Approaches to Sampling for Quality Control of Artificial Intelligence in Biomedical Research.

The aim of the study is to evaluate the efficacy of approaches to sampling during periodic quality control of the artificial intelligence (AI) results in biomedical practice. Materials and Methods: The approaches to sampling based on point statistical estimation, statistical hypothesis testing, employing ready-made statistical tables, as well as options of the approaches presented in GOST R ISO 2859-1-2007 "Statistical methods. Sampling procedures for inspection by attributes" have been analyzed. We have considered variants of sampling of different sizes for general populations from 1000 to 100,000 studies.The analysis of the approaches to sampling was carried out as part of an experiment on the use of innovative technologies in computer vision for the analysis of medical images and their further application in the healthcare system of Moscow (Russia). Results: Ready-made tables have specific statistical input data, which does not make them a universal option for biomedical research. Point statistical estimation helps to calculate a sample based on given statistical parameters with a certain confidence interval. This approach is promising in the case when only a type I error is important for the researcher, and a type II error is not a priority. Using the approach based on statistical hypothesis testing makes it possible to take account of type I and II errors based on the given statistical parameters. The application of GOST R ISO 2859-1-2007 for sampling allows using ready-made values depending on the given statistical parameters.When evaluating the efficacy of the studied approaches, it was found that for our purposes, the optimal number of studies during AI quality control for the analysis of medical images is 80 items. This meets the requirements of representativeness, balance of the risks to the consumer and the AI service provider, as well as optimization of labor costs of employees involved in the process of quality control of the AI results.

Methodology for Conducting Post-Marketing Surveillance of Software as a Medical Device Based on Artificial Intelligence Technologies.

The aim of the study was to develop a methodology for conducting post-registration clinical monitoring of software as a medical device based on artificial intelligence technologies (SaMD-AI). Materials and Methods: The methodology of post-registration clinical monitoring is based on the requirements of regulatory legal acts issued by the Board of the Eurasian Economic Commission. To comply with these requirements, the monitoring involves submission of the review of adverse events reports, the review of developers' routine reports on the safety and efficiency of SaMD-AI, and the assessment of the system for collecting and analyzing developers' post-registration data on the safety and efficiency of medical devices. The methodology was developed with regard to the recommendations of the International Medical Device Regulators Forum and the documents issued by the Food and Drug Administration (USA). Field-testing of this methodology was carried out using SaMD-AI designed for diagnostic imaging. Results: The post-registration monitoring of SaMD-AI consists of three key stages: collecting user feedback, technical monitoring and clinical validation. Technical monitoring involves routine evaluation of SaMD-AI output data quality to detect and remove flaws in a timely manner, and to secure the product stability. Major outcomes include an ordered list of technical flaws in SaMD-AI and their classification using evidence from diagnostic imaging studies. The application of this methodology resulted in a gradual reduction in the number of studies with flaws due to timely improvements in artificial intelligence algorithms: the number of flaws decreased to 5% in various aspects during subsequent testing. Clinical validation confirmed that SaMD-AI is capable of producing clinically meaningful outputs related to its intended use within the functionality determined by the developer. The testing procedure and the baseline testing framework were established during the field testing. Conclusion: The developed methodology will ensure the safety and efficiency of SaMD-AI taking into account its specifics as intangible medical devices. The methodology presented in this paper can be used by SaMD-AI developers to plan and carry out the post-registration clinical monitoring.

A simplified cluster model and a tool adapted for collaborative labeling of lung cancer CT scans.

BACKGROUND AND OBJECTIVE: Lung cancer is the most common type of cancer with a high mortality rate. Early detection using medical imaging is critically important for the long-term survival of the patients. Computer-aided diagnosis (CAD) tools can potentially reduce the number of incorrect interpretations of medical image data by radiologists. Datasets with adequate sample size, annotation, and truth are the dominant factors in developing and training effective CAD algorithms. The objective of this study was to produce a practical approach and a tool for the creation of medical image datasets. METHODS: The proposed model uses the modified maximum transverse diameter approach to mark a putative lung nodule. The modification involves the possibility to use a set of overlapping spheres of appropriate size to approximate the shape of the nodule. The algorithm embedded in the model also groups the marks made by different readers for the same lesion. We used the data of 536 randomly selected patients of Moscow outpatient clinics to create a dataset of standard-dose chest computed tomography (CT) scans utilizing the double-reading approach with arbitration. Six volunteer radiologists independently produced a report for each scan using the proposed model with the main focus on the detection of lesions with sizes ranging from 3 to 30 mm. After this, an arbitrator reviewed their marks and annotations. RESULTS: The maximum transverse diameter approach outperformed the alternative methods (3D box, ellipsoid, and complete outline construction) in a study of 10,000 computer-generated tumor models of different shapes in terms of accuracy and speed of nodule shape approximation. The markup and annotation of the CTLungCa-500 dataset revealed 72 studies containing no lung nodules. The remaining 464 CT scans contained 3151 lesions marked by at least one radiologist: 56%, 14%, and 29% of the lesions were malignant, benign, and non-nodular, respectively. 2887 lesions have the target size of 3-30 mm. Only 70 nodules were uniformly identified by all the six readers. An increase in the number of independent readers providing CT scans interpretations led to an accuracy increase associated with a decrease in agreement. The dataset markup process took three working weeks. CONCLUSIONS: The developed cluster model simplifies the collaborative and crowdsourced creation of image repositories and makes it time-efficient. Our proof-of-concept dataset provides a valuable source of annotated medical imaging data for training CAD algorithms aimed at early detection of lung nodules. The tool and the dataset are publicly available at https://github.com/Center-of-Diagnostics-and-Telemedicine/FAnTom.git and https://mosmed.ai/en/datasets/ct_lungcancer_500/, respectively.

