Predicting Clinical Events by Combining Static and Dynamic Information Using Recurrent Neural Networks

In clinical data sets we often find static information (e.g. patient gender, blood type, etc.) combined with sequences of data that are recorded during multiple hospital visits (e.g. medications prescribed, tests performed, etc.). Recurrent Neural Networks (RNNs) have proven to be very successful for modelling sequences of data in many areas of Machine Learning. In this work we present an approach based on RNNs, specifically designed for the clinical domain, that combines static and dynamic information in order to predict future events. We work with a database collected in the Charit\'{e} Hospital in Berlin that contains complete information concerning patients that underwent a kidney transplantation. After the transplantation three main endpoints can occur: rejection of the kidney, loss of the kidney and death of the patient. Our goal is to predict, based on information recorded in the Electronic Health Record of each patient, whether any of those endpoints will occur within the next six or twelve months after each visit to the clinic. We compared different types of RNNs that we developed for this work, with a model based on a Feedforward Neural Network and a Logistic Regression model. We found that the RNN that we developed based on Gated Recurrent Units provides the best performance for this task. We also used the same models for a second task, i.e., next event prediction, and found that here the model based on a Feedforward Neural Network outperformed the other models. Our hypothesis is that long-term dependencies are not as relevant in this task

Einflussfaktoren auf das Outcome nach Nierentransplantation

Diese Habilitationsarbeit entwickelt Konzepte zur Erweiterung des Donor-Pools und zur Verbesserung des Langzeit-Transplantatüberlebens. Eine Kompensation der sinkenden Zahl von post mortem Spenden kann nicht nur durch eine Steigerung der Lebendspenden, sondern auch durch eine kluge Nutzung von marginalen Spendernieren, durch eine optimale Allokation mit dem besten immunologischen und funktionellem Match und durch eine individuelle Transplantationsnachsorge insbesondere der Risikopatienten erreicht werden

Lotne związki organiczne (VOCs) w wydychanym powietrzu pacjentek z rakiem piersi w warunkach klinicznych

Background: Carcinogenic products in the exhaled breath of cancer patients are of growing medical interest as they can serve as noninvasive disease markers. Breath analysis can be used as an alternative or complementary diagnostic tool in breast cancer patients who have a different pattern of chemical composition in their breath. This study aims to verify the existence of specific volatile organic compounds (VOCs) in the breath of breast cancer patients. Methods: This prospective study included ten patients suffering from breast cancer and ten healthy pair-matched women. Breath samples of each member of the two respective groups were taken and scanned by gas chromatography/mass spectometry for the presence of volatile organic compounds such as alkanes, ketones, halogenated hydrocarbon, aldehydes, and esters. Results: The spectrum of VOCs differed significantly within the two groups. Five specific VOCs could be identified as typical discriminatory markers in the breath samples. Four VOCs were elevated in the healthy controls, one specific VOC was found to be elevated in women affected by breast cancer. Conclusions: This pilot study revealed a specific VOC pattern using gas chromatography in the breath of breast cancer patients. Five specific breast cancer-VOCs were identified. At relatively low cost the identification of VOCs may be used to detect breast cancer.Streszczenie Cel: Coraz bardziej rośnie zainteresowanie medycyny produktami karcinogenezy w wydychanym powietrzu pacjentów chorych na raka jako możliwych nieinwazyjnych markerów choroby. Analiza powietrza wydychanego może być wykorzystana jako alternatywne lub pomocnicze narzędzie w raku piersi u pacjentek, które mają odmienny skład chemiczny oddechu. Celem tego badania była weryfikacja obecności lotnych związków organicznych (VOCs) w wydychanym powietrzu pacjentek z rakiem piersi. Metoda: Przeprowadzono prospektywne badanie, do którego włączono 10 pacjentek cierpiących na raka piersi i 10 zdrowych dobranych do pary kobiet. Pobrano próbki wydychanego powietrza od każdego uczestnika badania i poddano gazowej chromatografii/spektrometrii masowej na obecność następujących lotnych związków organicznych: alkanów, ketonów, halogenowanych wodorowęglanów, aldehydów i estrów. Wyniki: Spektrum VOCs różniło się istotnie w obu grupach. Pięć specyficznych VOCs zdefiniowano jako typowe markery w wydychanych próbkach. Cztery VOCs były podwyższone w grupie kontrolnej, natomiast jeden specyficzny VOC był podwyższony w grupie kobiet z rakiem piersi. Wnioski: To badanie pilotażowe, przy pomocy gazowej chromatografii, wykazało specyficzny wzór VOC w wydychanym powietrzu u pacjentek chorych na raka piersi. Zidentyfikowano pięć specyficznych dla raka piersi VOCs. Przy relatywnie niskich kosztach identyfikacja VOCs może być wykorzystana do wykrywania raka piersi

