� �m�o�d�i�f�i�c�a�t�i�o�n�s� �a�s� �r�e�p�o�r�t�e�d� �i�n� �t�h�e� �r�e�c�e�n�t�l�y� �s�u�b�m�i�t�t�e�d� �P�e�a�r�c�e� �e�t� �a�l�.� �p�a�p�e�r� � � �"�E�v�a�l�u�a�t�i�o�n� �a�n�d� �C�a�l�i�b�r�a�t�i�o�n� �o�f� �H�i�g�h� T�h�r�o�u�g�h�p�u�t� �P�r�e�d�i�c�t�i�o�n�s� �o�f� �C�h�e�m�i�c�a�l� �D�i�s�t�r�i�b�u�t�i�o�n� �t�o� �T�i�s�s�u�e�s�"�.� � � �T�h�e� �S�c�h�m�i�t�t� �(�2�0�0�8�)� �m�e�t�h�o�d� �f�o�r� �p�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t�s� �h�a�s� �b�e�e�n� �m�o�d�i�f�i�e�d� �a�n�d� �c�a�l�i�b�r�a�t�e�d� �u�s�i�n�g� �e�x�p�e�r�i�m�e�n�t�a�l� �d�a�t�a�.� � � �T�h�e� �n�e�w� �m�e�t�h�o�d� �i�s� �n�o�w� �d�e�f�a�u�l�t�,� �a�l�t�h�o�u�g�h� �t�h�e� �p�r�e�v�i�o�u�s� �a�p�p�r�o�a�c�h� �i�s� �a�v�a�i�l�a�b�l�e� �(�s�e�t� �r�e�g�r�e�s�s�i�o�n�=�F�A�L�S�E� �a�n�d� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a�.�p�c�.�c�o�r�r�e�c�t�i�o�n�=�F�A�L�S�E� � �f�o�r� �o�t�h�e�r� �m�o�d�e�l�s�)�.� � �T�h�e� �m�e�m�b�r�a�n�e� �a�f�f�i�n�i�t�y� �r�e�g�r�e�s�s�i�o�n� �i�s� �n�e�w� �a�n�d� �a�l�w�a�y�s� �u�s�e�d� �i�n� �p�l�a�c�e� �o�f� �t�h�e� �o�l�d�.� � � � � �a�d�d�e�d� �f�u�n�c�t�i�o�n�s�:� �a�v�a�i�l�a�b�l�e�_�r�b�l�o�o�d�2�p�l�a�s�m�a� � �i�n� �v�i�v�o� �R�b�l�o�o�d�2�p�l�a�s�m�a� �u�s�e�d� �w�h�e�n� �a�v�a�i�l�a�b�l�e� � �w�e�l�l�-�s�t�i�r�r�e�d� �b�l�o�o�d� �c�o�r�r�e�c�t�i�o�n� �a�n�d� �r�e�s�t�r�i�c�t�i�v�e�.�c�l�e�a�r�a�n�c�e� �o�p�t�i�o�n�s� �a�d�d�e�d� � � �N�e�w� �i�n� �v�i�t�r�o� �d�a�t�a� �f�r�o�m� �U�c�h�i�m�u�r�a� �2�0�1�0�,� �b�r�o�w�n� �2�0�0�7� �a�n�d� �P�i�r�o�v�a�n�o� �2�0�1�6�,� �G�u�l�d�e�n� �2�0�0�2� � �T�o�n�n�e�l�i�e�r� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �v�a�l�u�e�s� �o�f� �0�.�0�0�5� �c�h�a�n�g�e�d� �t�o� �0� �i�n� �c�h�e�m�.�p�h�y�s�i�c�a�l�_�a�n�d�_�i�n�v�i�t�r�o�.�d�a�t�a� � �n�e�w� �t�i�s�s�u�e�.