Non-inferiority Test Research Articles

Conducting the non-inferiority test for the means with unknown coefficient of variation in a three-arm trial

BackgroundThe non-inferiority test is a reasonable approach to assessing a new treatment in a three-arm trial. The three-arm trial consists of a placebo, reference, and an experimental treatment. The non-inferiority is often measured by the mean differences between the experimental and the placebo groups relative to the mean differences between the reference and the placebo groups.MethodsTo cope with possible estimation distortion due to the allowance of heteroskedasticity, we adjust the measurement of non-inferiority by the incorporation of coefficient of variation (CV) of the experimental, the reference and the placebo groups. In this research, we propose a generalized p-value based method (GPV-based method) to facilitate non-inferiority tests for the means with unknown coefficient of variation in a three-arm trial.ResultsThe simulation results show that the GPV-based method can not only adequately control type I error rate at nominal level better but also provide power higher than those from Delta method and the empirical bootstrap method, which verifies the feasibility of our adjustment.ConclusionsWe revise the measurement of non-inferiority by deducting the CV of each kind of treatment from the average effect of trials. CVs are included in the non-inferiority explicitly to help prevent possible estimating distortion if heteroskedasticity is allowed. Through the simulation study, the performance of GPV-based method for facilitating non-inferiority tests for the means with unknown CV in a three-arm trial is better than those from empirical bootstrap method and Delta method for small, medium and large sample sizes. Hence, the GPV-based method is recommended to be used to conduct the non-inferiority test for the means with unknown CV in a three-arm trial. The GPV-based method still performs well in non-normality cases.

Simultaneous confidence intervals for an extended Koch-Röhmel design in three-arm non-inferiority trials.

Three-arm 'gold-standard' non-inferiority trials are recommended for indications where only unstable reference treatments are available and the use of a placebo group can be justified ethically. For such trials, several study designs have been suggested that use the placebo group for testing 'assay sensitivity', that is, the ability of the trial to replicate efficacy. Should the reference fail in the given trial, then non-inferiority could also be shown with an ineffective experimental treatment and hence becomes useless. In this article, we extend the so-called Koch-Röhmel design where a proof of efficacy for the experimental treatment is required in order to qualify for the non-inferiority test. While the efficacy of the experimental treatment is an indication of assay sensitivity, it does not guarantee that the reference is sufficiently efficient to let the non-inferiority claim be meaningful. It has, therefore, been suggested to adaptively test the non-inferiority only if the reference demonstrates superiority to placebo and otherwise to test -superiority of the experimental treatment over placebo, where is chosen in such a way that it provides proof of non-inferiority with regard to the reference's historical effect. In this article, we extend the previous work by complementing its adaptive test with compatible simultaneous confidence intervals. Confidence intervals are commonly used and suggested by regulatory guidelines for non-inferiority trials. We show how to adopt different approaches to simultaneous confidence intervals from the literature to the setting of three-arm non-inferiority trials and compare these methods in a simulation study. Finally, we apply these methods to a real clinical trial example.

Reduced-visit antenatal care model combined with telemedicine for low-risk pregnant women: protocol for a randomised controlled trial

IntroductionAntenatal care (ANC) is a critical measure to reduce maternal and perinatal morbidity and mortality. However, there are issues of too many visits and cumbersome procedures of ANC in many...

Unified Protocol for the Transdiagnostic Treatment of Emotional Disorders in Group Format in Spain: Results of a Noninferiority Randomized Controlled Trial at 15 Months after Treatment Onset

Evidence-based psychological treatments (EBPT) are an effective and efficient solution for the treatment of emotional disorders (EDs). However, their implementation and dissemination are not yet widespread. The Unified Protocol for Transdiagnostic Treatment of EDs (UP), applied in a group format, could be an effective option to be implemented in specialized public mental health services in Spain. The sample consisted of 533 users of public specialized mental health centers (77.3% women), with a mean age of 42.0 years ( SD = 12.62 ), who were randomized to the UP in group format condition ( n = 277 ) or treatment as usual (specific cognitive behavioral therapy for each disorder in individual format, n = 256 ). Assessments were performed at preintervention (T1) and at 3, 6, 9 and 15 months after treatment onset (T2, T3, T4, and T5, respectively). The results showed a main effect of time in both conditions for all primary outcomes ( p < 0.05 ) and no statistically significant Time ∗ Condition interaction. Similarly, the noninferiority tests showed that UP results were statistically noninferior compared to TAU. Effect sizes for psychological variables were higher in the UP condition at T5, even though the differences were not statistically significant. Statistically significant differences ( p < 0.05 ) in the evolution of the diagnostic criteria and comorbidity were found, with the highest percentage of patients no longer meeting main and secondary diagnosis criteria in the UP condition at all assessment moments (except for secondary diagnosis at T3). The results showed statistically significant differences in treatment retention between conditions at T5, being the UP condition the one with less dropouts. Finally, participants in the group UP condition showed high satisfaction with the treatment. The UP is an EBPT that has been shown to be effective when applied in groups and may represent an efficient option for its implementation in public mental health services in Spain. This trial is registered with NCT03064477.

P-709 Predictive heatmap in Preimplantation Genetic Testing for Monogenic disorders (PGT-M) and Structural Rearrangements (PGT-SR)

Abstract Study question What is the predicted cumulative live birth rate (CLBR) relative to AMH-level for women undergoing preimplantation genetic testing (PGT) for monogenic disorders and structural rearrangements? Summary answer Anti-müllerian hormone (AMH) and age allow to give an estimate of the CLBR in PGT and becomes poor when AMH is ≤ 2µg/L and age ≥42y. What is known already Ovarian response is an important contributory factor in PGT in order to obtain a sufficient number of embryos for genetic analysis. A proportion of the obtained embryos will be carrier of the disease tested, and another small proportion of the embryos will fail to have a genetic diagnosis hence will not be available for embryo transfer. The number of embryos not suitable for embryo transfer as a result of PGT varies between 25-81% according to the indication for PGT. The combination of female age and AMH are good predictors for CLBR in conventional IVF. Study design, size, duration This is a single-centre retrospective cohort study including 1,522 females undergoing 3,130 PGT cycles over a 6-year period (01/01/2015-31/12/2020) at a university-based referral centre for PGT. The principal outcome measure was CLBR per intention to treat (ITT), and the secondary outcome was live birth rate (LBR) per embryo transfer, in couples undergoing PGT-M and PGT-SR either by polymerase chain reaction (PCR), single nucleotide polymorphism (SNP) array, microarray-based comparative genomic hybridization (aCGH), or next-generation sequencing (NGS). Participants/materials, setting, methods Mean ±SD was applied for continuous outcomes, whereas (relative) frequency was applied for dichotomous outcomes. Multivariable logistic regression analysis was applied with dependent variable being the CLBR or LBR and the independent variables the AMH, female age, BMI, inheritance mode and PGT-technique. Best-fit (Akaike information criterion (AIC)) versus polynomials were analysed. Non-inferiority testing between different technologies was performed. A 3D-prediction mosaic (including AMH, age and CLBR) was created, which can be used for counseling purposes. Main results and the role of chance The mean female age is 32.46 years (SD 4.43), with a mean AMH level of 2.75 µg/L (SD 2.58) and a mean BMI of 24.24 (SD 4.43). Age and AMH significantly affect CLBR irrespective of the inheritance mode or PGT technique used. There is a gradual decline of CLBR from a female age of 25 years onwards reaching a critical threshold of less than 10% CLBR per ITT over the age of 42 with AMH levels ≤2 µg/L. Between cleavage stage biopsy techniques (PCR) and trophectoderm biopsy PGT techniques (SNP array, aCGH, NGS) used there was no significant difference in outcome per ITT, however per embryo transfer there is a significantly higher chance of live birth in SNP array, aCGH and NGS cycles compared to PCR cycles. Limitations, reasons for caution Despite the large sample size, the findings are confined by limited confounder adjustment. Wider implications of the findings In a PGT-program, couples need to be informed on the limited prognosis, if the combination of female age and AMH is unfavourable, in order to allow them to make other reproductive choices. The prediction mosaic produced in this study can be used as an insightful visual tool in counseling PGT-couples. Trial registration number Not applicable

P-211 “Survival rates after vitrification of oocytes obtained after luteal phase vs follicular phase ovarian stimulation”

