Causal analyses with target trial emulation for real-world evidence removed large self-inflicted biases: systematic bias assessment of ovarian cancer treatment effectiveness.

BACKGROUND AND OBJECTIVES: Drawing causal conclusions from real-world data (RWD) poses methodological challenges and risk of bias. We aimed to systematically assess the type and impact of potential biases that may occur when analyzing RWD using the case of progressive ovarian cancer. METHODS: We retrospectively compared overall survival with and without second-line chemotherapy (LOT2) using electronic medical records. Potential biases were determined using directed acyclic graphs. We followed a stepwise analytic approach ranging from crude analysis and multivariable-adjusted Cox model up to a full causal analysis using a marginal structural Cox model with replicates emulating a reference randomized controlled trial (RCT). To assess biases, we compared effect estimates (hazard ratios [HRs]) of each approach to the HR of the reference trial. RESULTS: The reference trial showed an HR for second line vs. delayed therapy of 1.01 (95% confidence interval [95% CI]: 0.82-1.25). The corresponding HRs from the RWD analysis ranged from 0.51 for simple baseline adjustments to 1.41 (95% CI: 1.22-1.64) accounting for immortal time bias with time-varying covariates. Causal trial emulation yielded an HR of 1.12 (95% CI: 0.96-1.28). CONCLUSION: Our study, using ovarian cancer as an example, shows the importance of a thorough causal design and analysis if one is expecting RWD to emulate clinical trial results.

Onset features and time to diagnosis in Friedreich's Ataxia.

BACKGROUND: In rare disorders diagnosis may be delayed due to limited awareness and unspecific presenting symptoms. Herein, we address the issue of diagnostic delay in Friedreich's Ataxia (FRDA), a genetic disorder usually caused by homozygous GAA-repeat expansions. METHODS: Six hundred eleven genetically confirmed FRDA patients were recruited within a multicentric natural history study conducted by the EFACTS (European FRDA Consortium for Translational Studies, ClinicalTrials.gov -Identifier NCT02069509). Age at first symptoms as well as age at first suspicion of FRDA by a physician were collected retrospectively at the baseline visit. RESULTS: In 554 of cases (90.7%), disease presented with gait or coordination disturbances. In the others (n = 57, 9.3%), non-neurological features such as scoliosis or cardiomyopathy predated ataxia. Before the discovery of the causal mutation in 1996, median time to diagnosis was 4(IQR = 2-9) years and it improved significantly after the introduction of genetic testing (2(IQR = 1-5) years, p < 0.001). Still, after 1996, time to diagnosis was longer in patients with a) non-neurological presentation (mean 6.7, 95%CI [5.5,7.9] vs 4.5, [4.2,5] years in those with neurological presentation, p = 0.001) as well as in b) patients with late-onset (3(IQR = 1-7) vs 2(IQR = 1-5) years compared to typical onset < 25 years of age, p = 0.03). Age at onset significantly correlated with the length of the shorter GAA repeat (GAA1) in case of neurological onset (r = - 0,6; p < 0,0001), but not in patients with non-neurological presentation (r = - 0,1; p = 0,4). Across 54 siblings' pairs, differences in age at onset did not correlate with differences in GAA-repeat length (r = - 0,14, p = 0,3). CONCLUSIONS: In the genetic era, presentation with non-neurological features or in the adulthood still leads to a significant diagnostic delay in FRDA. Well-known correlations between GAA1 repeat length and disease milestones are not valid in case of atypical presentations or positive family history.

[Linkage of Clinical and Claims Data in the Evaluation of Post-Stroke Care - SeDaStro: Experiences from the Tyrolian StrokeCard Program]. / Linkage von klinischen Primärdaten und Krankenkassenabrechnungsdaten in der Evaluation der Schlaganfallversorgung ­ SeDaStro: Erfahrungen aus dem Tiroler StrokeCard-Programm.

