Geraldine Rauch

A weighted combined effect measure for the analysis of a composite time-to-first-event endpoint with components of different clinical relevance

Composite endpoints combine several events within a single variable, which increases the number of expected events and is thereby meant to increase the power. However, the interpretation of results can be difficult as the observed effect for the composite does not necessarily reflect the effects for the components, which may be of different magnitude or even point in adverse directions. Moreover, in clinical applications, the event types are often of different clinical relevance, which also complicates the interpretation of the composite effect. The common effect measure for composite endpoints is the all-cause hazard ratio, which gives equal weight to all events irrespective of their type and clinical relevance. Thereby, the all-cause hazard within each group is given by the sum of the cause-specific hazards corresponding to the individual components. A natural extension of the standard all-cause hazard ratio can be defined by a weighted all-cause hazard ratio where the individual hazards for each component are multiplied with predefined relevance weighting factors. For the special case of equal weights across the components, the weighted all-cause hazard ratio then corresponds to the standard all-cause hazard ratio. To identify the cause-specific hazard of the individual components, any parametric survival model might be applied. The new weighted effect measure can be tested for deviations from the null hypothesis by means of a permutation test. In this work, we systematically compare the new weighted approach to the standard all-cause hazard ratio by theoretical considerations, Monte-Carlo simulations, and by means of a real clinical trial example.

Revival of transcatheter PFO closure: A meta-analysis of randomized controlled trials - impact of shunt size and age

Background: Transcatheter foramen ovale closure (TPC) has emerged as a potential treatment option for patients with cryptogenic strokes and persistent foramen ovale (PFO). However, previous randomized controlled trials could hardly demonstrate any benefit compared to medical treatment (Med‐Tx). Recently new data have become available which may change current practice of transcatheter PFO closure. Methods: A systematic review and meta‐analysis comparing TPC and Med‐Tx based on all available multicentric randomized controlled trials was performed. The primary outcome of interest was the recurrence of stroke in both groups. Results: Five studies met the inclusion criteria with 1829 patients in the TPC and 1622 in the Med‐Tx group. The median follow‐up was 4 years. In the intention‐to‐treat analysis we found a statistically significant relative risk reduction in recurrence of strokes in the TPC group compared to the Med‐Tx group (pooled hazard ratio (HR): 0.32; 95% CI: 0.13–0.8; P = .018). Excluding one study due to potential publication bias resulted in a pooled HR of 0.48 (95% CI: 0.25–0.91, P = .024). Patients younger than 45 years of age (pooled HR: 0.35; 95% CI: 0.16–0.75; P = .007) and those with moderate to severe shunt (pooled HR: 0.28; 95% CI: 0.14–0.55; P < .001) were more likely to benefit from closure. Conclusion: According to our meta‐analysis TPC plus antiplatelets was superior in terms of stroke prevention when compared to Med‐Tx. Furthermore, patients with moderate to severe shunts and those younger than 45 years of age were found to benefit most from TPC.

Development and psychometric validation of a shorter version of the Breast Cancer Treatment Outcome Scale (BCTOS-12)

OBJECTIVESnAesthetic and functional outcomes after oncoplastic breast-conserving surgery (BCS) are directly related to the patients quality of life (QoL). The Breast Cancer Treatment Outcome Scale (BCTOS) is a validated but burdensome questionnaire for the assessment of these outcomes. The aim of the study was to strengthen and focus the BCTOS instrument by reducing the number of items and subscales without loss of information and validity.nnnMETHODSnThis study used a dataset of 871 patients with stage 0 - III breast cancer, from a prospective cohort study, who underwent BCS. We investigated correlations and other criteria of homogeneity of the BCTOS items to identify redundancies. An exploratory factor analysis was used to remodel the item-factor structure. Correlation and linear regression analysis with validated QoL subscales assessed the convergent and discriminant validity of the modified BCTOS structure.nnnRESULTSnThe factor analysis revealed two distinct subscales for aesthetic and functional outcomes. It was possible to reduce the 22 items of the original BCTOS to 12 items, thus the BCTOS-12. The two new scales had very good internal consistency: Cronbachs αxa0=xa00.86 for the new Aesthetic Status subscale and αxa0=xa00.81 for the new Functional Status subscale. Bootstrapping confirmed the item-factor structure for all 10,000 samples, remarkably.nnnCONCLUSIONnThe modified BCTOS questionnaire with only 12 items (BCTOS-12) is shorter, easier to interpret, and shows good validity.

What makes a biostatistician

Biostatisticians play an important role in medical research. They are co-responsible for an appropriate and efficient study design, they are involved in monitoring the study conduct, they plan and perform the data analysis, and they are involved in interpreting and publishing the results. However, how are the biostatisticians prepared for their tasks and responsibilities? Graduate programs in biostatistics are being offered, but some practicing biostatisticians completed their studies in a mathematical or epidemiological program, or obtained their degree in subject-specific fields (such as medicine or biology). Therefore, the expertise and the competencies can vary widely between the individual biostatisticians, also depending on the application field. In this article, focusing on European and US practices, we discuss the required professional expertise for the main areas of applications in the medical field as well as the necessary soft skill competencies of a biostatistician.

Study on sacroiliac joint diagnostics

BackgroundAs there is currently no gold standard for the diagnosis of SIJ dysfunction, axa0broad variety of tests exist to clinically identify pelvic girdle pain caused by reversible SIJ dysfunction. Some of the pain provocation tests have already been evaluated. However, the tests used by the majority of German physicians competent in manual medicine (MM) have not yet been evaluated. Therefore, such an evaluation is necessary.ObjectiveThe aims of the study were to evaluate the reliability of functional and pain provocation tests used in SIJ diagnostics, and to propose axa0useful set of reliable tests.MethodsTwo raters investigated 161xa0subjects (81xa0symptomatic with low back pain, 80xa0asymptomatic controls) in axa0blinded setting, each with axa0set of three functional and six pain provocation tests. Three of the pain provocation tests had already been evaluated and these were used for comparison with the non-evaluated tests.ResultsThe Cohen’s kappa coefficients of the newly evaluated tests were better (κu202f=u20090.76–1.00) than those of the previously evaluated tests (κu202f=u20090.65–0.89). The functional tests had axa0lower κ‑coefficient and an overly wide confidence interval (CI), and were thus evaluated as being not reliable and only suitable as screening tests.ConclusionsThe pain provocation tests, which use palpable irritation deep in the gluteal muscles with provocation in two planes, are at least as reliable as the already evaluated tests. We recommend adding SIJ irritation point diagnostics to the set of “3xa0out of 5xa0positive pain provocation tests” for safe diagnosis of SIJ dysfunction.ZusammenfassungHintergrundDa es bisher keinen Goldstandard zur Diagnostik einer Funktionsstörung des Sakroiliakalgelenks (SIG) gibt, existiert ein großes Angebot an Tests, um klinisch eine reversible SIG-Dysfunktion als Ursache von Beckengürtelschmerzen zu identifizieren. Einige Schmerzprovokationstest wurden bereits evaluiert. Eine Prüfung der Tests, die von der Mehrheit der deutschen Manualmediziner genutzt werden, ist jedoch noch nicht erfolgt.Ziel der StudieZiel waren die Evaluation der Reliabilität von Funktions- und Schmerzprovokationstests, die für die SIG-Diagnostik verwendet werden, und der Vorschlag eines zuverlässigen Testsets.MethodikZwei Untersucher prüften verblindet 161xa0Probanden (81xa0symptomatisch mit Kreuzschmerzen, 80xa0asymptomatisch) mit jeweils 3xa0Funktions- und 6xa0Schmerzprovokationstests. Bereits evaluiert sind 3xa0der Schmerzprovokationstest; sie wurden mit den noch nicht evaluierten verglichen.ErgebnisseDie Ergebnisse der Cohens-Kappa-Koeffizienten der neu evaluierten Test waren besser (κu202f=u20090,76–1,00) als die der bereits früher evaluierten (κu202f=u20090,65–0,89). Die Ergebnisse für Funktionstests zeigten niedrigere κ‑Koeffizienten und zu breite Konfidenzintervalle; daher sollten diese allenfalls als Screeningtests verwendet werden.SchlussfolgerungenDie Provokationsschmerztests, die die Irritation der tiefen Glutealmuskulatur mit einer Provokation in 2xa0Dimensionen verwenden, sind mindestens so zuverlässig wie die bereits evaluierten Vergleichstests. Wir empfehlen daher, die Irritationspunktdiagnostik in das Testset „3xa0aus 5xa0Provokationstests positiv“ aufzunehmen, um eine SIG-Dysfunktion sicher zu diagnostizieren.

Hepatitis E seroprevalence in the Americas: A systematic review and meta-analysis

While hepatitis E virus infections are a relevant topic in Europe, knowledge about epidemiology of hepatitis E virus infections in the USA and Latin America is still limited. Aim of this study was to estimate anti‐hepatitis E virus IgG seroprevalence in the Americas and to assess whether low socioeconomic status is associated with hepatitis E virus exposure.

