Retrospective analyses, lead optimization

Many predictive, validated models have been developed using these QSAR techniques and have often assisted in the selection of structures for lead optimization. Often the QSAR results are not available until after the process of lead optimization has already progressed, and these models represent retrospective analysis of the lead optimization process rather than a direct influence on the design of the lead optimization compounds. 

The statistical analysis of data requires a proper design of experiments to prove or disprove a certain hypothesis which has been formulated in advance. From the viewpoint of a puritanical statistician most QSAR analyses are forbidden , because they are retrospective studies and, in addition, many different hypotheses (i.e. combinations of independent variables) are tested sequentially. Indeed, many problems arise from the application of regression analysis in ill-conditioned data sets. Only in later stages of lead structure optimization are certain hypotheses, e.g. on the influence of more lipophilic, electronegative, polar, or bulky substituents in a certain position, systematically tested, now fulfilling the requirements for the proper application of statistical methods. 

There are no prospective studies that compare cure rates for antibiotic treatment alone vs antibiotic therapy combined with CIED system removal. However, the high rate of uncontrolled or relapsing bacteremia, even after prolonged medical therapy, makes removal of the entire CIED system optimal. In one recent retrospective case analysis [11] that included patients with an infected pacemaker or ICD, infection relapse was strongly associated with failure to completely remove all hardware. This case series included 123 patients, 119 (97%) of whom had transvenous implanted leads. Only one (0.86%) of 117 patients who underwent removal of their entire system had infection relapse. In contrast, three of six (50%, P = 0.003) without complete hardware removal suffered relapse. The only patient who had hardware removal and still had infection relapse had a new generator implanted in an old pocket site. All other patients had new devices placed at different sites at... 

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