AIMS AND OBJECTIVES: Data linkage is of paramount importance in the evaluation of treatment regimens for chronic diseases where different health care sectors are involved. A comprehensive picture of long-term treatment effects and, in particular, the cost-effectiveness ratio of treatment approaches can only be drawn when data from various sources are merged and analyzed together. METHODOLOGICAL PROBLEMS AND CHALLENGES: Regarding post-acute stroke care, the present study gives an example of an exact deterministic data linkage procedure including clinical patient records and claims data of TGKK, the main Tyrolean statutory health insurance fund. Typical problems known from other data linkage projects also emerged in the so-called StrokeCard program conducted at the Medical University of Innsbruck. Distinctive Austrian features (the majority of the Austrian population benefits from a mandatory social insurance system without freedom of choice) facilitated the feasibility of the data linkage procedures. RESULTS: Over the recruitment period 01/2014-12/2015, 540 patients could be assigned to the operative dataset. Of these, 367 patients were part of the StrokeCard group (i. e. the treatment group), and 173 belonged to the usual care group (i. e. the control group); 11 patients did not complete the one-year follow-up period (7 treatment group patients vs. 4 control group patients); 7 of them died during the study (5 treatment group patients vs. 2 control group patients). For all 540 patients, TGKK claims data were available for the time-frames of one year before recruitment and one year after discharge from the University hospital. All data could be used in the health-economic evaluation of the StrokeCard program. CONCLUSIONS: The linking of clinical patient records with data collected by SHI funds opens a window of opportunities for analyses of medical care. Counter-intuitively, Austrian health services research activities have limited experience in data linkage approaches, alhough studies based on the linkage of clinical patient records and claims data are indispensable for the evaluation of complex multi-sectoral treatment schemes. The current project proves the feasibility of data linkage mechanisms in the Austrian context. This should be regarded as an impetus for extending data linkage principles to evaluation studies in the future.

Recurrence of genitals warts in pre-HPV vaccine era after laser treatment.

PURPOSE: Human papillomavirus (HPV) can cause condylomata acuminata, also known as genital warts. Our aim was to evaluate the long-term recurrence of genital warts after primary carbon dioxide laser treatment before the introduction of the vaccination against HPV. METHODS: Recurrence rate and localization of genital warts were analysed in a retrospective study in 1798 women presenting with a new diagnosis of genital warts from 1992 to 2009 at a University hospital and had received laser treatment. Additionally, data on topography, pregnancy status, and cervical smear were available for women treated from 2003 to 2009 (n = 825, data subset 1) and systematic follow-up data for women treated in 2006 and 2007 (n = 242, data subset 2). RESULTS: Median time from laser treatment to first recurrence was 14.6 weeks (data subset 2). The site most affected was the vulva (90.7%) followed by the perineum/perianal region (59.3%) and the vagina (47.3%). Abnormal Pap smear was observed in 22.6%. Systematic follow-up with a median follow-up time of 3.1 years revealed at least one recurrence in 68 (28.1%) of 242 women. Women with multifocal genital warts had a 2.9 times increased risk for recurrence compared to women with unifocal lesions (p = 0.01). CONCLUSIONS: Nearly 30% of women presenting with genital warts experienced at least one recurrence after treatment with carbon dioxide laser. Multifocal lesions are the strongest indicator of recurrence. These data provide an important insight to recurrence rates of genital warts before HPV vaccination and underline the significance of a long-term follow-up and HPV vaccination.

Mediator Effect of Balance Problems on Association Between Grip Strength and Falls in Older Adults: Results From the KORA-Age Study.

Objective: To examine the association between grip strength and history of falls among older individuals, and to assess the possible mediating effect of balance problems on this relationship. Method: Data originate from KORA (Cooperative Health Research in the Region of Augsburg)-Age Study of 808 individuals (65 years and above). Follow-up assessment occurred 3 years later. Results: The risk of falls within the last 12 months was reduced on average by 3% (odds ratio [OR] 95% confidence interval [95% CI] = 0.97 [0.94, 0.99]; p value = .026) per 1-kg increase in maximum grip strength after adjusting for age and gender. There was a trend toward an indirect effect of grip strength through the mediator variable balance problems (p value = .043). Discussion: Increased muscular strength is associated with a reduced risk of falls in older age after adjustment for age and gender. The association is partially mediated by balance problems. Thus, in older adults, muscle-strengthening exercises may decrease the risk of falling.

A bias-adjusted evidence synthesis of RCT and observational data: the case of total hip replacement.

