Do Common Risk Adjustment Methods Do Their Job Well if Center Effects are Correlated With the Center-Specific Mean Values of Patient Characteristics?

BACKGROUND: Direct and indirect standardization are well-established approaches to performing risk adjustment when comparing outcomes between healthcare providers. However, it is an open question whether they work well when there is an association between the center effects and the distributions of the patient characteristics in these centers. OBJECTIVES AND METHODS: We try to shed further light on the impact of such an association. We construct an artificial case study with a single covariate, in which centers can be classified as performing above, on, or below average, and the center effects correlate with center-specific mean values of a patient characteristic, as a consequence of differential quality improvement. Based on this case study, direct standardization and indirect standardization-based on marginal as well as conditional models-are compared with respect to systematic differences between their results. RESULTS: Systematic differences between the methods were observed. All methods produced results that partially reflect differences in mean age across the centers. This may mask the classification as above, on, or below average. The differences could be explained by an inspection of the parameter estimates in the models fitted. CONCLUSIONS: In case of correlations of center effects with center-specific mean values of a covariate, different risk adjustment methods can produce systematically differing results. This suggests the routine use of sensitivity analyses. Center effects in a conditional model need not reflect the position of a center above or below average, questioning its use in defining the truth. Further empirical investigations are necessary to judge the practical relevance of these findings.

Variability in human tooth cementum thickness reflecting functional processes.

OBJECTIVE: The aim of this study was to investigate the thickness of acellular extrinsic fibre cementum (AEFC) at four root positions of anterior and posterior teeth with special focus on functional aspects. Furthermore, the correlations between cementum thickness and chronological age and sex are investigated. BACKGROUND: While numerous studies confirm continuous cementum apposition with age, masticatory forces as well as physiological and orthodontically induced tooth movements also have the potential to affect tooth cementum thickness. MATERIALS AND METHODS: Undecalcified teeth were embedded in resin and transverse-sectioned in the cervical third of the root. Two sections per root were selected, and digital images at four positions were obtained (mesial, distal, oral, and vestibular) using light microscopy. The AEFC thickness of 99 teeth (anterior = 66, posterior = 33, male = 54, female = 45) were measured in both sections. The differences in mean values between root positions and the association of root position variation with tooth type, age, sex, and subject as well as the overall effects of age and sex were analysed using a mixed model. RESULTS: First incisors and canines showed the greatest mean AFEC thickness, in contrast to premolars which had the lowest values. Differences were found across the four root positions, with a pattern varying considerably between anterior and posterior teeth and between maxilla and mandible in the anterior teeth. An interaction between root position and subject pointed to the existence of an individual component in the variation of AEFC thickness across the four root positions. There was an age trend with an almost linear increase in cementum thickness of 1 µm per year. Overall, females tended to exhibit a significantly lesser AEFC thickness compared to males. CONCLUSIONS: Distinct differences in the pattern of thickness values across the four root positions in anterior and posterior teeth support the assumption that the AEFC is strongly affected by functional processes. In addition to sex-specific differences and age-related trends, the root position variation of AEFC thickness varies from individual to individual.

Anchor-based minimal important difference values are often sensitive to the distribution of the change score.

PURPOSE: Anchor-based studies are today the most popular approach to determine a minimal important difference value for an outcome variable. However, a variety of construction methods for such values do exist. This constitutes a challenge to the field. In order to distinguish between more or less adequate construction methods, meaningful minimal requirements can be helpful. For example, minimal important difference values should not reflect the intervention(s) the patients are exposed to in the study used for construction, as they should later allow to compare interventions. This requires that they are not sensitive to the distribution of the change score observed. This study aims at investigating to which degree established construction methods fulfil this minimal requirement. METHODS: Six constructions methods were considered, covering very popular and recently suggested methods. The sensitivity of MID values to the distribution of the change score was investigated in a simulation study for these six construction methods. RESULTS: Five out of six construction methods turned out to yield MID values which are sensitive to the distribution of the change score to a degree that questions their usefulness. Insensitivity can be obtained by using construction methods based solely on an estimate of the conditional distribution of the anchor variable given the change score. CONCLUSION: In future the computation of MID values should be based on construction methods avoiding sensitivity to the distribution of the change score.