Abstract Study question Do the oocytes retrieved after luteal phase ovarian stimulation (OS) have the same survival rate as those retrieved after follicular phase (OS)? Summary answer Oocyte survival rate after vitrification is similar in oocytes retrieved in a follicular phase OS compared to those in luteal phase. What is known already Oocytes retrieved in luteal phase have recently captured scientific interest as dual stimulation is gaining popularity. Oocytes obtained in luteal phase OS added to those obtained in follicular phase shorten time to pregnancy per intention to treat in poor responders. Embryos obtained with these oocytes show similar ploidy rates, as well as clinical outcomes. Study design, size, duration We analyzed data from a randomized, non-inferiority Duo Stim Preimplantation Genetic Testing for aneuploidies (PGT-A) trial performed from 2017 to 2021 in women >38 years old. Only cycles with at least one oocyte retrieved in both follicular and luteal were included. We compared survival rates from oocytes obtained in after follicular phase OS (n = 154 oocytes) versus luteal phase OS (n = 201 oocytes) within the same patient. Participants/materials, setting, methods A subtotal of 38 patients were included who underwent 2, 3, or 4 OS cycles to accumulate oocytes for subsequent ICSI with PGT-A. After retrieval and decumulation, oocyte vitrification was performed with Kitazato vitrification protocol (Kitazato, Japan) and Cryotop device, same as subsequent thawing. Main results and the role of chance Mean of age in the selected patients was 39,7 years. In total, 195 cumulus-oocyte complexes were retrieved after follicular phase OS vs 245 in luteal phase. From this group of oocytes, 145/195 were mature (78.97%) vs 201/245 (82.04%), respectively. No statistically significant differences were observed in survival rate whether oocytes came from a follicular phase OS 81.16 % (125/154) versus luteal phase 87.06% (175/201) (p = 0.3312). Our results confirm that survival rate of oocyte obtained in a luteal phase OS is comparable to conventional follicular phase OS, validating oocyte accumulation strategy in a Duo Stim protocol. Limitations, reasons for caution The limited sample size was due to the nature of the randomized, controlled trial. Our results need to be replicated in larger series for validation. Wider implications of the findings Luteal phase OS oocytes showed similar survival rates after thawing than conventional OS cycles, opening a new venue for oocyte vitrification in oncological patients or poor responders accumulating oocytes. This approach might be of interest as well in patients or countries where ethical/legal limitations may limit embryo accumulation. Trial registration number not applicable

985-P: Is Insulin Titration Supported by a Titration App Safe? Safety Results of an RCT

A multicenter RCT in people with type 2 diabetes has shown that the use of a basal insulin titration app (myDose Coach) reduced A1c levels by 0.35 percentage points compared to titration without an app. Is the use of such a titration app associated with safety issues? We used negative binomial regressions to analyze the occurrence of adverse and serious adverse events (AE, SAE) and exposure to dangerously low (<54 mg/dl) or high (>250 mg/dl) glucose levels in 251 participants (age 60.0 years IQR 56.0 - 66.5; HbA1c 8.2 IQR 7.7 - 9.1%) randomized equally to the control and intervention groups. A total of 30 AEs (16 vs. 14 events) occurred in the control and intervention groups, of which 14 were SAEs (7 vs. 7 events). No event was judged to be associated with study participation or the interventions. The rates of dangerous low and high glucose in the control and intervention group were 0.12% vs. 0.10% for %< 54 mg/dl and 4.9% vs. 3.6% for %< 250 mg/dl, respectively (see Figure 1 for IRR and p values for superiority). A post-hoc non-inferiority test for the occurrence of %< 54 mg/dl and >250 mg/dl with non-inferiority margins of < 1% and < 5%, respectively, showed significant non-inferiority regarding the intervention group (both p < 0.01) with a post-hoc power by 75% respectively 55%. The results did not indicate an increased risk for insulin titration by the evaluated app compared to the control condition in terms of AE or extreme glucose excursions. Disclosure B.Kulzer: Advisory Panel; Berlin-Chemie AG, Abbott Diabetes, Bayer Inc., Dexcom, Inc., Novo Nordisk, Insulet Corporation, embecta, Research Support; Sanofi, Roche Diabetes Care. D.Ehrmann: Advisory Panel; Roche Diabetes Care, mySugr, Dexcom, Inc., Speaker's Bureau; Berlin-Chemie AG, Dexcom, Inc. T.Roos: None. K.Finke-groene: None. N.Hermanns: Advisory Panel; Insulet Corporation, Research Support; Sanofi-Aventis Deutschland GmbH, Roche Diagnostics, Becton, Dickinson and Company, Speaker's Bureau; Dexcom, Inc., Berlin-Chemie AG. Funding Sanofi

6 compared with 12 weeks treatment in the von Rosen splint is sufficient for Barlow and Ortolani positive hips: a comparative study of 237 neonates.