Evaluation of clinical effectiveness of medical devices differs in some aspects from the evaluation of pharmaceuticals. One of the main challenges identified is lack of robust evidence and a will to make use of experimental and observational studies (OSs) in quantitative evidence synthesis accounting for internal and external biases. Using a case study of total hip replacement to compare the risk of revision of cemented and uncemented implant fixation modalities, we pooled treatment effect estimates from OS and RCTs, and simplified existing methods for bias-adjusted evidence synthesis to enhance practical application. We performed an elicitation exercise using methodological and clinical experts to determine the strength of beliefs about the magnitude of internal and external bias affecting estimates of treatment effect. We incorporated the bias-adjusted treatment effects into a generalized evidence synthesis, calculating both frequentist and Bayesian statistical models. We estimated relative risks as summary effect estimates with 95% confidence/credibility intervals to capture uncertainty. When we compared alternative approaches to synthesizing evidence, we found that the pooled effect size strongly depended on the inclusion of observational data as well as on the use bias-adjusted estimates. We demonstrated the feasibility of using observational studies in meta-analyses to complement RCTs and incorporate evidence from a wider spectrum of clinically relevant studies and healthcare settings. To ensure internal validity, OS data require sufficient correction for confounding and selection bias, either through study design and primary analysis, or by applying post-hoc bias adjustments to the results. © 2017 The Authors. Health Economics published by John Wiley & Sons, Ltd.

Remote ischemic preconditioning in the prevention of ischemic brain damage during intracranial aneurysm treatment (RIPAT): study protocol for a randomized controlled trial.

BACKGROUND: The treatment of intracranial aneurysms may be associated with cerebral ischemia. We hypothesize that pre-interventional remote ischemic preconditioning (RIPC) reduces ischemic cerebral tissue damage in patients undergoing elective intracranial aneurysm treatment. METHODS/DESIGN: This study is a single-center, prospective, randomized, double-blind explorative trial. Patients with an unruptured intracranial aneurysm admitted to Innsbruck Medical University Hospital for coiling or clipping will be consecutively randomized to either the intervention group (= RIPC by inflating an upper extremity blood-pressure cuff for 3 x 5 min to 200 mmHg) or the control group after induction of anesthesia. Participants will be randomized 1:1 to either the preconditioning group or the sham group using a random allocation sequence and block randomization. The precalculated sample size is n = 24 per group. The primary endpoint is the area-under-the-curve concentration of serum biomarkers (S100B, NSE, GFAP, MMP9, MBP, and cellular microparticles) in the first five days after treatment. Secondary endpoints are the number and volume of new ischemic lesions in magnetic resonance imaging and clinical outcome evaluated with the National Institutes of Health Stroke Scale, the modified Rankin Scale, and neuropsychological tests at six and twelve months. All outcome variables will be determined by observers blinded to group allocation. This study was approved by the local institutional Ethics Committee (UN5164), version 3.0 of the study protocol, dated 20 October 2013. DISCUSSION: This study uses the elective treatment of intracranial aneurysms as a paradigmatic situation to explore the neuroprotective effects of RIPC. If effects are demonstrable in this pilot trial, a larger, prospective phase III trial will be considered.

Short-term effects of bright light therapy in adults with chronic nonspecific back pain: a randomized controlled trial.

OBJECTIVE: The present trial evaluated incorporation of bright light therapy in the treatment of chronic nonspecific back pain (CNBP). DESIGN: A prospective, randomized, controlled, multicenter, open design with three parallel trial arms was used. SETTING: Subjects received a novel therapeutic, an expected therapeutic ineffective low dose, or no light exposure at three different medical centers. PATIENTS: A total of 125 CNBP patients reporting pain intensity of ≥3 points on item 5 of the Brief Pain Inventory (BPI) were included. INTERVENTION: Over 3 weeks, 36 active treatment, 36 placebo controls, and 33 controls received 3 or no supplementary light exposures of 5.000 lx or 230 lx, respectively. OUTCOME MEASURES: Changes in self-reported scores of pain intensity (BPI sub-score 1) and depression (Hospital Anxiety and Depression Questionnaire) were the primary outcome measures. Secondary outcome measures were changes in self-reported overall pain sensation (BPI total score), grade of everyday life impairment (BPI sub-score 2), mood (visual analog scale), and well-being (World Health Organization-Five Well-Being Index). RESULTS: Changes in pain intensity were higher (1.0 [0.8-1.6]) in the bright light group compared with controls (0.3 [-0.1-0.8]; effect size D = 0.46). Changes in the depression score were also higher in the intervention group (1.5 [0.0-2.5]) compared with controls (0.0 [0.0-2.0]; effect size D = 0.86). No differences were seen in change scores between intervention vs sham group. CONCLUSION: The present randomized controlled trial shows that light therapy even in low dose could improve depressive symptoms and reduce pain intensity in CNBP patients. Further research is needed for optimizing parameters of frequency, dose, and duration of therapeutic light exposure.