Response monitoring in metastatic breast cancer: a comparison of survival times between FDG-PET/CT and CE-CT.

BACKGROUND: We compared overall survival for metastatic breast cancer (MBC) patients monitored with CE-CT, FDG-PET/CT or a combination of them in an observational setting. METHODS: Patients with biopsy-verified (recurrent or de novo) MBC (n = 300) who were treated at Odense university hospital (Denmark) and response monitored with FDG-PET/CT (n = 83), CE-CT (n = 144), or a combination of these (n = 73) were followed until 2019. Survival was compared between the scan groups, and were adjusted for clinico-histopathological variables representing potential confounders in a Cox proportional-hazard regression model. RESULTS: The study groups were mostly comparable regarding baseline characteristics, but liver metastases were reported more frequently in CE-CT group (38.9%) than in FDG-PET/CT group (19.3%) and combined group (24.7%). Median survival was 30.0 months for CE-CT group, 44.3 months for FDG-PET/CT group and 54.0 months for Combined group. Five-year survival rates were significantly higher for FDG-PET/CT group (41.9%) and combined group (43.3%), than for CE-CT group (15.8%). Using the CE-CT group as reference, the hazard ratio was 0.44 (95% CI: 0.29-0.68, P = 0.001) for the FDG-PET/CT group after adjusting for baseline characteristics. FDG-PET/CT detected the first progression 4.7 months earlier than CE-CT, leading to earlier treatment change. CONCLUSIONS: In this single-center, observational study, patients with metastatic breast cancer who were response monitored with FDG-PET/CT alone or in combination with CE-CT had longer overall survival than patients monitored with CE-CT alone. Confirmation of these findings by further, preferably randomised clinical trials is warranted.

Sample size recalculation based on the prevalence in a randomized test-treatment study.

BACKGROUND: Randomized test-treatment studies aim to evaluate the clinical utility of diagnostic tests by providing evidence on their impact on patient health. However, the sample size calculation is affected by several factors involved in the test-treatment pathway, including the prevalence of the disease. Sample size planning is exposed to strong uncertainties in terms of the necessary assumptions, which have to be compensated for accordingly by adjusting prospectively determined study parameters during the course of the study. METHOD: An adaptive design with a blinded sample size recalculation in a randomized test-treatment study based on the prevalence is proposed and evaluated by a simulation study. The results of the adaptive design are compared to those of the fixed design. RESULTS: The adaptive design achieves the desired theoretical power, under the assumption that all other nuisance parameters have been specified correctly, while wrong assumptions regarding the prevalence may lead to an over- or underpowered study in the fixed design. The empirical type I error rate is sufficiently controlled in the adaptive design as well as in the fixed design. CONCLUSION: The consideration of a blinded recalculation of the sample size already during the planning of the study may be advisable in order to increase the possibility of success as well as an enhanced process of the study. However, the application of the method is subject to a number of limitations associated with the study design in terms of feasibility, sample sizes needed to be achieved, and fulfillment of necessary prerequisites.

The methodologies to assess the effectiveness of non-pharmaceutical interventions during COVID-19: a systematic review.

Non-pharmaceutical interventions, such as school closures and stay-at-home orders, have been implemented around the world to control the spread of SARS-CoV-2. Their effectiveness in improving health-related outcomes has been the subject of numerous empirical studies. However, these studies show fairly large variation among methodologies in use, reflecting the absence of an established methodological framework. On the one hand, variation in methodologies may be desirable to assess the robustness of results; on the other hand, a lack of common standards can impede comparability among studies. To establish a comprehensive overview over the methodologies in use, we conducted a systematic review of studies assessing the effectiveness of non-pharmaceutical interventions between January 1, 2020 and January 12, 2021 (n = 248). We identified substantial variation in methodologies with respect to study setting, outcome, intervention, methodological approach, and effectiveness assessment. On this basis, we point to shortcomings of existing studies and make recommendations for the design of future studies.