De-novo malignancies after kidney transplantation: A long-term observational study

Background: De-novo malignancies after kidney transplantation represent one major cause for mortality after transplantation. However, most of the studies are limited due to small sample size, short follow-up or lack of information about cancer specific mortality. Methods: This long-term retrospective analysis included all adult patients with complete follow-up that underwent kidney transplantation between 1995 and 2016 at our centre. All patients with diagnosis of malignancy excluding non-melanoma skin cancer (NMSC) were identified and a matched control group was assigned to the kidney transplant recipients with post-transplant malignancies. Results: 1417 patients matched the inclusion criteria. 179 malignancies posttransplant were diagnosed in 154 patients (n = 21 with two, n = 2 patients with three different malignancies). Mean age at cancer diagnosis was 60.3±13.3 years. Overall incidence of de-novo malignancies except NMSC was 1% per year posttransplant. Renal cell carcinoma was the most common entity (n = 49, incidence 4.20 per 1000 patient years; cancer specific mortality 12%), followed by cancer of the gastro-intestinal tract (n = 30, 2.57; 50%), urinary system (n = 24, 2.06; 13%), respiratory system (n = 18, 1.54; 89%), female reproductive system (n = 15, 1.29; 13%), posttransplant lymphoproliferative disorders and haematological tumours (n = 14, 1.20; 21%), cancers of unknown primary (n = 7, 0.60 100%) and others (n = 22, 1.89; 27%). Male sex, re-transplantation and time on dialysis were associated with de-novo malignancies after transplantation. Conclusion: De-novo malignancies continue to be a serious problem after kidney transplantation. To improve long-term outcome after Kidney transplantation, prevention and cancer screening should be more tailored and intensified

The underestimated burden of monogenic kidney disease in adults waitlisted for kidney transplantation

Purpose: Chronic kidney disease (CKD) is a major health-care burden. Increasing evidence suggests that a considerable proportion of patients are affected by a monogenic kidney disorder. Methods: In this study, the kidney transplantation waiting list at the Charité was screened for patients with undetermined cause of CKD. By next-generation sequencing (NGS) we targeted all 600 genes described and associated with kidney disease or allied disorders. Results: In total, 635 patients were investigated. Of these, 245 individuals had a known cause of CKD (38.5%) of which 119 had a proven genetic disease (e.g., ADPKD, Alport). The other 340 patients (53.5%) were classified as undetermined diagnosis, of whom 87 had kidney failure (KF) onset <40 years. To this latter group genetic testing was offered as well as to those patients (n = 29) with focal segmental glomerulosclerosis (FSGS) and all individuals (n = 21) suspicious for thrombotic microangiopathy (TMA) in kidney biopsy. We detected diagnostic variants in 26 of 126 patients (20.6%) of which 14 of 126 (11.1%) were pathogenic or likely pathogenic. In another 12 of 126 (9.5%) patients, variants of unknown significance (VUS) were detected. Conclusion: Our study demonstrates the diagnostic value of comprehensive genetic testing among patients with undetermined CKD

Function of the molecular chaperon Hsp70 and the J proteins

Hitzeschockproteine der Hsp70-Familie interagieren in allen bekannten Systemen mit ihren Partnern, den J-Proteinen. Mit einem quantitativer Echtzeitassay (SPR-Assay) zum Nachweis der Interaktionen von Hsp70-Proteinen mit ihren J-Partnern und Substraten wurde gezeigt, dass Hsp70-Moleküle durch die J-Domäne katalytisch aktiviert werden können, unspezifisch Peptide zu binden, die sich in unmittelbarer Nähe der J-Domäne befinden. Der Mechanismus der Aktivierung ist durch die Stimulation der ATP-Hydrolyse erklärbar. Hsp70 bindet nach Aktivierung durch die J-Domäne ein breites Spektrum von Substraten, die es alleine nicht bindet.Heat shock proteins of the Hsp70 family function together with J proteins. Using a quantitative real-time assay, we demonstrate that the J domain catalytically activates Hsp70 molecules to bind peptides in its vicinity. The mechanism can be explained by stimulation of ATP hydrolysis. After activation Hsp70 binds a wide range of peptide substrates

