Der IBD-Control-Fragebogen: Deutsche Übertragung und Validierung des standardisierten Fragebogens zur Messung des Outcomes aus Patientensicht bei chronisch entzündlichen Darmerkrankungen

Hintergrund Auf dem Weg zu einer wertebasierten und patientenzentrierten medizinischen Versorgung rückt das subjektiv vom Patienten empfundene Ergebnis einer Behandlung zunehmend in den Fokus. Als Messinstrument dienen dabei Patient-reported Outcome Measures (PROMs). Bei chronisch entzündlichen Darmerkrankungen hat sich der englischsprachig validierte Fragebogen IBD-Control zur Messung des Behandlungserfolgs aus Patientensicht etabliert. Da dieser bisher nicht auf Deutsch vorliegt, machte sein Einsatz in der deutschsprachigen Schweiz im Vorfeld eine Übersetzung sowie Validierung notwendig. Methoden Die englischsprachige Originalversion des IBD-Control-Fragebogens wurde mittels „forward-backward translation“ ins Deutsche übertragen und anschließend an 154 Patienten mit Morbus Crohn oder Colitis ulcerosa validiert. Resultat Die Übersetzung des IBD-Control erfolgte durch eine multidisziplinäre Expertengruppe sowie Fachübersetzer. Der IBD-Control-D zeigte eine große Akzeptanz. Eine starke Korrelation zwischen dem IBD-Control-8-Subscore mit der visuellen Analogskala des IBD-Control-D (r=0,632) zeigt die Validität des Instruments. Die Konstruktvalidität zeigt sich in der starken Korrelation zwischen der Krankheitsaktivität der letzten 6 Monate und dem IBD-Control-8-Subscore (r=0,640) sowie dem IBD-Control-VAS-Score (r=0,622) sowie zwischen dem IBD-Control-8-Subscore und dem Harvey Bradshaw Index (r=–0,620) und dem partiellen Mayo Score (r=–0,679) wie auch zwischen dem IBD-Control-VAS-Score und dem Harvey Bradshaw Index (r=–0,484) sowie dem Mayo Score (r=–0,435). Die interne Konsistenz ist gegeben (Cronbachs α = 0,840). Schlussfolgerung Mit der hier vorgestellten deutschen Version des IBD-Control, dem IBD-Control-D, liegt nun auch im deutschsprachigen Raum ein valides, benutzerfreundliches und geeignetes Instrument vor, um das subjektive Krankheitsempfinden und das Behandlungsoutcome im Kontext chronisch entzündlicher Darmerkrankungen zu erfassen. = Background Subjectively perceived results of treatment will be in the center of defining treatment success on the way to value-based and patient-centered health care. Patient-reported outcome measures (PROMs) serve as an instrument to measure treatment success. In inflammatory bowel disease (IBD), measuring treatment success from a patient’s point of view is performed with the validated IBD-Control questionnaire. Because the IBD-Control questionnaire has not been published in German yet, the translation and validation of the IBD-Control in the German-speaking part of Switzerland was necessary before use. Methods We have translated the English original version of the IBD-Control questionnaire into German in a state-of-the-art procedure of „forward-backward translation” and validated the translated IBD-Control questionnaire with 154 patients with Crohn’s disease or with ulcerative colitis. Results Professional health care and translation experts have contributed to the translation of the IBD-Control into German. The IBD-Control-D is an accepted questionnaire. Spearmans Rho showed high consistency between the IBD-Control-8-Subscore and the IBD-Control-VAS-Score (r=0.632). The disease activity in the past 6 months highly correlated with the IBD-8 subscore (r=0.640) as well as with the IBD-Control-VAS-Score (r=0.622). The IBD-Control-8-Subscore highly correlated with the Harvey Bradshaw Index (r=–0.620) and the partial Mayo Score (r=–0.679), as well as the IBD-Control-VAS-Score with the Harvey Bradshaw Index (r=–0.484) and the Mayo Score (r=–0.435), showing sufficient construct validity. The result is the German version of the IBD-Control, the IBD-Control-D, published here. Conclusion The original English version is a valid instrument, and its use has proven to be a suitable instrument in German-speaking areas to make the subjective feeling of illness and treatment outcome measurable

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles

Abstract Background Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. Methods While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. Results Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. Conclusions Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology

UBTF tandem duplications are rare but recurrent alterations in adult AML and associated with younger age, myelodysplasia, and inferior outcome

Abstract Tandem-duplication mutations of the UBTF gene (UBTF-TDs) coding for the upstream binding transcription factor have recently been described in pediatric patients with acute myeloid leukemia (AML) and were found to be associated with particular genetics (trisomy 8 (+8), FLT3-internal tandem duplications (FLT3-ITD), WT1-mutations) and inferior outcome. Due to limited knowledge on UBTF-TDs in adult AML, we screened 4247 newly diagnosed adult AML and higher-risk myelodysplastic syndrome (MDS) patients using high-resolution fragment analysis. UBTF-TDs were overall rare (n = 52/4247; 1.2%), but significantly enriched in younger patients (median age 41 years) and associated with MDS-related morphology as well as significantly lower hemoglobin and platelet levels. Patients with UBTF-TDs had significantly higher rates of +8 (34% vs. 9%), WT1 (52% vs. 7%) and FLT3-ITD (50% vs. 20.8%) co-mutations, whereas UBTF-TDs were mutually exclusive with several class-defining lesions such as mutant NPM1, in-frame CEBPA bZIP mutations as well as t(8;21). Based on the high-variant allele frequency found and the fact that all relapsed patients analyzed (n = 5) retained the UBTF-TD mutation, UBTF-TDs represent early clonal events and are stable over the disease course. In univariate analysis, UBTF-TDs did not represent a significant factor for overall or relapse-free survival in the entire cohort. However, in patients under 50 years of age, who represent the majority of UBTF-mutant patients, UBTF-TDs were an independent prognostic factor for inferior event-free (EFS), relapse-free (RFS) and overall survival (OS), which was confirmed by multivariable analyses including established risk factors such as age and ELN2022 genetic risk groups (EFS [HR: 2.20; 95% CI 1.52–3.17, p < 0.001], RFS [HR: 1.59; 95% CI 1.02–2.46, p = 0.039] and OS [HR: 1.64; 95% CI 1.08–2.49, p = 0.020]). In summary, UBTF-TDs appear to represent a novel class-defining lesion not only in pediatric AML but also younger adults and are associated with myelodysplasia and inferior outcome in these patients

CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation