Subject:[NMusers] NONMEM Wish List Date:Fri, 24 May 2002 09:07:32 -0400 To the NONMEM Users Network: The GloboMax NONMEM Project Team and the UCSF NONMEM Project Group are soliciting your thoughts and ideas regarding future enhancements to the NONMEM software program and to related software and associated support services. To stimulate your input, a list of possible enhancements has been compiled. Please send us an indication of the 3 or 4 items from this list to which you would have us give highest priority. We also ask you to provide additional items which you would have us consider for inclusion in a future version of NONMEM or GloboMax's interface PDx-POP, and most importantly, with all items you describe or prioritize, would you please provide a brief rationale and/or brief description of a situation that exemplifies the desirability for the item. It would also be helpful if you would indicate the operating system and Fortran compiler that you currently use with NONMEM. Certain items may be addressed by enhancements in NONMEM version VI, currently under development at UCSF. Other may be accomplished through the development of the PDx-POP interface or later versions of NONMEM beyond VI. This is an opportunity for you to help guide this future development. Please take a few minutes to respond to the above request. Responses can be sent directly to us (email@example.com or firstname.lastname@example.org). We will organize the responses and provide feedback to the network. This feedback will include the identity of the responder unless there is a request for anonymity. Many users have contributed to this list by volunteering their requests to the GloboMax NONMEM Project Team. We wish to sincerely thank these individuals for their interest. We also thank you in advance for taking time to review this list and to provide your own requests and priorities. Sincerely, Tom Ludden and Bill Bachman GloboMax NONMEM Project Team I. Software enhancements. A. Input 1. Libraries of control files that can serve as templates for further customization by the user. These might be made available via menus. Eventual interface features might include a menu-based or graphical model development environment. 2. Facilitate the analysis of log-transformed data. 3. Allow the ID item to be alphanumeric with expanded number of characters. 4. Remove case-sensitivity for NM-TRAN control streams. 5. Make tabs acceptable in control streams and data files. 6. Allow specification of a symbol/value for missing data. Help the user to recognize that missing data must be handled in the NM-TRAN control stream. Missing data in output tables would be identified by a user-selectable symbol. 7. Provide a way to use meaningful, user-specified variable names instead of THETA's, ETA's/OMEGA's, ERR and EPS/SIGMA to specify a model and the initial parameter estimates. The relationship between user-specified variable names and NONMEM variable names would be part of the summary output from the interface. This would allow the interpretation of any error messages generated by NMTRAN, NONMEM, and PREDPP. 8. Provide a mechanism by which the data files submitted to the PDx-POP interface do not need to be modified for modeling purposes. The interface would use separate files containing 1) dosing information, 2) covariate information and 3) dependent variables, each indexed by ID, DATE, TIME and appropriate indicator variables to distinguish different dosing routes, PK vs PD observations, etc. 9. Develop a separate utility that would facilitate the assembly of NMTRAN data sets (This would not necessarily address the issue described in item 8). 10. Provide a utility feature that facilitates changes to NSIZES, PSIZES, etc. These files specify various constants used to control the size of arrays in NONMEM, PREDPP and NMTRAN 11. Using the PDx-POP interface, facilitate the implementation of interoccasion variability. 12. Provide a way to define initial conditions for compartments within the NM-TRAN control stream. 13. Provide better documentation for the use of the CONT data item to allow more than 20 data items/event record. 14. Users frequently have the intermediate NONMEM output, which contains scaled, transformed parameter, printed to the screen in order to track program execution. It would be possible to have the PDx-POP interface automatically display the INTER file, in addition to the intermediate output, to track program execution. 15. Provide interpretation of gradients. Alert the user to potential problems both at the beginning and end of a problem. For example, a zero gradient for a parameter at the 0'th iteration would generate an error message; large gradients at the end of a "Successful" termination would yield a warning message. 16. Provide more help in NMTRAN for defining recursive models using $PRED. For a recursive model, the predictions and derivatives at a specific event record depend upon the predictions and derivatives from the previous event record. 17. Provide a root finder that can be called by user-specified NM-TRAN code. 18. Provide user-friendly interfaces for new, special features that may become available in the future. 19. Automatically compute certain items such as IPRED,IRES, IWRES, etc if they are tabled or plotted. B. Output 1. Use flexible, user-selectable, formatting that gives the user control of the number of digits reported and provides output formatted for reports and tables. 2. Provide more extensive and helpful discussion of error messages. 3. If OMEGA or SIGMA are not diagonal matrices, provide correlations in the summary. 4. Provide easy access to post-run processing software such as EXCEL, SPLUS, Xpose and SAS. (Access to EXCEL, SPLUS and Xpose is currently available through PDx-POP for Windows). 5. Provide an intermediate output file with more information than is currently available in the INTER file. 6. The meaning of the reserved label PRED, appearing in NONMEM tables and scatterplots, would be used only when the LIKELIHOOD or -2LL options are not used. When these options are used, another label would appear. C Functionality and Control 1. Improve processes for performing iterative calls to NONMEM and for summarizing the desired output. Iterative calls can currently be implemented through the use of superproblems and subproblems. Ways to facilitate the iterative calls needed for procedures such as likelihood profiling and the bootstrap are being considered. 2. Improve guidance for selection of estimation method. 3. Provide a broader choice of distributions for simulation. 4. Prevent premature termination during superproblem or subproblem iterations. 5. Expand the PREDPP library to include PD models. II. Enhancements only achievable through major changes to NONMEM code and outside the scope of current development plans. 1. Obviate need for prespecifying size of arrays. NONMEM is written in Fortran 77 and Fortran 77 does not allow dynamic allocation of memory for arrays. 2. Provide a measure of precision for the parameter estimates for individual subjects. With a population data set, NONMEM focuses on the estimation of population parameters, and only from a frequentist point of view. NONMEM generates parameter estimates for individual subjects using an Empirical Bayes approach, but only as means to approximate the frequentist likelihood of the population parameters, and to aid in simple model building strategies. Although, the posterior variance of an individual's parameter vector can be computed, such a Bayesian computation is not natural within NONMEM. Indeed, even the posterior mean is not computed (it is the posterior mode that is used as the estimate for the individual's parameter vector). Has anyone an example of how this posterior variance can really be useful for the analysis of population data? 3. Provide for mixture models at the observation level. (NONMEM currently allows mixture models at the parameter level but not the observation level.) III. Improved User Training and Support 1. Web-based process for user input regarding NONMEM development. 2. Web-based access to Frequently Asked Questions. 3. Web-based NONMEM Users Guide including example control streams and data sets created by user input. 4. Web-based access to patches/bug-fixes. 5. Web-based access to exemplary data analyses perhaps through a revitalized repository or electronic journal. 6. Web-based access to step-by-step instructions for compiling NONMEM on several common platforms/operating systems. 7. Web-based access to information regarding choice of compiler options for various compilers. 8. Instruction on the use of an appropriate debugger. 9. Provide a set of interactive tutorials that would be useful for beginning and intermediate users. IV. Improved Installation and Testing 1. Provide for installation of NONMEM source code and associated files from a CD. 2. Provide benchmarks and qualification kit.