Focusing on individual morphological fracture characteristics of pelvic ring fractures in elderly patients can support clinical decision making.

INTRODUCTION: Pelvic ring fractures in the elderly are often caused by minor trauma. Treatment of these patients is currently based on fracture classification, clinical course, and ability to mobilize. Our aim was to identify morphological fracture characteristics with potential prognostic relevance and evaluate their association with clinical decision making and outcome, as well as their interobserver reliability. METHODS: Five fracture characteristics were investigated as potential variables: 1. Extent of the dorsal pelvic ring fracture (absent, unilateral, bilateral); 2. Extent of the ventral pelvic ring fracture (absent, unilateral, bilateral); 3. Presence of a horizontal sacral fracture; 4. Ventral dislocation; 5. Ventral comminution. These characteristics were assessed retrospectively in a series of 548 patients. The association of their presence with the decision to perform surgery, failure of conservative treatment and the length of hospital stay (LOS) was determined. Further, the inter-observer reliability for the specific characteristics was calculated and the relation with survival assessed. RESULTS: Four of the five evaluated characteristics showed an association with clinical decision making and patient management. In particular the extent of the dorsal fractures (absent vs. unilateral vs. bilateral) (OR = 7.0; p < 00.1) and the presence of ventral comminution/dislocation (OR = 2.4; p = 0.004) were independent factors for the decision to perform surgery. Both the extent of the dorsal fracture (OR = 1.8; p < 0.001) and the presence of ventral dislocation (OR = 1.7; p = 0.003) were independently associated with a prolonged overall LOS. The inter-observer agreement for the fracture characteristics ranged from moderate to substantial. A relevant association with increased mortality was shown for horizontal sacral and comminuted ventral fractures with hazard ratios (HR) of 1.7 (95% CI: 1.1, 2.5; p = 0.008) and HR = 1.5 (95% CI: 1.0, 2.2; p = 0.048). CONCLUSION: In the elderly, the extent of the dorsal fractures and the presence of ventral comminution/dislocation were associated to the decision to undergo surgery, failure of conservative treatment and length of stay. Survival was related to horizontal sacral fractures and ventrally comminuted fractures. These characteristics thus represent a simplified but highly informative approach for the evaluation of pelvic ring fractures in the elderly. This approach can support clinical decision making, promote patient-centred treatment algorithms and thus improve the outcome of individualized care.

The impact of specific fracture characteristics of low-energy fractures of the pelvis on mortality.

BACKGROUND: Pelvic fractures in older patients are associated with relevant morbidity and mortality. Both might be determined by fracture morphology and/or patient characteristics. The aim of this project is to investigate the prognostic value of specific fracture characteristics with respect to overall survival and to compare it with an established classification system. METHODS: Retrospective analysis of patients ≥ 60 years, treated conservatively for a CT-scan verified, low-energy pelvic ring fracture between August 2006 and December 2018. Survival data was available from patients' charts and cantonal or national registries. The prognostic value of fracture characteristic describing the anterior and posterior involvement of the pelvic ring was investigated. This analysis was repeated after patients were stratified into a high-risk vs a low-risk group according to patient characteristic (age, gender, comorbidities, mobility, living situation). This allowed to assess the impact of the different fracture morphologies on mortality in fit vs. frail senior patients separately. RESULTS: Overall, 428 patients (83.4% female) with a mean age of 83.7 years were included. Two thirds of patients were still living in their home and mobile without walking aid at baseline. In-hospital mortality was 0.7%, overall, one-year mortality 16.9%. An independent and significant association of age, gender and comorbidities to overall survival was found. Further, the occurrence of a horizontal sacral fracture as well as a ventral comminution or dislocation was associated with an increased mortality. The effect of a horizontal sacral fracture was more accentuated in low-risk patients while the ventral fracture components showed a larger effect on survival in high-risk patients. CONCLUSION: Specific fracture characteristics may indicate a higher risk of mortality in conservatively treated patients with a low-energy pelvic ring fracture. Hence, they should be taken into account in future treatment algorithms and decisions on patient management.