At our institution, newborns with Barlow or Ortolani positive hips have been treated for 12 weeks with the von Rosen abduction splint until 2012 when the treatment length was halved. We investigate whether acetabular development at 12 months of age and complications differ between hips treated with the von Rosen splint for 6 compared with 12 weeks. 99 patients were included in the 6-week program and 138 patients in the 12-week program. We measured the acetabular index (AI) on standard anteroposterior pelvic radiographs taken at 12 months of age. Medical records were reviewed for complications and additional treatments until age 12 months. We used non-inferiority testing with an equivalence margin of 1° with a 95% confidence interval (CI) to compare the 2 groups. The mean AI at 12 months in the 6-week group was 25° (CI 24-26) compared with 25° (CI 25-26) in the 12-week group. Non-inferiority was demonstrated for the 6-week program: -0.2° (CI -1.1 to 0.7). In the 6-week group, 8 patients received additional treatment, including 1 hip dislocation that occurred between 6 weeks and 3 months. There were no additional treatments or complications in the 12-week group. AI was equal at 12 months of age for patients treated for 6 compared with 12 weeks in the von Rosen splint. The hip dislocation which occurred indicates that follow-up around 3 months of age is indicated.

Efficacy of vaginal natural orifice transluminal endoscopic sentinel lymph node biopsy for endometrial cancer: a prospective multicenter cohort study.

Natural orifice transluminal endoscopic surgery (NOTES) is performed increasingly often despite the lack of high-quality evidence confirming its safety, especially for malignant diseases. The aim of this prospective study is to verify that vaginal NOTES (vNOTES) can be performed safely and effectively in early endometrial cancer staging surgery. This prospective study was conducted in two tertiary hospitals in southern China from January 2021 to May 2022. A total of 120 patients with stage I endometrial cancer were included. vNOTES or multiport laparoscopic staging surgery was selected according to each patient's wishes. The primary outcome was the sentinel lymph node detection rate, analyzed by a noninferiority test. The secondary outcomes were perioperative outcomes. Among the 120 patients enrolled, 57 underwent vNOTES, and 63 underwent multiport laparoscopy. The patient-specific detection rates of sentinel lymph nodes were 94.73 and 96.82% in the vNOTES and laparoscopy groups, respectively. Additionally, the bilateral detection rates were 82.46 and 84.13%, and the side-specific detection rates were 88.60 and 90.48% in these two groups, respectively. All three detection rates in the vNOTES group were noninferior to those of laparoscopy group at a noninferiority cutoff of -15%. The median operation times of the vNOTES and laparoscopy groups were 132.35 and 138.73min ( P =0.362), and the median estimated blood loss were 75 and 50ml ( P =0.096), respectively. No intraoperative complications occurred in either group. The pain scores on the Numerical Rating Scale at both 12h and 24h after operation were significantly lower in the vNOTES group ( P <0.001) and the median postoperative hospital stay was significantly shorter in the vNOTES group ( P =0.001). This study illustrates the potential applicability of vNOTES in gynecological malignancy surgery by demonstrating its safety and effectiveness in endometrial cancer staging. However, its long-term survival outcomes require further exploration.

Technology-enhanced acceleration of germline evaluation for therapy (TARGET): Results of a randomized controlled trial of a pretest patient-driven webtool vs. genetic counseling for prostate cancer germline testing.

10598 Background: Germline genetic testing is important for prostate cancer management, clinical trial eligibility and hereditary cancer risk assessment. Despite this, genetic testing is underutilized and there is a shortage of genetic counselors. To address these gaps, we designed a webtool to provide patient-driven genetic education and conducted a randomized non-inferiority trial to compare it with traditional pre-test genetic counseling. Methods: TARGET is a multi-center randomized controlled trial comparing standard pre-test genetic counseling versus web-based genetic education (intervention) (NCT04447703). The study protocol was previously published (PMID 35710085). Briefly, patients with prostate cancer who met criteria for germline testing (based on tumor features, ancestry or family history) were randomized to pre-test genetic education through genetic counseling vs a 9-module webtool created by the study team and Prostate Cancer Foundation. The primary endpoint was non-inferiority in reducing decisional conflict between the webtool and genetic counseling by a margin of 4 (set in advance) on the validated Decision Conflict Scale. Analysis of covariance was used to compare decisional conflict between groups. All participants opting for testing received a 51-gene Invitae panel, with results delivered to the patient and their provider. Results: 346 patients with prostate cancer with a mean age of 63.7 years were randomized to genetic counseling (n=174) or web-based genetic education (n=172). Compared to baseline, there were reductions in decisional conflict in both arms following pre-test genetic education (Table). Adjusting for study site and baseline decisional conflict, the test of non-inferiority in reducing decisional conflict between arms was statistically significant (difference = -0.04, 95% CI: -∞ to 1.95, p&lt;0.001). Overall 265 (76.6%) participants underwent genetic testing, including 146 (83.9%) in the genetic counseling and 119 (69.2%) in webtool arm, with the following results: negative (49.4%), variant of uncertain significance (35.5%) and pathogenic variant (15.1%). Conclusions: Delivery of pre-test genetic education through a webtool was non-inferior to genetic counseling in reducing decisional conflict. These results support a new standard of care for the use of patient-driven digital webtools for expanding access to pretest genetic education and informed decision-making for prostate cancer genetic testing. Clinical trial information: NCT04447703 . [Table: see text]