Recall responses to tetanus and diphtheria vaccination are frequently insufficient in elderly persons.

UNLABELLED: Demographic changes and a more active life-style in older age have contributed to an increasing public awareness of the need for lifelong vaccination. Currently many older persons have been vaccinated against selected pathogens during childhood but lack regular booster immunizations. The impact of regular vaccinations when started late in life was analyzed in an open, explorative trial by evaluating the immune response against tetanus and diphtheria in healthy older individuals. 252 persons aged above 60 years received a booster vaccination against tetanus, diphtheria, pertussis and polio and a subcohort (n=87) was recruited to receive a second booster vaccination against tetanus, diphtheria and pertussis 5 years later. The percentage of unprotected individuals at the time of enrollment differed substantially for tetanus (12%) and diphtheria (65%). Despite protective antibody concentrations 4 weeks after the first vaccination in almost all vaccinees, antibodies had again dropped below protective levels in 10% (tetanus) and 45% (diphtheria) of the cohort after 5 years. Protection was restored in almost all vaccinees after the second vaccination. No correlation between tetanus- and diphtheria-specific responses was observed, and antibody concentrations were not associated with age-related changes in the T cell repertoire, inflammatory parameters, or CMV-seropositivity suggesting that there was no general biological "non-responder type." Post-vaccination antibody concentrations depended on pre-existing plasma cells and B cell memory as indicated by a strong positive relationship between post-vaccination antibodies and pre-vaccination antibodies as well as antibody-secreting cells. In contrast, antigen-specific T cell responses were not or only weakly associated with antibody concentrations. In conclusion, our findings demonstrate that single shot vaccinations against tetanus and/or diphtheria do not lead to long-lasting immunity in many elderly persons despite administration at relatively short intervals. Sufficient antigen-specific B cell memory B generated by adequate priming and consecutive booster vaccinations and/or exposure is a prerequisite for long-term protection. TRIAL REGISTRATION: EU Clinical Trials Register (EU-CTR); EudraCT number 2009-011742-26; www.clinicaltrialsregister.eu/ctr-search/trial/2009-011742-26/AT.

Effects of long-term head-down-tilt bed rest and different training regimes on the coagulation system of healthy men.

Immobility plus preexisting chronic disease or acute trauma can activate the coagulation system, thus increasing the risk for thromboembolic events. The effects of long-term bed-rest immobility and microgravity on the coagulation system of healthy persons (e.g., during crewed Mars missions) have not yet been studied. The main objective of the second Berlin BedRest Study (BBR2-2) "Coagulation Part" was to investigate adaptations of the hemostatic system during long-term bed rest (60 days) under simulated microgravity (6° head-down-tilt [6°HDT]) and after mobilization in three different volunteer groups (randomly assigned to CTR= inactive control group; RE= resistive exercise only group; and RVE= resistive exercise with whole-body vibration group). In 24 males (aged 21-45 years), before, during, and after long-term bed rest, key parameters of coagulation were measured from venous blood samples: D-dimer (DD), thrombin-antithrombin III complex (TAT), and prothrombin fragment F1 + 2 (PT-F1 + 2). Additionally, modified rotational thrombelastometry (ROTEM (®) ) analysis was performed. Times of exploratory analyses were as follows: baseline data collection 2 days before bed rest (BDC-2); eight different days of 6°HDT bed rest (HDT1-HDT60), and two different days after reambulation (R + 3 and R + 6). We found significant changes in DD, TAT, and PT-F1 + 2 over the total time course, but no consistent effect of physical interventions (RE, RVE) on these parameters. Notably, no parameter reached levels indicative of intravascular thrombin formation. All ROTEM® parameters remained within the normal range and no pathological traces were found. Sixty days of 6°HDT bed rest are not associated with pronounced activation of the coagulation system indicative of intravascular thrombus formation in healthy volunteers independent of the training type during the bed rest.