Item Parameter Estimation in Multistage Designs: A Comparison of Different Estimation Approaches for the Rasch Model

There is some debate in the psychometric literature about item parameter estimation in multistage designs. It is occasionally argued that the conditional maximum likelihood (CML) method is superior to the marginal maximum likelihood method (MML) because no assumptions have to be made about the trait distribution. However, CML estimation in its original formulation leads to biased item parameter estimates. Zwitser and Maris (2015, Psychometrika) proposed a modified conditional maximum likelihood estimation method for multistage designs that provides practically unbiased item parameter estimates. In this article, the differences between different estimation approaches for multistage designs were investigated in a simulation study. Four different estimation conditions (CML, CML estimation with the consideration of the respective MST design, MML with the assumption of a normal distribution, and MML with log-linear smoothing) were examined using a simulation study, considering different multistage designs, number of items, sample size, and trait distributions. The results showed that in the case of the substantial violation of the normal distribution, the CML method seemed to be preferable to MML estimation employing a misspecified normal trait distribution, especially if the number of items and sample size increased. However, MML estimation using log-linear smoothing lea to results that were very similar to the CML method with the consideration of the respective MST design.

Redundancy-selection trade-off in phenotype-structured populations

Realistic fitness landscapes generally display a redundancy-fitness trade-off: highly fit trait configurations are inevitably rare, while less fit trait configurations are expected to be more redundant. The resulting sub-optimal patterns in the fitness distribution are typically described by means of effective formulations. However, the extent to which effective formulations are compatible with explicitly redundant landscapes is yet to be understood, as well as the consequences of a potential miss-match. Here we investigate the effects of such trade-off on the evolution of phenotype-structured populations, characterised by continuous quantitative traits. We consider a typical replication-mutation dynamics, and we model redundancy by means of two dimensional landscapes displaying both selective and neutral traits. We show that asymmetries of the landscapes will generate neutral contributions to the marginalised fitness-level description, that cannot be described by effective formulations, nor disentangled by the full trait distribution. Rather, they appear as effective sources, whose magnitude depends on the geometry of the landscape. Our results highlight new important aspects on the nature of sub-optimality. We discuss practical implications for rapidly mutant populations such as pathogens and cancer cells, where the qualitative knowledge of their trait and fitness distributions can drive disease management and intervention policies.

The impact of phenotypic heterogeneity of tumour cells on treatment and relapse dynamics

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.

The impact of phenotypic heterogeneity of tumour cells on treatment and relapse dynamics

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.Author summaryThe individual cells within a cancer cell population are not all equal. The heterogeneity among them can strongly affect disease progression and treatment success. Recent diagnostic advances allow measuring how the characteristics of this heterogeneity change over time. To match these advances, we developed deterministic and stochastic trait-based models that capture important characteristics of the intratumour heterogeneity and allow to evaluate different treatment types that either do or do not interact with this heterogeneity. We focus on growth rate as the decisive characteristic of the intratumour heterogeneity. We find that by shifting the trait distribution of the cancer cell population, the growth rate-dependent treatment delays an eventual relapse compared to the growth rate-independent treatment. As a downside, however, we observe a refuge effect where slower-growing subpopulations are less affected by the growth rate-dependent treatment, which may decrease the likelihood of successful therapy. We find that navigating along this trade-off may be achieved by sequentially combining both treatment types, which agrees qualitatively with current clinical practice. Interestingly, even rather large intervals between treatment changes allow for close-to-optimal treatment results, which again hints towards a practical applicability.

Impact of herbivore preference on the benefit of plant trait variability

We explore the hypothesis that intraspecific trait variability can be per se beneficial for the plant when the curvature of the herbivore response to this trait is concave downwards. This hypothesis is based on a mathematical relation for nonlinear averaging (Jensen’s inequality), leading to reduced herbivory when the trait distribution becomes broader. Our study introduces and investigates a model for plants and their insect herbivores that includes an unequal distribution of nutrient content between leaves. In contrast to earlier publications, we take into account the ability of herbivores to choose leaves, and the associated costs of this preference behavior. By performing computer simulations and analytic calculations, we find that this herbivore preference can considerably alter the conclusion cited above. In particular, we demonstrate that herbivore populations that show preference for leaves on which they grow well can benefit from large nutrient-level variability independently of the curvature of the herbivore response function, despite the cost for preference.

MORPHOLOGY OF THE CAECUM IN LABORATORY ANIMALS IN HEALTH: SPECIES COMPARISON

In recent decades, the prevalence of gastrointestinal diseases has increased thus posing the immediate, both therapeutic and surgical treatment. It brings forth a problem of searching new and improving existing approaches and techniques for correcting the above-mentioned diseases. Preclinical studies in this area are conducted exclusively on laboratory animals and peculiarities of the morphological features of their organs are of great importance when comparing with the human morphology. The methodology used in the study included histological, morphometric and statistical techniques; biopsy samples of caecum taken from 5 rabbits were investigated. We assessed the correctness of the trait distribution by each of the variations, the mean values for each trait studied, standard errors and standard deviations. The significance of the difference of values between independent micrometric values in the normal trait distribution was determined by Student's criterion. The paper describes the main morphological characteristics of the caecum in rabbits and compared the findings obtained with similar structures of the human caecum. The caecum of rabbits, as of humans, has four layers: mucous, submucosal, muscular and serous. The mucous membrane consists of the epithelial layer located on the basement membrane and the muscular plate and contains cellular elements. The submucosa is composed of loose fibrous connective tissue, which contains collagen and reticular fibres, elements of diffuse lymphoid tissue, blood vessels, and nerve endings. The muscular and serous membranes are quite similar to the human caecum. Thus, the optic light microscopy has demonstrated the morphology of the caecum in rabbits is similar to that in the human caecum.