[Morpho-densitometric researches of cell nuclei at atypical hyperplasia and initial breast cancer].

There were performed researches on morphometric (the nuclear area, perimeter, the maximum and minimum diameters) and densitometric (optical density, integrated optical density) parameters of nuclei of cells on the cytologic smears received from 28 patients with atypical hyperplasia and an initial breast cancer. Significant reduction of measured nuclei parameters was noted among: moderately - and high-grade ductal carcinoma in situ, atypical ductal hyperplasia, lobular carcinoma in situ, an invasive papillary cancer, intraductal papilloma. The lowest value of the measured parameters was noted at love-grade ductal carcinoma in situ and intraductal papillary cancer. It was established that morphometric and densitometric indicators at atypical hyperplasia of an epithelium and an initial breast cancer in some cases overlap each other that is at the bottom of difficulties of differential cytomorphological diagnostics and quite often forces to formulate the cytologic conclusion in the presumable form.

Effectiveness of cytological diagnosis of breast cancer metastases in regional lymph nodes.

Results are presented of preoperative and intraoperative cytological diagnosis of breast cancer metastases in regional lymph nodes in 84 patients. Of them in 42 there was studied material of fine-needle aspiration biopsy, in 42 - smears of sentinel lymph nodes. In all cases cytohistological comparisons were carried out. The effectiveness of cytological examination of material of fine-needle aspiration biopsy was 90.5%. Urgent cytology of smears of sentinel lymph nodes allowed revealing metastases in 5 of 10 patients. The use of immunohistochemical examination increases the likelihood of detection of micrometastases and isolated tumor cell clusters.

[An evaluation of effectiveness of cytological method in diagnostics of breast tumors].

This paper presents an analysis of the results of cytological diagnostics of breast tumors in 3415 patients who underwent tests in the Laboratory of Cytology for 2009-2013. In 1434 patients there were performed cytohistological correlations. Sensitivity of cytology was 99.1%, specificity--93.5%, predictive value of the positive test--98.5%, predictive value of the negative test--95.9%, accuracy--98%. Non-informative material was obtained in 13.5% of cases. The main factors that reduced effectiveness of cytological method were non-informative and little informative material and also difficulties in conducting of differential cytomorphological diagnostics.

[Assessment of applicability of archived cytological lung cancer specimens for molecular genetic analysis].

Molecular genetic analysis of lung tumors is often essential for the proper choice of therapy. EGFR mutation is a well-known marker of sensitivity to gefitinib, erlotinib and afatinib; ALK-translocations make tumor sensitive to several ALK inhibitors; low intratumoral expression of DNA repair genes (ERCC1, BRCA1, etc.) may increase the therapeutic index of platinum-based drugs. Usually these markers are evaluated using formalin-fixed paraffin-embedded tumor tissues. The goal of this work was to assess utility of archived cytological lung cancer specimens as an alternative source of material for molecular genetic testing. We analyzed paired histological and cytological lung adenocarcinoma specimens. Comparison of results within the pairs showed that cytological material can be used instead of histological material for qualitative analyses (detection of EGFR mutations or ALK-translocations); however, gene expression measurements, obtained by quantitative real-time PCR, may differ significantly in histological and cytological samples from the same patient.

[Cervical intraepithelial neoplasia combined in pregnancy: diagnosis, management, outcomes].

Cervical cancer is the leading gynecological tumor associated with pregnancy accounting for 1.2-4.5 cases per 10,000 births. Precancerous diseases of the cervix, which include cervical intraepithelial neoplasia of high severity (H-SIL) combined with pregnancy, are even more relevant since the frequency of their occurrence can achieve 5.0%. Besides the peak of dysplastic cervical changes occurs in the mean age at delivery in the Russian Federation (28 years). The features of diagnosis and management of these patients during pregnancy, delivery and postpartum require a multidisciplinary approach from doctors of different specialties.