Improved Left Ventricular Structure and Function After Successful Kidney Transplantation

Background/Aims: Cardiac changes observed in chronic kidney disease patients are of multifactorial origin including chronic uremia, hemodynamics or inflammation. Restoration of renal function by kidney transplantation (KTX) may reverse cardiac changes. Novel echocardiographic methods such as speckle tracking echocardiography (STE) allow early and sensitive detection of subtle changes of cardiac parameters. We evaluated changes of cardiac structure and function after KTX by advanced echocardiographic modalities. Methods: Thirty-one KTX recipients (female n=11) were evaluated by medical examination, laboratory testing and echocardiography before and after KTX (median follow-up 19 months). Left ventricular (LV) and right ventricular (RV) diameters and function were assessed by echocardiographic standard parameters. Longitudinal 2D strain of the LV (GLPS) and left atrium (LA) was determined by 2D STE. Results: After KTX, median serum creatinine level was 1.3 mg/dl (IQR, 1.2-1.5). Systolic blood pressure decreased significantly after KTX. Echocardiography showed a significant reduction in LV end-diastolic septal and posterior wall thickness and LV mass index after KTX, which was accompanied by an improvement of GLPS. There were no relevant changes in parameters of LA (reservoir, conduit or contractile) function, LV diastolic or RV function after KTX. Conclusion: LV hypertrophy reversed after successful KTX and was accompanied by an improvement in longitudinal LV function as assessed by STE. Diastolic function and STE-derived LA function parameters did not change significantly after KTX

Analysis of Risk Factors and Long-Term Outcomes in Kidney Transplant Patients with Identified Lymphoceles

The collection of lymphatic fluids (lymphoceles) is a frequent adverse event following renal transplantation. A variety of surgical and medical factors has been linked to this entity, but reliable data on risk factors and long-term outcomes are lacking. This retrospective single-center study included 867 adult transplant recipients who received a kidney transplantation from 2006 to 2015. We evaluated for patient and graft survival, rejection episodes, or detectable donor-specific antibodies (dnDSA) in patients with identified lymphoceles in comparison to controls. We identified 305/867 (35.2%) patients with lymphocele formation, of whom 72/867 (8.3%) needed intervention. Multivariate analysis identified rejection episode as an independent risk factor (OR 1.61, CI 95% 1.17-2.21, p = 0.003) for lymphocele formation, while delayed graft function was independently associated with symptomatic lymphoceles (OR 1.9, CI 95% 1.16-3.12, p = 0.011). Interestingly, there was no difference in detectable dnDSA between groups with a similar graft and patient survival in all groups after 10 years. Lymphoceles frequently occur after transplantation and were found to be independently associated with rejection episodes, while symptomatic lymphoceles were associated with delayed graft function in our cohort. As both are inflammatory processes, they might play a causative role in the formation of lymphoceles. However, development or intervention of lymphoceles did not lead to impaired graft survival in the long-term

Preformed donor-specific HLA antibodies in living and deceased donor transplantation: a multicenter study

Background and objectivesThe prognostic value of preformed donor-specific HLA antibodies (DSA), which are only detectable by sensitive methods, remains controversial for kidney transplantation.Design, setting, participants, & measurementsThe outcome of 4233 consecutive kidney transplants performed between 2012 and 2015 in 18 German transplant centers was evaluated. Most centers used a stepwise pretransplant antibody screening with bead array tests and differentiation of positive samples by single antigen assays. Using these screening results, DSA against HLA-A, -B, -C, -DRB1 and -DQB1 were determined. Data on clinical outcome and possible covariates were collected retrospectively.ResultsPretransplant DSA were associated with lower overall graft survival, with a hazard ratio of 2.53 for living donation (95% confidence interval [95% CI], 1.49 to 4.29; P= 3000 MFI resulted in overlapping survival curves. Therefore, separate analyses were performed for 3-month and long-term graft survival. Although DSA = 3000 MFI were only associated with worse long-term transplant survival in deceased donation. In living donation, only strong DSA were associated with reduced graft survival in the first 3 months, but both weak and strong DSA were associated with reduced long-term graft survival. A higher incidence of antibody-mediated rejection within 6 months was only associated with DSA >= 3000 MFI.ConclusionsPreformed DSA were associated with an increased risk for graft loss in kidney transplantation, which was greater in living than in deceased donation. Even weak DSA <3000 MFI were associated with worse graft survival. This association was stronger in living than deceased donation