Assessing the effect of a regional integrated care model over ten years using quality indicators based on claims data - the basic statistical methodology of the INTEGRAL project.

BACKGROUND: The regional integrated health care model "Healthy Kinzigtal" started in 2006 with the goal of optimizing health care and economic efficiency. The INTEGRAL project aimed at evaluating the effect of this model on the quality of care over the first 10 years. METHODS: This methodological protocol supplements the study protocol and the main publication of the project. Comparing quality indicators based on claims data between the intervention region and 13 structurally similar control regions constitutes the basic scientific approach. Methodological key issues in performing such a comparison are identified and solutions are presented. RESULTS: A key step in the analysis is the assessment of a potential trend in prevalence for a single quality indicator over time in the intervention region compared to the corresponding trends in the control regions. This step has to take into account that there may be a common - not necessarily linear - trend in the indicator over time and that trends can also appear by chance. Conceptual and statistical approaches were developed to handle this key step and to assess in addition the overall evidence for an intervention effect across all indicators. The methodology can be extended in several directions of interest. CONCLUSIONS: We believe that our approach can handle the major statistical challenges: population differences are addressed by standardization; we offer transparency with respect to the derivation of the key figures; global time trends and structural changes do not invalidate the analyses; the regional variation in time trends is taken into account. Overall, the project demanded substantial efforts to ensure adequateness, validity and transparency.

Randomized test-treatment studies with an outlook on adaptive designs.

BACKGROUND: Diagnostic accuracy studies aim to examine the diagnostic accuracy of a new experimental test, but do not address the actual merit of the resulting diagnostic information to a patient in clinical practice. In order to assess the impact of diagnostic information on subsequent treatment strategies regarding patient-relevant outcomes, randomized test-treatment studies were introduced. Various designs for randomized test-treatment studies, including an evaluation of biomarkers as part of randomized biomarker-guided treatment studies, are suggested in the literature, but the nomenclature is not consistent. METHODS: The aim was to provide a clear description of the different study designs within a pre-specified framework, considering their underlying assumptions, advantages as well as limitations and derivation of effect sizes required for sample size calculations. Furthermore, an outlook on adaptive designs within randomized test-treatment studies is given. RESULTS: The need to integrate adaptive design procedures in randomized test-treatment studies is apparent. The derivation of effect sizes induces that sample size calculation will always be based on rather vague assumptions resulting in over- or underpowered study results. Therefore, it might be advantageous to conduct a sample size re-estimation based on a nuisance parameter during the ongoing trial. CONCLUSIONS: Due to their increased complexity, compared to common treatment trials, the implementation of randomized test-treatment studies poses practical challenges including a huge uncertainty regarding study parameters like the expected outcome in specific subgroups or disease prevalence which might affect the sample size calculation. Since research on adaptive designs within randomized test-treatment studies is limited so far, further research is recommended.

Abductor Muscle Strength Deficit in Patients After Total Hip Arthroplasty: A Systematic Review and Meta-Analysis.

BACKGROUND: The aims of this study were to assess and quantify hip abductor muscle strength deficits after total hip arthroplasty (THA) and to determine associations with external factors. METHODS: Studies reporting on hip abductor muscle strength before and/or after THA performed for osteoarthritis or atraumatic osteonecrosis of the hip were considered for inclusion. Data sources were Embase, Medline, and the Cochrane Central Register of Controlled Trials. Muscle strength on the affected side was compared with the healthy contralateral side or with control subjects. Study quality was assessed using a modified Newcastle-Ottawa Scale. RESULTS: Nineteen studies reporting on 875 subjects met the inclusion criteria. Patients scheduled for THA had a mean strength deficit of 18.6% (95% confidence interval (CI) [-33.9, -3.2%]) compared with control subjects. Abductor muscle strength then increased by 20.2% (CI [5.6, 34.8%]) at 4-6 months, 29.6% (CI [4.7, 54.4%]) at 9-12 months, and 49.8% (CI [-31.0, 130.6%]) at 18-24 months postoperatively compared with preoperative values. For unilateral THA, the mean torque ratio was 86.3% (CI [75.4, 97.2%]) and 93.4% (CI [75.1, 111.6%]) before and >24 months after THA, respectively. Study quality was low to moderate. CONCLUSION: Hip abductor muscle strength deficits may gradually improve during 24 months after THA possibly without complete recovery. Cautious interpretation of these findings is warranted because high-quality evidence is largely missing.