[Verification of histologic diagnosis in cervical carcinoma in situ with contradictory morphological data].

The medical technology of in situ cervical carcinoma cytological verification using computer-assisted morphometric and density analysis of atypical cells nuclei was developed. The technology is aimed at diagnosis verification in cases with contradictory morphological data. The malignant transformation of cervical epithelium undetectable by conventional morphology methods can be diagnosed using the Felgen-stained samples nuclear DNA distribution data. The right DNA distribution diagram shift with modal class 4C or higher, mean DNA contents higher than 4C, the ratio between aneuploidic and polyploidic cells higher than 0.2 are the signs of cervical epithelium malignant transformation.

[Organ-preserving interventions in combined therapy of children and adolescents with osteosarcoma].

An analyzed cohort consists of 50 pediatric patients with osteosarcoma receiving combined therapy in N. N. Petrov Research Institute for Oncology (1999-2010). Thirty nine of them had localized disease, 11 patients had distant metastases. The treatment scheme included neoadjuvant therapy with cisplatin and doxorubicin, surgical treatment and adjuvant therapy depended on initial response and could include cisplatin, doxorubicin, high-dose methotrexate, ifosfamide, etoposide. Four-year overall and relapse-free survival in children with localized disease was 74.3% and 69.2% accordingly. In 62% of patients were performed organ-preserving surgical interventions, in 22 patients was performed endoprosthetics, in 4 patients the defect was replaced by a bone autograft on a vascular bundle. The effectiveness of initial treatment and secondary endoprosthetics were analyzed. Six patients with lung metastases received normotermic lung chemoperfusion, 4 of them are alive and disease-free for 8 to 24 months.

Morphological changes in human skin melanoma treated by high-energy pulsed neodymium laser radiation.

PURPOSE: The neodymium (Nd) laser irradiation has been successfully applied to the treatment of slightly elevated skin melanoma. At the same time the histologic aspects of such a treatment have not been precisely investigated. The aim of this study was to retrace the histological features in human primary cutaneous melanomas after 1060 nm high energy mono pulsed Nd laser treatment in the dynamic healing of the affected tissues. METHODS: Histologic analysis of cutaneous melanomas irradiated by Nd laser was carried out. Tissue specimens were taken before and immediately after exposure to laser and 1 hour, and 1, 2 and 3 days after wards. Also the wounds that appeared after the scab fell off and the scars formed following laser irradiation were also the subject of histologic analysis at 2, 4 and 6 months post-treatment. RESULTS: The Nd laser irradiation caused coagulation necrosis of melanoma, epidermis and dermis with skin appendices and superficial layers of subcutaneous fatty tissue. Foci of laser destruction were characterized by strict locality and efficient separation from the adjacent tissues, by the presence of stasis, thrombosis and coagulation of blood and lymphatic vessels. There was an increase of lymphocytes, macrophages and histiocytes in the area damaged by laser as well as in wounds and scars. CONCLUSION: The pulsed Nd laser induces acute photothermal damages of melanoma tissue, which differs from the usual thermal lesions and the most critical difference of the effect of this modality is gain of immunocompetent cells in the affected tissue after laser beam application.

[Application of automated quantitative cytometry in diagnosis of lung cancer].

The paper deals with evaluation of the literature data and our experience with automated quantitative cytometric examination of sputum for diagnosis of lung cancer and, in particular, early one. This novel procedure uses measurement of quantitative indices which characterise tumors-induced alterations. The LungSign computerized system was employed to scan cellular nuclei. The results were evaluated by linear discriminative analysis with the aid of ROC-curves and underlying areas. The procedures were run in 248 cases and its sensitivity was significantly higher that of a standard cytological one (36.6% and 13.3%, respectively; p = 0.033), albeit a slight decrease in specificity (93.7% and 100%, respectively; p = 0.003). Automated quantitative cytometric indices varied significantly in cohorts of patients with confirmed (-0.275871) and false (-1.24990) diagnosis of lung cancer (p = 0.0001).

[Clinico-morphological diagnosis of adenocarcinoma in situ of the cervix uteri].

Clinical and morphological investigation involved 57 patients with adenocarcinoma in situ of the cervix uteri (poorly-differentiated (precancerous) cell carcinoma in situ (PAIS)--30; adenocarcinoma in situ (AIS)--27). Morphometric measurements using microimaging technique were carried out on 31 cytological patterns. Clinical symptoms appeared non-specific. Cytological examination of smears detected tumor cells in all patients. Predictions for PAIS histotype were confirmed in 83%, cytological findings--78%; AIS--52% and 58%, respectively. Accuracy for PAIS and AIS biopsy was 52% and 32%, respectively. The most accurate data were obtained by histological examination of resected material. However, our procedure failed to detect malignant process in 17.5% (PAIS--6 cases and AIS--4) which was established by use of smears (Feulgen).

