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Reproduction of patterns in melanocytic proliferations by agent-based simulation and geometric modeling.

ABSTRACT: Spatio-temporal patterns of melanocytic proliferations observed in vivo are important for diagnosis but the mechanisms that produce them are poorly understood. Here we present an agent-based model for simulating the emergence of the main biologic patterns found in melanocytic proliferations. Our model portrays the extracellular matrix of the dermo-epidermal junction as a two-dimensional manifold and we simulate cellular migration in terms of geometric translations driven by adhesive, repulsive and random forces. Abstracted cellular functions and melanocyte-matrix interactions are modeled as stochastic events. For identification and validation we use visual renderings of simulated cell populations in a horizontal perspective that reproduce growth patterns observed in vivo by sequential dermatoscopy and corresponding vertical views that reproduce the arrangement of melanocytes observed in histopathologic sections. Our results show that a balanced interplay of proliferation and migration produces the typical reticular pattern of nevi, whereas the globular pattern involves additional cellular mechanisms. We further demonstrate that slight variations in the three basic cellular properties proliferation, migration, and adhesion are sufficient to produce a large variety of morphological appearances of nevi. We anticipate our model to be a starting point for the reproduction of more complex scenarios that will help to establish functional connections between abstracted microscopic behavior and macroscopic patterns in all types of melanocytic proliferations including melanoma.

SUBMITTER: Schneckenreither G

PROVIDER: S-EPMC7888658 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Reproduction of patterns in melanocytic proliferations by agent-based simulation and geometric modeling.

Schneckenreither Günter G Tschandl Philipp P Rippinger Claire C Sinz Christoph C Brunmeir Dominik D Popper Nikolas N Kittler Harald H

PLoS computational biology 20210204 2

Spatio-temporal patterns of melanocytic proliferations observed in vivo are important for diagnosis but the mechanisms that produce them are poorly understood. Here we present an agent-based model for simulating the emergence of the main biologic patterns found in melanocytic proliferations. Our model portrays the extracellular matrix of the dermo-epidermal junction as a two-dimensional manifold and we simulate cellular migration in terms of geometric translations driven by adhesive, repulsive a ...[more]

PMID: 33539342

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Project description:ImportancePopulation-based information on the distribution of histologic diagnoses associated with skin biopsies is unknown. Electronic medical records (EMRs) enable automated extraction of pathology report data to improve our epidemiologic understanding of skin biopsy outcomes, specifically those of melanocytic origin.ObjectiveTo determine population-based frequencies and distribution of histologically confirmed melanocytic lesions.Design, setting, and participantsA natural language processing (NLP)-based analysis of EMR pathology reports of adult patients who underwent skin biopsies at a large integrated health care delivery system in the US Pacific Northwest from January 1, 2007, through December 31, 2012.ExposuresSkin biopsy procedure.Main outcomes and measuresThe primary outcome was histopathologic diagnosis, obtained using an NLP-based system to process EMR pathology reports. We determined the percentage of diagnoses classified as melanocytic vs nonmelanocytic lesions. Diagnoses classified as melanocytic were further subclassified using the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) reporting schema into the following categories: class I (nevi and other benign proliferations such as mildly dysplastic lesions typically requiring no further treatment), class II (moderately dysplastic and other low-risk lesions that may merit narrow reexcision with <5-mm margins), class III (eg, melanoma in situ and other higher-risk lesions warranting reexcision with 5-mm to 1-cm margins), and class IV/V (invasive melanoma requiring wide reexcision with ≥1-cm margins and potential adjunctive therapy). Health system cancer registry data were used to define the percentage of invasive melanoma cases within MPATH-Dx class IV (stage T1a) vs V (≥stage T1b).ResultsA total of 80 368 skin biopsies, performed on 47 529 patients, were examined. Nearly 1 in 4 skin biopsies were of melanocytic lesions (23%; n = 18 715), which were distributed according to MPATH-Dx categories as follows: class I, 83.1% (n = 15 558); class II, 8.3% (n = 1548); class III, 4.5% (n = 842); class IV, 2.2% (n = 405); and class V, 1.9% (n = 362).Conclusions and relevanceApproximately one-quarter of skin biopsies resulted in diagnoses of melanocytic proliferations. These data provide the first population-based estimates across the spectrum of melanocytic lesions ranging from benign through dysplastic to malignant. These results may serve as a foundation for future research seeking to understand the epidemiology of melanocytic proliferations and optimization of skin biopsy utilization.