Influence of 18F-FDG PET/CT on clinical management and outcome in patients with advanced melanoma not primarily selected for surgery based on a linked evidence approach.

PURPOSE: To evaluate the clinical benefit of positron emission tomography (PET)/computed tomography (CT) in patients with advanced melanoma, primarily not selected for surgery based on management changes and survival data using the linked evidence approach (LEA). METHODS: A total of 201 18F-FDG PET/CT examinations (n = 33, stage III and n = 168, stage IV) in 119 melanoma patients, primarily not scheduled for surgery, were analysed regarding their impact on clinical management. Patients were selected from a prospective oncological PET/CT registry. The three PET/CT indication groups included unclear lesions in conventional imaging (n = 8), routine follow-up after multiple surgeries (n = 115) and therapy response evaluation of systemic therapy (n = 78). PET/CT-induced management changes were categorized either as major (change from follow-up to surgical or systemic treatment or vice versa, change from surgery to systemic therapy or vice versa) or minor (modifications in systemic therapy). The expected benefit of changes was determined via the linked evidence approach (LEA) connecting registry data, outcome data including overall survival and evidence of diagnostic accuracy of PET/CT based on existing literature. RESULTS: Related to the total study cohort, a change of management after PET/CT was observed in 48% of scans, including 10% minor and 38% major changes. Major changes involved a shift either from follow-up (33/201) or therapy pause (7/201) to systemic therapy, to surgical or other local therapy (26/201) and BSC (2/201). Nine out of 201 cases resulted in treatment pause of systemic therapy. We could confirm the prognostic value of PET/CT-based management by observing a 5-year survival rate more than roughly doubled in patients followed up after tumour exclusion or under local therapy compared with patients under systemic therapy. We could argue for a patient benefit from PET/CT-based management changes using results on accuracy and therapeutic effects from the literature. CONCLUSION: The use of PET/CT in advanced melanoma patients, primarily not considered for surgery, resulted in frequent changes of management associated with a relevant expected clinical benefit especially in patients classified by PET/CT as tumour-free or eligible for radical surgery.

Hidden analyses: a review of reporting practice and recommendations for more transparent reporting of initial data analyses.

BACKGROUND: In the data pipeline from the data collection process to the planned statistical analyses, initial data analysis (IDA) typically takes place between the end of the data collection and do not touch the research questions. A systematic process for IDA and clear reporting of the findings would help to understand the potential shortcomings of a dataset, such as missing values, or subgroups with small sample sizes, or shortcomings in the collection process, and to evaluate the impact of these shortcomings on the research results. A clear reporting of findings is also relevant when making datasets available to other researchers. Initial data analyses can provide valuable insights into the suitability of a data set for a future research study. Our aim was to describe the practice of reporting of initial data analyses in observational studies in five highly ranked medical journals with focus on data cleaning, screening, and reporting of findings which led to a potential change in the analysis plan. METHODS: This review was carried out using systematic search strategies with eligibility criteria for articles to be reviewed. A total of 25 papers about observational studies were selected from five medical journals published in 2018. Each paper was reviewed by two reviewers and IDA statements were further discussed by all authors. The consensus was reported. RESULTS: IDA statements were reported in the methods, results, discussion, and supplement of papers. Ten out of 25 papers (40%) included a statement about data cleaning. Data screening statements were included in all articles, and 18 (72%) indicated the methods used to describe them. Item missingness was reported in 11 papers (44%), unit missingness in 15 papers (60%). Eleven papers (44%) mentioned some changes in the analysis plan. Reported changes referred to missing data treatment, unexpected values, population heterogeneity and aspects related to variable distributions or data properties. CONCLUSION: Reporting of initial data analyses were sparse, and statements on IDA were located throughout the research articles. There is a lack of systematic reporting of IDA. We conclude the article with recommendations on how to overcome shortcomings in the practice of IDA reporting in observational studies.