Sexual dimorphism in campylobacteriosis.

Sexual dimorphism in infectious diseases whereby disease incidence is more prevalent in one gender has been reported repeatedly in the scientific literature. Both behavioural and physiological differences have been suggested as a cause of this gender bias but there is a paucity of data to support either of these viewpoints. Here it is hypothesized that for campylobacteriosis physiological factors play an important role in the higher incidence in males. We demonstrate in the human population (from several countries in three continents) that this bias exists in young children (<1 year) where behavioural differences between genders are likely to be minimal. Further we demonstrate this difference in an animal model where both infection rates and shedding rates of the organism are greater in male mice.

[Analysis of morphometric data and ploidy of nuclear DNA from the bronchial epithelial cells in benign processes and different histological forms of lung cancer].

Morphometric data and the ploidity of bronchial epitheliocytic nuclear DNA were studied in benign processes and different histological forms of lung cancer (LC), by using smears taken from 42 patients at fibrobronchoscopy. There were certain differences in the mean values of the area and content of DNA between basal-cell hyperplasia, squamous-cell metaplasia and dysplasia, small-cell and non-small-cell LC, which may be used in the differential cytological diagnosis in difficult cases.

[Prognostic significance of tumor cell ploidy in advanced ovarian carcinoma].

A micro-imaging retrospective investigation of tumor cell ploidy using exudates smears from 52 patients with serous ovarian adenocarcinoma (stage III-IV) showed survival in those with diploid tumor to be significantly longer (38 months) than in cases of aneuploid malignancies (16 months). Significant differences in survival versus ploidy, stage, residual tumor size, therapy modality and age were established with the aid of univariate analysis (Caplan-Meyer) of 5-year survival. Multivariate step-by-step regressive analysis (Cox) was carried out on the prognostic significance of such factors as residual tumor size (p=0.013), stage (p=0.019) and tumor ploidy (p=0.035). Further study showed ploidy to be a fully independent factor like any other factors of ovarian carcinoma development.

[Cytological diagnosis and prognosis in Ewing's sarcoma in children].

143 cytological studies of the material obtained from 98 children aged from 2 to 18 years with tentative diagnosis of Ewing's sarcoma were made. Histocytological correlations showed 96.2% cases to be of informative value, 87% of them with precise cytological diagnosis of the above sarcoma. The analysis of images specified mean values of square (S) and ploidity (P) of tumor cell nuclei in 21 children with a good (10), and bad (11) outcome of the disease. It was established that if ploidy is higher than expected one (p = 0.0357 S), bad prognosis can be supposed and a good prognosis in the opposite case. In case of good prognosis differentiated tumor cells with large clear nuclei are seen in the smears, and poorly differentiated cells with hyperchromic nuclei are observed in cases with bad prognosis.

[New potential of estrogen and progesterone receptor assay in cytological smears sampled from breast cancer patients]. / Vozmozhnosti opredeleniia retseptorov éstrogenov i progesterona v rake molochnoi zhelezy na tsitologicheskikh mazkakh.

Estrogen (ER) and progesterone (PR) receptors were assayed immunohistochemically in cytological smears and histological samples from 30 breast cancer patients. Since the results reported by the two research centers matched by 73%, it is suggested that running ER and PR determinations on cytological smears in cases of inoperable cancer, preoperative therapy and monitoring may be recommended. Therefore, the 3-4 year old records on ER and PR determinations should be regarded as null and void.

[Correlation of cytologic and DNA ploidy evidence and prognosis in childhood Wilm's tumor]. / Sopostavleniia dannykh tsitologicheskogo issledovaniia i opredeleniia ploidnosti DNK s iskhodom zabolevaniia pri opukholi Vil'msa u detei.

A retrospective evaluation of the clinical features, cytological, biological (DNA) and histological data on 29 children with Wilms' tumor. Two prognosis-related groups were identified: (1) good outcome (17)--all children, aged 4-15, had survived by end of follow-up; (2) bad outcome (12)--all children died within 4 months--4 years. Cytological examination by fine-needle biopsy of smears was carried out prior to preoperative neoadjuvant therapy in all 29 patients; in addition, print smears from resected tumor were taken from 21. Blastemal, stromal, epithelial and anaplastic cells levels were estimated by the semi-quantitative procedure (0, 1+, 2+, 3+). DNA ploidy was determined by image cytometry after destaining slides and re-staining them according to Feulgen. It was shown that favorable outcome could be expected when fine-needle biopsy of print smears identified DNA diploidy and marked drug-related pathomorphosis involving fewer blastemal cells and signs of cell dystrophy and tumor necrosis. When anaplastic and aneuploid cells were detected, matched by the absence of therapeutic pathomorphosis, outcome was poor.