Standardisation and optimisation of radiomic techniques for the identification of robust imaging biomarkers in oncology

Radiomics is a rapidly evolving field within oncology. It explores the extraction of quantitative features from medical scans to aid in diagnosis, prognosis and monitoring of disease. In effect, these features may act as imaging biomarkers. Radiomics is a potential piece of a multifaceted data puzzle, powering precision medicine approaches, where treatment strategies could be tailored more to the individual than relying on a one-size-fits-all strategy. However, there are crucial challenges within the field regarding reproducibility and reliability of many common radiomic features. This thesis explored the hypothesis that varying but valid approaches to engineered feature extraction can cause discrepancy that harms identification and validation of potential radiomic biomarkers. As a research community, we require guidelines, standards and references to see forward progression and to avoid a replication crisis. Through development of radiomics software, results from this work significantly contributed to a large collaborative consensus benchmarking effort to address this standardisation need. This work investigated the effect of implementation choices on compliance to this new standard. Alongside this, the role of interpolation in radiomics became a key focus through the lens of robustness. Optimal feature extraction should avoid redundancy and utilise robust features. Finally, benchmarking methodology and tools were developed in an effort to standardise the application of filters in image processing steps prior to feature extraction. Discrepancies between radiomics software were identified and evaluated using these tools. The uncertainties in developing optimal and robust radiomic imaging biomarkers that result in clinically useful models are discussed

Sensitivity of standardised radiomics algorithms to mask generation across different software platforms

The field of radiomics continues to converge on a standardised approach to image processing and feature extraction. Conventional radiomics requires a segmentation. Certain features can be sensitive to small contour variations. The industry standard for medical image communication stores contours as coordinate points that must be converted to a binary mask before image processing can take place. This study investigates the impact that the process of converting contours to mask can have on radiomic features calculation. To this end we used a popular open dataset for radiomics standardisation and we compared the impact of masks generated by importing the dataset into 4 medical imaging software. We interfaced our previously standardised radiomics platform with these software using their published application programming interface to access image volume, masks and other data needed to calculate features. Additionally, we used super-sampling strategies to systematically evaluate the impact of contour data pre processing methods on radiomic features calculation. Finally, we evaluated the effect that using different mask generation approaches could have on patient clustering in a multi-center radiomics study. The study shows that even when working on the same dataset, mask and feature discrepancy occurs depending on the contour to mask conversion technique implemented in various medical imaging software. We show that this also affects patient clustering and potentially radiomic-based modelling in multi-centre studies where a mix of mask generation software is used. We provide recommendations to negate this issue and facilitate reproducible and reliable radiomics

Rapid detection by hydrops panel of Noonan syndrome with PTPN11 mutation (p.Thr73Ile) and persistent thrombocytopenia

Background: Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. Methods DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. Results: The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). Conclusion: The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia

Rapid detection by hydrops panel of Noonan syndrome with PTPN11 mutation (p.Thr73Ile) and persistent thrombocytopenia

Background: Nonimmune hydrops fetalis (NIHF) is still a challenging diagnosis. The differential diagnosis is extensive and the success of identifying a cause depends on the thoroughness of efforts to establish a diagnosis. For the early diagnosis of NIHF, a virtual gene panel diagnostic tool was developed. The female premature baby in question was delivered via emergency cesarean at 30 1 weeks of gestational age (GA) due to rapidly developing NIHF to a healthy mother. The family history was noncontributory. Methods DNA of the family was extracted and sequenced by the virtual hydrops panel with whole-exome sequencing. Results: The hydrops panel revealed Noonan syndrome (NS) with a germline mutation in PTPN11 c.218C>T (p.Thr73Ile). Conclusion: The diagnosis of our patient was rapidly confirmed by the hydrops panel. The variant of c.218C>T (p.Thr73Ile) has not yet been described in literature relating to NIHF. Only a few case reports of this variant are known. This particular mutation is associated with Noonan syndrome, congenital heart defect and persistent thrombocytopenia. Few reveal juvenile myelomonocytic leukemia

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy

Standardised convolutional filtering for radiomics

The Image Biomarker Standardisation Initiative (IBSI) aims to improve reproducibility of radiomics studies by standardising the computational process of extracting image biomarkers (features) from images. We have previously established reference values for 169 commonly used features, created a standard radiomics image processing scheme, and developed reporting guidelines for radiomic studies. However, several aspects are not standardised. Here we present a preliminary version of a reference manual on the use of convolutional image filters in radiomics. Filters, such as wavelets or Laplacian of Gaussian filters, play an important part in emphasising specific image characteristics such as edges and blobs. Features derived from filter response maps have been found to be poorly reproducible. This reference manual forms the basis of ongoing work on standardising convolutional filters in radiomics, and will be updated as this work progresses.Comment: 62 pages. For additional information see https://theibsi.github.io

The cardiovascular profile score in patients with non-immune hydrops fetalis and cardiac anomalies : a pilot study