Improved Carotid Stenosis Quantification on Novel 4D/3D-Doppler Ultrasonography Indexing to the Common Carotid Artery.

PURPOSE: The accuracy of internal carotid artery stenosis (ICAS) quantification depends on the method of stenosis measurement, impacting therapeutic decisions and outcomes. The NASCET method references the stenotic to the distal ICAS lumen, the ECST method to the local outer and the common carotid artery (CC) method to the CC diameter. Direct morphometric stenosis measurement with four-dimensionally guided three-dimensional ultrasonography (4D/3DC-US) demonstrated good validity for the commonly used NASCET method. The NASCET definition has clinically relevant drawbacks. Our purpose was to investigate the validity of the ECST and CC methods. MATERIALS AND METHODS: 4D/3DC-US percent-stenosis measures of 103 stenoses (80 patients) were compared to quantitative catheter angiography and duplex ultrasonography (DUS) in a blinded fashion. RESULTS: The 4D/3DC-US versus angiography intermethod standard deviation of differences (SDD, n = 103) was lower for the CC method (5.7 %) compared to the NASCET (8.1 %, p < 0.001) and ECST methods (9.1 %, p < 0.001). Additionally, it was lower than the NASCET angiography interrater SDD of 52 stenoses (SDD 7.2 %, p = 0.047) and non-inferior for the ECST method (p = 0.065). Interobserver analysis of equivalent grading methods showed no differences for the SDDs between angiography and 4D/3DC-US observers (p > 0.076). Binary comparison to angiography showed equal Kappa values > 0.7 and an accuracy ≥ 85 % for the NASCET and CC methods, higher than for the ECST method. The binary accuracy of ICAS grading did not differ from DUS for all methods. CONCLUSION: The new 4D/3DC-US CC method is an accurate and well reproducible alternative to the NASCET and ECST methods and offers potential for clinical application.

On the use of comparison regions in visualizing stochastic uncertainty in some two-parameter estimation problems.

When considering simultaneous inference for two parameters, it is very common to visualize stochastic uncertainty by plotting two-dimensional confidence regions. This allows us to test post hoc null hypotheses about a single point in a simple manner. However, in some applications the interest is not in rejecting hypotheses on single points, but in demonstrating evidence for the two parameters to be in a convex subset of the parameter space. The specific convex subset to be considered may vary from one post hoc analysis to another. Then it is of interest to have a visualization allowing to perform corresponding analyses. We suggest comparison regions as a simple tool for this task.

Baseline Characteristics May Help Indicate the Best Choice of Health Care Provider for Back Pain Patients in Primary Care: Results From a Prospective Cohort Study.

OBJECTIVE: Baseline characteristics of patients low back pain differ substantially between care settings, but it is largely unknown whether predictors are of equal importance across settings. The aim of this study was to investigate whether 8 known predictors relate differently to outcomes in chiropractic practice and in general practice and to which degree these factors may be helpful in selecting patients benefiting more from one setting or the other. METHODS: Patient characteristics were collected at baseline, and outcomes of pain intensity (numeric rating scale 0-10) and activity limitation (Roland-Morris Disability Questionnaire 0-100) after 2, 12, and 52 weeks. Differences in the prognostic strength between settings were investigated for each prognostic factor separately by estimating the interaction between setting and the prognostic factor using regression models. Between-setting differences in outcome in high-risk and low-risk subgroups, formed by single prognostic factors, were assessed in similar models adjusted for a propensity score to take baseline differences between settings into account. RESULTS: Prognostic factors were generally associated more strongly with outcomes in general practice compared with chiropractic practice. The difference was statistically significant for general health, duration of pain, and musculoskeletal comorbidity. After propensity score adjustment, differences in outcomes between settings were insignificant, but negative prognostic factors tended to be less influential in chiropractic practice except for leg pain and depression, which tended to have less negative impact in general practice. CONCLUSION: Known prognostic factors related differently to outcomes in the 2 settings, suggesting that some subgroups of patients might benefit more from one setting than the other.