�d�a�t�a� �t�a�b�l�e� �w�i�t�h� �R�u�a�r�k� �2�0�1�4� �t�h�a�t� �c�o�n�t�a�i�n�s� �d�i�f�f�e�r�e�n�t� �f�o�r�m�a�t�t�i�n�g� �w�i�t�h� �h�u�m�a�n� �a�n�d� �r�a�t� �s�p�e�c�i�f�i�c� �d�a�t�a� � �p�a�r�a�m�e�t�e�r�i�z�e�_�s�c�h�m�i�t�t�:� �a�d�d�e�d� �f�o�r�c�e�.�h�u�m�a�n�.�f�u�b� �a�r�g�u�m�e�n�t� � �a�d�d�e�d� �p�l�a�s�m�a� �p�r�o�t�e�i�n� �a�n�d� �n�e�u�t�r�a�l� �l�i�p�i�d� �v�o�l�u�m�e� �f�r�a�c�t�i�o�n�s� �t�o� �p�h�y�s�i�o�l�o�g�y�.�d�a�t�a� �f�o�r� �u�s�e� �i�n� �p�a�c�k�a�g�e� � �c�a�l�c�_�m�c�_�c�s�s�:� �d�e�f�a�u�l�t�s� �t�o� �d�i�r�e�c�t� �r�e�s�a�m�p�l�i�n�g�.� �n�o� �l�o�n�g�e�r� �c�o�e�r�c�e�s� �s�p�e�c�i�e�s� �t�o� �h�u�m�a�n� �w�h�e�n� �h�t�t�k�p�o�p�=�T�.� � � � � � � � � � � � � � � � � �W�h�e�n� �a�n�o�t�h�e�r� �s�p�e�c�i�e�s� �i�s� �e�n�t�e�r�e�d�,� �a� �w�a�r�n�i�n�g� �i�s� �t�h�r�o�w�n� �a�n�d� �t�h�e� �f�u�n�c�t�i�o�n� �b�e�h�a�v�e�s� �a�s� �i�f� �h�t�t�k�p�o�p�=�F�.� � �u�p�d�a�t�e�d� �h�e�l�p� �f�i�l�e� �r�e�f�e�r�e�n�c�e�s� �a�n�d� �e�x�a�m�p�l�e�s� � �f�i�x�e�d� �p�a�r�a�m�e�t�e�r�i�z�e�_�3�c�o�m�p� �d�e�f�a�u�l�t�.�t�o�.�h�u�m�a�n� �b�u�g�:� �a�l�w�a�y�s� �s�e�t� �t�o� �f�a�l�s�e� � �r�e�m�o�v�e�d� �t�e�m�p�e�r�a�t�u�r�e� �f�r�o�m� �s�c�h�m�i�t�t� �p�a�r�a�m�e�t�e�r�s� � �o�v�e�r�w�r�i�t�e� �0� �v�a�l�u�e�s� �f�o�r� �F�u�b�o�u�n�d�.�p�l�a�s�m�a� �w�h�e�n� �o�v�e�r�w�r�i�t�e�=�F� �i�n� �a�d�d�_�c�h�e�m�t�a�b�l�e� � �a�d�d�e�d� �v�i�g�n�e�t�t�e� �f�o�r� �g�e�n�e�r�a�t�i�n�g� �p�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t� �p�l�o�t�s� � �a�d�d�e�d� �d�s�s�t�o�x� �i�n�f�o�:� �n�e�w� �c�o�l�u�m�n�s�:� �"�D�S�S�T�o�x�_�S�u�b�s�t�a�n�c�e�_�I�d�"�,�"�S�t�r�u�c�t�u�r�e�_�F�o�r�m�u�l�a�"�,� �o�r� �"�S�u�b�s�t�a�n�c�e�_�T�y�p�e�"�.� � �o�v�e�r�w�r�o�t�e�:� �M�W� �a�n�d� �S�M�I�L�E�S� � �a�d�d�e�d� �p�c�.�d�a�t�a� �a�n�d� �o�b�a�c�h�2�0�0�8� �t�a�b�l�e�s� � �h�t�t�k�p�o�p� �o�p�t�i�o�n� �i�n� �c�a�l�c�_�m�c�_�c�s�s�:� �w�e�l�l�-�s�t�i�r�r�e�d� �c�o�r�r�e�c�t�i�o�n� �a�n�d� �n�e�w� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �u�s�e�d� �b�y� �d�e�f�a�u�l�t�.� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �N�e�w� �p�a�r�t�i�t�i�o�n� �c�o�e�f�f�i�c�i�e�n�t�s� �u�s�e�d� �w�i�t�h� �o�t�h�e�r� �m�o�d�e�l�s� �b�y� �d�e�f�a�u�l�t�.� � � � �C�h�a�n�g�e�s� �i�n� �v�e�r�s�i�o�n� �1�.�5� � � � �T�h�i�s� �r�e�v�i�s�i�o�n� �p�r�o�v�i�d�e�s� �m�o�d�e�l�s�,� �d�a�t�a�,� �a�n�d� �v�i�g�n�e�t�t�e�s� �f�o�r� � h�t�t�k�-�p�o�p� �f�u�n�c�t�i�o�n�a�l�i�t�y�.� � h�t�t�k�-�p�o�p� �a�l�l�o�w�s� �M�o�n�t�e� �C�a�r�l�o� �s�i�m�u�l�a�t�i�o�n� �o�f� �p�h�y�s�i�o�l�o�g�i�c�a�l� � � �v�a�r�i�a�b�i�l�i�t�y� �a�s� �d�e�s�c�r�i�b�e�d� �i�n� �R�i�n�g� �e�t� �a�l�.� � I�d�e�n�t�i�f�y�i�n�g� �p�o�p�u�l�a�t�i�o�n�s� �s�e�n�s�i�t�i�v�e� �t�o� �e�n�v�i�r�o�n�m�e�n�t�a�l� �c�h�e�m�i�c�a�l�s� �b�y� �s�i�m�u�l�a�t�i�n�g� �t�o�x�i�c�o�k�i�n�e�t�i�c� �v�a�r�i�a�b�i�l�i�t�y� ,� � � �w�h�i�c�h� �i�s� �a�c�c�e�p�t�e�d� �f�o�r� �p�u�b�l�i�c�a�t�i�o�n� �a�t� �E�n�v�i�r�o�n�m�e�n�t� �I�n�t�e�r�n�a�t�i�o�n�a�l�.� �T�h�i�s� �n�e�w� �h�u�m�a�n� �v�a�r�i�a�b�i�l�i�t�y� �f�u�n�c�t�i�o�n�a�l�i�t�y� �i�s� �t�h�e� �n�e�w� �d�e�f�a�u�l�t�,� � � �a�l�t�h�o�u�g�h� �t�h�e� �p�r�e�v�i�o�u�s� �a�p�p�r�o�a�c�h� �i�s� �a�v�a�i�l�a�b�l�e� �(�s�e�t� �h�t�t�k�p�o�p�=�F�A�L�S�E�)�.� � � � �d�e�f�a�u�l�t�.�t�o�.�h�u�m�a�n� �a�r�g�u�m�e�n�t� �a�d�d�e�d� �t�o� �c�a�l�c�_�h�e�p�a�t�i�c�_�c�l�e�a�r�a�n�c�e� �a�n�d� �c�a�l�c�_�s�t�a�t�s�.� � �c�a�l�c�_�h�e�p�a�t�i�c�_�c�l�e�a�r�a�n�c�e� �a�n�d� �c�a�l�c�_�t�o�t�a�l�_�c�l�e�a�r�a�n�c�e� �d�o� �n�o�t� �n�e�c�e�s�s�a�r�i�l�y� �r�e�q�u�i�r�e� �a�l�l� �p�a�r�a�m�e�t�e�r�s�.� � �A�r�g�u�m�e�n�t� �"�t�i�s�s�u�e�"� �a�d�d�e�d� �t�o� �c�a�l�c�_�a�n�a�l�y�t�i�c�_�c�s�s�,� �c�a�l�c�_�m�c�_�c�s�s�,� �a�n�d� �c�a�l�c�_�m�c�_�o�r�a�l�_�e�q�u�i�v�,� �e�n�a�b�l�i�n�g� �t�i�s�s�u�e� �s�p�e�c�i�f�i�c� �c�a�l�c�u�l�a�t�i�o�n�s� �i�n� �a�d�d�i�t�i�o�n� �t�o� �p�l�a�s�m�a�.