Analytical validation of a multi-cancer early detection test with cancer signal origin using a cell-free DNA-based targeted methylation assay.

The analytical validation is reported for a targeted methylation-based cell-free DNA multi-cancer early detection test designed to detect cancer and predict the cancer signal origin (tissue of origin). A machine-learning classifier was used to analyze the methylation patterns of >105 genomic targets covering >1 million methylation sites. Analytical sensitivity (limit of detection [95% probability]) was characterized with respect to tumor content by expected variant allele frequency and was determined to be 0.07%-0.17% across five tumor cases and 0.51% for the lymphoid neoplasm case. Test specificity was 99.3% (95% confidence interval, 98.6-99.7%). In the reproducibility and repeatability study, results were consistent in 31/34 (91.2%) pairs with cancer and 17/17 (100%) pairs without cancer; between runs, results were concordant for 129/133 (97.0%) cancer and 37/37 (100%) non-cancer sample pairs. Across 3- to 100-ng input levels of cell-free DNA, cancer was detected in 157/182 (86.3%) cancer samples but not in any of the 62 non-cancer samples. In input titration tests, cancer signal origin was correctly predicted in all tumor samples detected as cancer. No cross-contamination events were observed. No potential interferent (hemoglobin, bilirubin, triglycerides, genomic DNA) affected performance. The results of this analytical validation study support continued clinical development of a targeted methylation cell-free DNA multi-cancer early detection test.

A cognitive psychometric model for the psychodiagnostic assessment of memory-related deficits.

Clinical tests used for psychodiagnostic purposes, such as the well-known Alzheimer's Disease Assessment Scale: Cognitive subscale (ADAS-Cog), include a free-recall task. The free-recall task taps into latent cognitive processes associated with learning and memory components of human cognition, any of which might be impaired with the progression of Alzheimer's disease (AD). A Hidden Markov model of free recall is developed to measure latent cognitive processes used during the free-recall task. In return, these cognitive measurements give us insight into the degree to which normal cognitive functions are differentially impaired by medical conditions, such as AD and related disorders. The model is used to analyze the free-recall data obtained from healthy elderly participants, participants diagnosed as having mild cognitive impairment, and participants diagnosed with early AD. The model is specified hierarchically to handle item differences because of the serial position curve in free recall, as well as within-group individual differences in participants' recall abilities. Bayesian hierarchical inference is used to estimate the model. The model analysis suggests that the impaired patients have the following: (1) long-term memory encoding deficits, (2) short-term memory (STM) retrieval deficits for all but very short time intervals, (3) poorer transfer into long-term memory for items successfully retrieved from STM, and (4) poorer retention of items encoded into long-term memory after longer delays. Yet, impaired patients appear to have no deficit in immediate recall of encoded words in long-term memory or for very short time intervals in STM.

Discrete-state models: comment on Pazzaglia, Dube, and Rotello (2013).

Pazzaglia, Dube, and Rotello (2013) have provided a lengthy critique of threshold and continuous models of recognition memory. Although the early pages of their article focus mostly on the problems they see with 3 vintage threshold models compared with models from signal detection theory (SDT), it becomes clear rather quickly that Pazzaglia et al. are concerned more generally with problems they see with multinomial processing tree (MPT) models. First, we focus on Pazzaglia et al.'s discussion of the evidence concerning receiver operating characteristics (ROCs) in simple recognition memory, then we consider problems they raise with a subclass of MPT models for more complex recognition memory paradigms, and finally we discuss the difference between scientific models and measurement models in the context of MPT and SDT models in general. We argue that Pazzaglia et al. have not adequately considered the evidence relevant to the viability of the simple threshold models and that they have not adequately represented the issues concerning validating a cognitive measurement model. We further argue that selective influence studies and model flexibility studies are as important as studies showing that a model can fit behavioral data. In particular, we note that despite over a half century of effort, no generally accepted scientific theory of recognition memory has emerged and that it is unlikely to ever emerge with studies using standard behavioral measures. Instead, we assert that useful measurement models of both the SDT and the MPT type have been and should continue to be developed.