Amyloid imaging for differential diagnosis of dementia: incremental value compared to clinical diagnosis and [18F]FDG PET.

PURPOSE: Cerebral beta-amyloid and regional glucose metabolism assessed by positron emission tomography (PET) are used as diagnostic biomarkers for Alzheimer's disease (AD). The present study validates the incremental diagnostic value of amyloid PET in addition to clinical diagnosis and [18F]FDG PET in a real-life memory clinic population. METHODS: Of 138 consecutive patients with cognitive impairment who received combined [18F]FDG and [11C]PIB PET, 84 were diagnosed with major neurocognitive disorder (DSM-5) and included. Baseline clinical and [18F]FDG PET diagnoses were independently established with and without access to amyloid PET results and were dichotomized into AD or non-AD disorders. The incremental value of amyloid PET was evaluated in terms of: (1) the change in clinical and [18F]FDG PET diagnoses, (2) the change in agreement between clinical and [18F]FDG PET diagnoses, and (3) diagnostic accuracy using an interdisciplinary consensus diagnosis after an extended follow-up (2.4 ± 1.3 years after PET) as the reference. RESULTS: After disclosure of the amyloid PET results, clinical and [18F]FDG PET diagnoses changed in 23% and 18% of patients, respectively, and agreement between both ratings increased from 62% to 86% (p < 0.001). The accuracy of clinical and [18F]FDG PET diagnoses improved from 71% to 89% (p < 0.01) and from 76% to 94% (p < 0.001), respectively. The additional value of amyloid PET was rather uniform in relation to age at onset and consistency with appropriate use criteria. CONCLUSION: Amyloid PET provides significant incremental diagnostic value beyond clinical and [18F]FDG PET diagnoses of AD. Given the high diagnostic accuracy of combined clinical and amyloid PET assessment, further studies are needed to clarify the role of an additional [18F]FDG PET scan in these patients.

Practice-based evidence for the clinical benefit of PET/CT-results of the first oncologic PET/CT registry in Germany.

PURPOSE: The purpose of this study was to evaluate the impact of PET/CT on clinical management of cancer patients based on a prospective data registry. The study was developed to inform consultations with public health insurances on PET/CT coverage. METHODS: We evaluated a prospective patient cohort having a clinically indicated PET/CT at a single German University Center from April 2013 to August 2016. The registry collected questionnaire data from requesting physicians on intended patient management before and after PET/CT. A total of 4,504 patients with 5,939 PET/CT examinations were enrolled in the registry, resulting in evaluable data from 3,724 patients receiving 4,754 scans. The impact of PET/CT on patient management was assessed across 22 tumor types, for different indications (diagnosis, staging, suspected recurrence) and different categories of management including treatment (curative or palliative) and non-treatment (watchful waiting, additional imaging, invasive tests). RESULTS: The most frequent PET/CT indication was tumor staging (59.7%). Melanoma, lung cancer, lymphoma, neuroendocrine tumor and prostate cancer accounted for 70% of cases. Overall, the use of PET/CT resulted in a 37.1% change of clinical management (95% CI, 35.7-38.5), most frequently (30.6%) from an intended non-treatment strategy before PET/CT to active treatment after PET/CT. The frequency of changes ranged from 28.3% for head and neck cancers up to 46.0% for melanomas. The impact of PET/CT was greatest in reducing demands for additional imaging which decreased from 66.1% before PET/CT to 6.1% after PET/CT. Pre-PET/CT planned invasive tests could be avoided in 72.7% of cases. The treatment goal changed after PET/CT in 21.7% of cases, in twice as many cases from curative to palliative therapy than vice versa. CONCLUSIONS: The data of this large prospective registry confirm that physicians often change their intended management on the basis of PET/CT by initiating treatment and reducing additional imaging as well as invasive tests. This applies to various cancer types and indications.

Retrograde aortic blood flow as a mechanism of stroke: MR evaluation of the prevalence in a population-based study.

OBJECTIVES: Retrograde blood flow from complex atheroma in the descending aorta (DAo) has only recently been described as a potential mechanism of stroke. However, prevalence of this mechanism in the general population and the exact factors influencing stroke risk are unclear. METHODS: One hundred twenty-six consecutively recruited inhabitants of Freiburg, Germany, between 20 and 80 years of age prospectively underwent 3-T MRI. Aortic plaque location and thickness were determined by 3D T1 MRI (1 mm3). 4D flow MRI (spatial/temporal resolution 2 mm3/20 ms) and dedicated software were used to determine prevalence and extent of flow reversal and potential embolization from DAo plaques. Flow was correlated with baseline characteristics and echocardiographic and MRI parameters (aortic diameter, wall thickness, and pulse wave velocity). RESULTS: The maximum length of retrograde blood flow connecting the DAo with the left subclavian artery (LSA) increased from 16.1 ± 8.3 mm in 20-29-year-old to 24.7 ± 11.7 mm in 70-80-year-old subjects, correlated with age (r = 0.37; p < 0.001), and was lower in females (p = 0.003). Age was the only independent predictor of increased flow reversal. Complex DAo plaques ≥ 4-mm thickness were found in eight subjects (6.3%) and were connected with the LSA, left common carotid artery, and brachiocephalic trunk in 8 (100%), 1 (12.5%), and 0 (0%) cases, respectively. CONCLUSIONS: Retrograde blood flow from the DAo was very frequent. However, potential retrograde embolization was rare due to the low incidence of complex DAo plaques. The magnitude of flow reversal and prevalence of complex atheroma increased with age. Thus, older patients with aortic atherosclerosis are especially vulnerable to this stroke mechanism. KEY POINTS: • 4D flow MRI allows in vivo visualization and quantification of individual and three-dimensional blood flow patterns within the thoracic aorta including retrograde components. • This population-based study showed that blood flow reversal from the proximal descending aorta to the brain-supplying great arteries is very frequent and able to reach all brain territories. The extent of such flow reversal increases with age and with the extent of aortic atherosclerosis. • The combination of blood flow reversal with plaque rupture in the proximal descending aorta constitutes a potential stroke mechanism that should be considered in future trials and in the management of stroke patients in clinical routine.

Constructing treatment selection rules based on an estimated treatment effect function: different approaches to take stochastic uncertainty into account have a substantial effect on performance.

BACKGROUND: Today we are often interested in the predictive value of a continuous marker with respect to the expected difference in outcome between a new treatment and a standard treatment. We can investigate this in a randomized control trial, allowing us to assess interactions between treatment and marker and to construct a treatment selection rule. A first step is often to estimate the treatment effect as a function of the marker value. A variety of approaches have been suggested for the second step to define explicitly the rule to select the treatment, varying in the way to take uncertainty into account. Little is known about the merits of the different approaches. METHODS: Four construction principles for the second step are compared. They are based on the root of the estimated function, on confidence intervals for the root, or on pointwise or simultaneous confidence bands. All of them have been used implicitly or explicitly in the literature. As performance characteristics we consider the probability to select at least some patients, the probability to classify patients with and without a benefit correctly, and the gain in expected outcome at the population level. These characteristics are investigated in a simulation study. RESULTS: As to be expected confidence interval/band based approaches reduce the risk to select patients who do not benefit from the new treatment, but they tend to overlook patients who can benefit. Simply using positivity of the estimated treatment effect function for selection implies often a larger gain in expected outcome. CONCLUSIONS: The use of 95% confidence intervals/bands in constructing treatment selection rules is a rather conservative approach. There is a need for better construction principles for treatment selection rules aiming to maximize the gain in expected outcome at the population level. Choosing a confidence level of 80% may be a first step in this direction.