Initial results of the FUSION-X-US prototype combining 3D automated breast ultrasound and digital breast tomosynthesis

PurposeTo determine the feasibility of a prototype device combining 3D-automated breast ultrasound (ABVS) and digital breast tomosynthesis in a single device to detect and characterize breast lesions.MethodsIn this prospective feasibility study, the FUSION-X-US prototype was used to perform digital breast tomosynthesis and ABVS in 23 patients with an indication for tomosynthesis based on current guidelines after clinical examination and standard imaging. The ABVS and tomosynthesis images of the prototype were interpreted separately by two blinded experts. The study compares the detection and BI-RADS® scores of breast lesions using only the tomosynthesis and ABVS data from the FUSION-X-US prototype to the results of the complete diagnostic workup.ResultsImage acquisition and processing by the prototype was fast and accurate, with some limitations in ultrasound coverage and image quality. In the diagnostic workup, 29 solid lesions (23 benign, including three cases with microcalcifications, and six malignant lesions) were identified. Using the prototype, all malignant lesions were detected and classified as malignant or suspicious by both investigators.ConclusionSolid breast lesions can be localized accurately and fast by the Fusion-X-US system. Technical improvements of the ultrasound image quality and ultrasound coverage are needed to further study this new device.Key PointsThe prototype combines tomosynthesis and automated 3D-ultrasound (ABVS) in one device.It allows accurate detection of malignant lesions, directly correlating tomosynthesis and ABVS data.The diagnostic evaluation of the prototype-acquired data was interpreter-independent.The prototype provides a time-efficient and technically reliable diagnostic procedure.The combination of tomosynthesis and ABVS is a promising diagnostic approach.

A systematic comparison of recurrent event models for application to composite endpoints

BackgroundMany clinical trials focus on the comparison of the treatment effect between two or more groups concerning a rarely occurring event. In this situation, showing a relevant effect with an acceptable power requires the observation of a large number of patients over a long period of time. For feasibility issues, it is therefore often considered to include several event types of interest, non-fatal or fatal, and to combine them within a composite endpoint. Commonly, a composite endpoint is analyzed with standard survival analysis techniques by assessing the time to the first occurring event. This approach neglects that an individual may experience more than one event which leads to a loss of information. As an alternative, composite endpoints could be analyzed by models for recurrent events. There exists a number of such models, e.g. regression models based on count data or Cox-based models such as the approaches of Andersen and Gill, Prentice, Williams and Peterson or, Wei, Lin and Weissfeld. Although some of the methods were already compared within the literature there exists no systematic investigation for the special requirements regarding composite endpoints.MethodsWithin this work a simulation-based comparison of recurrent event models applied to composite endpoints is provided for different realistic clinical trial scenarios.ResultsWe demonstrate that the Andersen-Gill model and the Prentice- Williams-Petersen models show similar results under various data scenarios whereas the Wei-Lin-Weissfeld model delivers effect estimators which can considerably deviate under commonly met data scenarios.ConclusionBased on the conducted simulation study, this paper helps to understand the pros and cons of the investigated methods in the context of composite endpoints and provides therefore recommendations for an adequate statistical analysis strategy and a meaningful interpretation of results.

RESPONDER – diagnosis of pathological complete response by vacuum-assisted biopsy after neoadjuvant chemotherapy in breast Cancer - a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial

BackgroundNeoadjuvant chemotherapy (NACT) is a standard approach of the multidisciplinary treatment of breast cancer. Depending on the biological subtype a pathological complete response in the breast (bpCR) can be achieved in up to 60% of the patients. However, only limited accuracy can be reached when using imaging for prediction of bpCR prior to surgery. Due to this diagnostic uncertainty, surgery after NACT is considered to be obligatory for all patients in order to either completely remove residual disease or to diagnose a bpCR histologically. The purpose of this trial is to evaluate the accuracy of a vacuum-assisted biopsy (VAB) to diagnose a bpCR after NACT prior to surgery.MethodsThis study is a multicenter, confirmative, one-armed, intra-individually-controlled, open, diagnostic trial. The study will take place at 21 trial sites in Germany. Six hundred female patients with breast cancer after completed NACT showing at least a partial response to NACT treatment will be enrolled. A vacuum-assisted biopsy (VAB) guided either by ultrasound or mammography will be performed followed by histopathological evaluation of the VAB specimen before standard, guideline-adherent breast surgery. The study is designed to prove that the false negative rate of the VAB is below 10%.DiscussionAs a bpCR is becoming a more frequent result after NACT, the question arises whether breast surgery is therapeutically necessary in such cases. To study this subject further, it will be crucial to develop a reliable test to diagnose a bpCR without surgery.During the study we anticipate possible problems in patient recruitment as the VAB intervention does not provide participating patients with any personal benefit. Hence, a proficient informed consent discussion with the patient and a detailed explanation of the study aim will be crucial for patient recruitment. Another critical issue is the histopathological VAB evaluation of a non-tumorous specimen as this may have been taken either from the former tumor region (bpCR) or outside of the (former) tumor region (non-representative VAB, sampling error).Trial registrationThe trial has been registered at clinicaltrials.gov with the identifier NCT02948764 on October 28, 2016 and at the German Clinical Trials Register (DRKS00011761) on February 20, 2017. The date of enrolment of the first participant to the trial was on March 8, 2017.