The purpose of this paper is to explore whether the cardiovascular profile score (CVPS) correlates with fetal outcome in patients with non-immune hydrops fetalis (NIHF) and cardiac anomalies. In this retrospective study, we included fetuses with NIHF and the suspicion of a cardiac anomaly in prenatal ultrasound. The CVPS was calculated using information obtained by fetal echocardiographic examination. Feto-neonatal mortality (FNM) was defined as intrauterine fetal demise or death in the first 6 months of life. We reviewed 98 patients, who were referred to the Department of Obstetrics and Gynecology of the Johannes Gutenberg University in Mainz with the diagnosis of NIHF between January 2007 and March 2021. By eighteen of them, the suspicion of a cardiac anomaly was raised. After exclusion of six pregnancies (one termination of pregnancy and five because of incomplete data), 12 cases were left for analysis. Mean gestational age at which the CVPS was calculated was 29 + 2 weeks. Two fetuses died in utero. Of the remaining ten hydropic fetuses, three newborns died in the neonatal period, and seven survived after a 6-month surveillance period. Median CVPS of all fetuses was 6 points. Surviving fetuses showed statistically significantly higher CVPS values (median 8 points) than fetuses with FNM (median 5 points, p value = 0.009). Our results point towards a positive association between CVPS and fetal outcome in fetuses with NIHF and cardiac anomalies. The CVPS appears to be a useful marker in the assessment of heart failure in utero

Assessing radiomic feature robustness to interpolation in 18F-FDG PET imaging

Radiomic studies link quantitative imaging features to patient outcomes in an effort to personalise treatment in oncology. To be clinically useful, a radiomic feature must be robust to image processing steps, which has made robustness testing a necessity for many technical aspects of feature extraction. We assessed the stability of radiomic features to interpolation processing and categorised features based on stable, systematic, or unstable responses. Here, 18F-fluorodeoxyglucose (18F-FDG) PET images for 441 oesophageal cancer patients (split: testing = 353, validation = 88) were resampled to 6 isotropic voxel sizes (1.5 mm, 1.8 mm, 2.0 mm, 2.2 mm, 2.5 mm, 2.7 mm) and 141 features were extracted from each volume of interest (VOI). Features were categorised into four groups with two statistical tests. Feature reliability was analysed using an intraclass correlation coefficient (ICC) and patient ranking consistency was assessed using a Spearman’s rank correlation coefficient (ρ). We categorised 93 features robust and 6 limited robustness (stable responses), 34 potentially correctable (systematic responses), and 8 not robust (unstable responses). We developed a correction technique for features with potential systematic variation that used surface fits to link voxel size and percentage change in feature value. Twenty-nine potentially correctable features were re-categorised to robust for the validation dataset, after applying corrections defined by surface fits generated on the testing dataset. Furthermore, we found the choice of interpolation algorithm alone (spline vs trilinear) resulted in large variation in values for a number of features but the response categorisations remained constant. This study attempted to quantify the diverse response of radiomics features commonly found in 18F-FDG PET clinical modelling to isotropic voxel size interpolation

Charakteristika und klinische Manifestation katheterassoziierter Thrombosen bei Frühgeborenen

Hintergrund In der Neonatologie sind peripher eingeführte zentrale Katheter ein häufiger Zugangsweg zur parenteralen Ernährung und Verabreichung von Medikamenten und Flüssigkeit. Die Vorteile stehen den Risiken wie Infektion, Thrombose und Fehllage gegenüber. Fragestellung Welche Charakteristika und klinischen Zeichen weisen auf das Vorliegen einer katheterassoziierten Thrombose hin? Material und Methoden In einer retrospektiven Betrachung aus dem Zeitraum 2010–2016 wurden alle Fälle von katheterassoziierten Thrombosen untersucht. Identifiziert wurden 10 Frühgeborene, deren Indikation zur Katheteranlage, Zugangsweg, Lage der Katheterspitze, Liegedauer, klinische Symptome und Krankheitsverlauf analysiert wurden. Ergebnisse Bei 10 Frühgeborenen mit einem Gestationsalter von 23 + 4 bis 34 + 5 SSW wurden 11 Thromboseereignisse beobachtet. Zehn der 11 Thromboseereignisse betrafen die V. cava inferior nach Katheteranlage an der unteren Extremität. Die Indikation zur Katheteranlage waren parenterale Ernährung und chirurgische Eingriffe. Bei 9 Patienten traten perinatale Komplikationen auf. Bei allen Patienten bestand während der Liegedauer der Katheter der Verdacht auf eine Infektion. Das Auftreten der Thrombose wurde nach 3 bis 27 Tagen sonographisch dokumentiert. In 8 Thromboseereignissen war eine Thrombozytopenie, in 4 Fällen eine Beinschwellung auffällig. Diskussion Das Patientenkollektiv zeigt Gemeinsamkeiten im klinischen Verlauf und bei den Symptomen, welche auf das Vorliegen einer Thrombose deuten. Auffällig ist außerdem, dass die meisten Thromboseereignisse das Stromgebiet der V. cava inferior betrafen.Background In neonatology peripherally inserted central catheters are a frequently used access route for parenteral nutrition and for the administration of drugs and fluids. The advantages are offset by the risks, such as infection, thrombosis and malpositioning. Objective Which characteristics and clinical signs indicate the presence of catheter-associated thrombosis? Material and methods In a retrospective study all cases of catheter-associated thrombosis from 2010 to 2016 were analyzed and 10 premature infants were identified. Data on indications for catheter placement, access route, position of the catheter tip, length of stay, clinical symptoms and course of disease were collected. Results In 10 preterm infants with a gestational age of 23 + 4–34 + 5 weeks 11 thrombotic events were observed. Out of 11 thrombotic events 10 occurred in the inferior vena cava. Indications for catheter placement were parenteral nutrition and surgical interventions. Perinatal complications had occurred in 9 patients. All patients were suspected to have an infection while the catheters were in place. The occurrence of thrombosis was documented after 3–27 days by ultrasound. In 8 thrombotic events thrombocytopenia was conspicuous, in 4 cases leg swelling led to the diagnosis. Discussion In our patients, similarities in the clinical course and in the symptoms indicated the presence of thrombosis. Interestingly, most thrombotic events occurred in the inferior vena cava