Project description:Objective To quantify the accuracy and reproducibility of pathologists' diagnoses of melanocytic skin lesions.Design Observer accuracy and reproducibility study.Setting 10 US states.Participants Skin biopsy cases (n=240), grouped into sets of 36 or 48. Pathologists from 10 US states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least eight months apart.Main outcome measures Pathologists' interpretations were condensed into five classes: I (eg, nevus or mild atypia); II (eg, moderate atypia); III (eg, severe atypia or melanoma in situ); IV (eg, pathologic stage T1a (pT1a) early invasive melanoma); and V (eg, ≥pT1b invasive melanoma). Reproducibility was assessed by intraobserver and interobserver concordance rates, and accuracy by concordance with three reference diagnoses.Results In phase 1, 187 pathologists completed 8976 independent case interpretations resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intraobserver reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average interobserver concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% confidence interval 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases overinterpreted by the initial pathologist and 9.2% (8.8% to 9.6%) underinterpreted.Conclusion Diagnoses spanning moderately dysplastic nevi to early stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the USA. Efforts to improve clinical practice should include using a standardized classification system, acknowledging uncertainty in pathology reports, and developing tools such as molecular markers to support pathologists' visual assessments.

Project description:Methicillin-resistant Staphylococcus aureus (MRSA) has been a deadly pathogen in healthcare settings since the 1960s, but MRSA epidemiology changed since 1990 with new genetically distinct strain types circulating among previously healthy people outside healthcare settings. Community-associated (CA) MRSA strains primarily cause skin and soft tissue infections, but may also cause life-threatening invasive infections. First seen in Australia and the U.S., it is a growing problem around the world. The U.S. has had the most widespread CA-MRSA epidemic, with strain type USA300 causing the great majority of infections. Individuals with either asymptomatic colonization or infection may transmit CA-MRSA to others, largely by skin-to-skin contact. Control measures have focused on hospital transmission. Limited public health education has focused on care for skin infections.We developed a fine-grained agent-based model for Chicago to identify where to target interventions to reduce CA-MRSA transmission. An agent-based model allows us to represent heterogeneity in population behavior, locations and contact patterns that are highly relevant for CA-MRSA transmission and control. Drawing on nationally representative survey data, the model represents variation in sociodemographics, locations, behaviors, and physical contact patterns. Transmission probabilities are based on a comprehensive literature review.Over multiple 10-year runs with one-hour ticks, our model generates temporal and geographic trends in CA-MRSA incidence similar to Chicago from 2001 to 2010. On average, a majority of transmission events occurred in households, and colonized rather than infected agents were the source of the great majority (over 95%) of transmission events. The key findings are that infected people are not the primary source of spread. Rather, the far greater number of colonized individuals must be targeted to reduce transmission.Our findings suggest that current paradigms in MRSA control in the United States cannot be very effective in reducing the incidence of CA-MRSA infections. Furthermore, the control measures that have focused on hospitals are unlikely to have much population-wide impact on CA-MRSA rates. New strategies need to be developed, as the incidence of CA-MRSA is likely to continue to grow around the world.

Project description:Persons living with human immunodeficiency virus (HIV) have a disproportionately higher burden of human papillomavirus infection (HPV)-related cancers. Causal factors include both behavioral and biological. While pharmaceutical and care support interventions help address biological risk of coinfection, as social conditions are common drivers of behaviors, structural interventions are key part of behavioral interventions. Our objective is to develop a joint HIV-HPV model to evaluate the contribution of each factor, to subsequently inform intervention analyses. While compartmental modeling is sufficient for faster spreading HPV, network modeling is suitable for slower spreading HIV. However, using network modeling for jointly modeling HIV and HPV can generate computational complexities given their vastly varying disease epidemiology and disease burden across sub-population groups. We applied a recently developed mixed agent-based compartmental (MAC) simulation technique, which simulates persons with at least one slower spreading disease and their immediate contacts as agents in a network, and all other persons including those with faster spreading diseases in a compartmental model, with an evolving contact network algorithm maintaining the dynamics between the two models. We simulated HIV and HPV in the U.S. among heterosexual female, heterosexual male, and men who have sex with men (men only and men and women) (MSM), sub-populations that mix but have varying HIV burden, and cervical cancer among women. We conducted numerical analyses to evaluate the contribution of behavioral and biological factors to risk of cervical cancer among women with HIV. The model outputs for HIV, HPV, and cervical cancer compared well with surveillance estimates. Model estimates for relative prevalence of HPV (1.67 times) and relative incidence of cervical cancer (3.6 times), among women with HIV compared to women without, were also similar to that reported in observational studies in the literature. The fraction attributed to biological factors ranged from 22-38% for increased HPV prevalence and 80% for increased cervical cancer incidence, the remaining attributed to behavioral. The attribution of both behavioral and biological factors to increased HPV prevalence and cervical cancer incidence suggest the need for behavioral, structural, and pharmaceutical interventions. Validity of model results related to both individual and joint disease metrics serves as proof-of-concept of the MAC simulation technique. Understanding the contribution of behavioral and biological factors of risk helps inform interventions. Future work can expand the model to simulate sexual and care behaviors as functions of social conditions to jointly evaluate behavioral, structural, and pharmaceutical interventions for HIV and cervical cancer prevention.

Dataset Information

Reproduction of patterns in melanocytic proliferations by agent-based simulation and geometric modeling.

Publications

Reproduction of patterns in melanocytic proliferations by agent-based simulation and geometric modeling.

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