� � �g�e�t�_�c�h�e�m�i�n�f�o� �m�i�n�o�r� �b�u�g� �f�i�x�.� � �c�a�l�c�_�d�o�w�:� �f�r�a�c�t�i�o�n� �n�e�u�t�r�a�l� �a�r�g�u�m�e�n�t� �c�h�a�n�g�e�d� �t�o� �f�r�a�c�t�i�o�n� �c�h�a�r�g�e�d�,� �t�h�u�s� �t�r�e�a�t�i�n�g� �z�w�i�t�t�e�r�i�o�n�s� �a�s� �n�e�u�t�r�a�l�s� � �m�o�n�t�e�_�c�a�r�l�o� �b�u�g� �f�i�x�:� �U�p�p�e�r� �b�o�u�n�d� �p�l�a�c�e�d� �a�t� �l�i�m�i�t� �o�f� �d�e�t�e�c�t�i�o�n� �f�o�r� �c�e�n�s�o�r�e�d� �p�a�r�a�m�s� �t�r�u�n�c�a�t�e�d� �n�o�r�m�a�l� �d�i�s�t�r�i�b�u�t�i�o�n�.� � �H�o�w�e�v�e�r�,� �t�h�i�s� �h�a�s� �n�o� �i�m�p�a�c�t� �o�n� � � � � � � � � � � � � � � � � � � � � � � �t�h�e� �d�e�f�a�u�l�t� �c�a�s�e� �w�h�e�r�e� �t�h�e� �l�i�m�i�t� �o�f� �d�e�t�e�c�t�i�o�n� �i�s� �.�0�1� �t�h�e� �m�e�a�n� �.�0�0�5� �b�e�c�a�u�s�e� �o�f� �t�h�e� �s�m�a�l�l� �s�t�a�n�d�a�r�d� �d�e�v�i�a�t�i�o�n� �s�i�z�e� �(�.�0�0�1�5�)�.� � � � � � � � � � � � � � � � � � � � � � � � �O�n�l�y� �l�a�r�g�e� �c�o�e�f�f�i�c�i�e�n�t�s� �o�f� �v�a�r�i�a�t�i�o�n� �o�r� �F�u�n�b�o�u�n�d�.�p�l�a�s�m�a� �v�a�l�u�e�s� �c�l�o�s�e� �t�o� �t�h�e� �l�i�m�i�t� �o�f� �d�e�t�e�c�t�i�o�n� �w�o�u�l�d� �b�e� �a�f�f�e�c�t�e�d�.� � �M�u�l�t�i�p�l�e� �i�v� �d�o�s�e�s� �e�n�a�b�l�e�d� �i�n� �s�o�l�v�e� �f�u�n�c�t�i�o�n�s�.� � �g�e�t�_�r�b�l�o�o�d�2�p�l�a�s�m�a� �f�u�n�c�t�i�o�n� �a�d�d�e�d� �t�o� �r�e�t�r�i�e�v�e� �i�n� �v�i�v�o� �R�b�l�o�o�d�2�p�l�a�s�m�a� �f�r�o�m� �c�h�e�m�.�p�h�y�s�i�c�a�l�_�a�n�d�_�i�n�v�i�t�r�o�.�d�a�t�a�.� � � � �V�e�r�s�i�o�n�:� �1�.�4� � �T�h�i�s� �r�e�v�i�s�i�o�n� �i�n�c�o�r�p�o�r�a�t�e�s� �c�h�a�n�g�e�s� �s�u�g�g�e�s�t�e�d� �b�y� �t�h�e� �r�e�v�i�e�w�e�r�s� �o�f� �P�e�a�r�c�e� �e�t� �a�l�.� �"�h�t�t�k�:� �R� �P�a�c�k�a�g�e� �f�o�r� �H�i�g�h�-�T�h�r�o�u�g�h�p�u�t� �T�o�x�i�c�o�k�i�n�e�t�i�c�s�"�,� � �w�h�i�c�h� �w�a�s� �a�c�c�e�p�t�e�d�,� �p�e�n�d�i�n�g� �m�i�n�o�r� �r�e�v�i�s�i�o�n�,� �i�n� �t�h�e� �J�o�u�r�n�a�l� �o�f� � �S�t�a�t�i�s�t�i�c�a�l� �S�o�f�t�w�a�r�e�,� �i�n�c�l�u�d�e�d� �i�n� �v�i�g�n�e�t�t�e�s�.� � � � � �T�a�b�l�e� �n�a�m�e� �"�P�K�.�p�h�y�s�i�o�l�o�g�y�.�d�a�t�a�"� �c�h�a�n�g�e�d� �t�o� �"�p�h�y�s�i�o�l�o�g�y�.�d�a�t�a�"�.� � � � � � �V�e�r�s�i�o�n� �1�.�3� � �T�h�i�s� �r�e�v�i�s�i�o�n� �a�d�d�s� �~�2�0�0� �m�o�r�e� �c�h�e�m�i�c�a�l�s� �(�f�r�o�m� �t�w�o� �r�e�c�e�n�t� �p�u�b�l�i�c�a�t�i�o�n�s� �i�n�c�l�u�d�i�n�g� �W�e�t�m�o�r�e� �e�t� �a�l�.� �2�0�1�5�)� �a�n�d� �m�a�k�e� �s�e�v�e�r�a�l� �s�m�a�l�l� �c�h�a�n�g�e�s� �t�o� �i�m�p�r�o�v�e� �u�s�a�b�i�l�i�t�y� �a�n�d� �s�t�a�b�i�l�i�t�y�.� � � � � �V�e�r�s�i�o�n� �1�.�2� � �T�h�i�s� �r�e�v�i�s�i�o�n� �c�h�a�n�g�e�s� �s�o�m�e� �m�o�d�e�l� �p�a�r�a�m�e�t�e�r� �n�a�m�e�s� �t�o� �f�o�l�l�o�w� �a� �m�o�r�e� �s�y�s�t�e�m�a�t�i�c� �n�a�m�i�n�g� �c�o�n�v�e�n�t�i�o�n�.� � � �M�i�n�o�r� �b�u�g�s� �h�a�v�e� �b�e�e�n� �f�i�x�e�d�.� � � �T�h�i�s� �v�e�r�s�i�o�n� �i�s� �c�o�n�s�i�s�t�e�n�t� �w�i�t�h� �a� �n�e�w�l�y� �s�u�b�m�i�t�t�e�d� �a�r�t�i�c�l�e� �t�o� �J�S�S� �d�e�s�c�r�i�b�i�n�g� �u�s�e� �o�f� �t�h�e� �p�a�c�k�a�g�e�.� � � � � �V�e�r�s�i�o�n� �1�.�1� � � � �I�n�i�t�i�a�l� �p�u�b�l�i�c� �(�C�R�A�N�)� �r�e�l�e�a�s�e�.� � � � � � �

Reference manual

It appears you don't have a PDF plugin for this browser. You can click here to download the reference manual.

install.packages("httk")

1.8 by John Wambaugh, 6 months ago


Browse source code at https://github.com/cran/httk


Authors: John Wambaugh, Robert Pearce, Caroline Ring, Jimena Davis, Nisha Sipes, and R. Woodrow Setzer


Documentation:   PDF Manual  


GPL-3 license


Imports deSolve, msm, data.table, survey, mvtnorm, truncnorm, stats, utils

Suggests ggplot2, knitr, rmarkdown, R.rsp, GGally, gplots, scales, EnvStats, MASS, RColorBrewer, TeachingDemos, classInt, ks, reshape2, gdata, viridis, CensRegMod, gmodels, colorspace


See at CRAN