Prospective comparison of [18F]AlF-NOTA-octreotide PET/MRI to [68Ga]Ga-DOTATATE PET/CT in neuroendocrine tumor patients

BackgroundFluorine-18-labeled SSAs have the potential to become the next-generation tracer in SSTR-imaging in neuroendocrine tumor (NET) patients given their logistical advantages over the current gold standard gallium-68-labeled SSAs. In particular, [18F]AlF-OC has already shown excellent clinical performance. We demonstrated in our previous report from our prospective multicenter trial that [18F]AlF-OC PET/CT outperforms [68Ga]Ga-DOTA-SSA, but histological confirmation was lacking due to ethical and practical reasons. In this second arm, we therefore aimed to provide evidence that the vast majority of [18F]AlF-OC PET lesions are in fact true NET lesions by analyzing their MR characteristics on simultaneously acquired MRI. We had a special interest in lesions solely detected by [18F]AlF-OC (“incremental lesions”).MethodsTen patients with a histologically confirmed neuroendocrine tumor (NET) and a standard-of-care [68Ga]Ga-DOTATATE PET/CT, performed within 3 months, were prospectively included. Patients underwent a whole-body PET/MRI (TOF, 3 T, GE Signa), 2 hours after IV injection of 4 MBq/kg [18F]AlF-OC. Positive PET lesions were evaluated for a corresponding lesion on MRI. The diagnostic performance of both PET tracers was evaluated by determining the detection ratio (DR) for each scan and the differential detection ratio (DDR) per patient.ResultsIn total, 195 unique lesions were detected: 167 with [68Ga]Ga-DOTATATE and 193 with [18F]AlF-OC. The DR for [18F]AlF-OC was 99.1% versus 91.4% for [68Ga]Ga-DOTATATE, significant for non-inferiority testing (p = 0.0001). Out of these 193 [18F]AlF-OC lesions, 96.2% were confirmed by MRI to be NET lesions. Thirty-three incremental lesions were identified by [18F]AlF-OC, of which 91% were confirmed by MRI and considered true positives.ConclusionThe DR of [18F]AlF-OC was numerically higher and non-inferior to the DR of [68Ga]Ga-DOTATATE. [18F]AlF-OC lesions and especially incremental lesions were confirmed as true positives by MRI in more than 90% of lesions. Taken together, these data further validate [18F]AlF-OC as a new alternative for SSTR PET in clinical practice.Trial registration ClinicalTrials.gov: NCT04552847. Registered 17 September 2020, https://beta.clinicaltrials.gov/study/NCT04552847

Comparison of the clinical outcomes of resin-modified glass ionomer and self-adhesive resin cementations for full-coverage zirconia restorations

Both resin-modified glass ionomer cement (RMGIC) and self-adhesive resin cement (SAC) may be suitable for cementation of full-coverage zirconia restorations. This retrospective study aimed to investigate the clinical outcomes of zirconia-based restorations cemented with RMGIC and compare them with those cemented with SAC. Cases of full-coverage zirconia-based restorations cemented with either RMGIC or SAC between March 2016 and February 2019 were evaluated in this study. The clinical outcomes of the restorations were analyzed according to the type of cement used. In addition, cumulative success and survival rates were evaluated according to the cement and abutment types. Non-inferiority, Kaplan-Meier, and Cox hazard tests were conducted (α=.05). A total of 288 full-coverage zirconia-based restorations (natural teeth, 157; implant restorations, 131) were analyzed. Loss of retention occurred in only one case; a single-unit implant crown cemented with RMGIC, which decemented 4.25 years post-restoration. RMGIC was non-inferior to SAC in terms of loss of retention (<5%). For single-unit natural tooth restorations, the four-year success rates in the RMGIC and SAC groups were 100% and 95.65%, respectively (p=.122). For single-unit implant restorations, the four-year success rates in the RMGIC and SAC groups were 95.66% and 100%, respectively (p=.365). The hazard ratios of all the predictor variables, including cement type, were not significant (p>.05). Cementation of full-coverage zirconia restorations of both natural teeth and implants using RMGIC and SAC yields satisfactory clinical outcomes. Furthermore, RMGIC is non-inferior to SAC in terms of cementation success. Cementation with RMGIC or SAC for full-coverage zirconia restorations has favorable clinical outcomes in both natural teeth and implants. Both RMGIC and SAC have advantages in the cementation of full-coverage zirconia restorations to abutments with favorable geometries.

Safety and efficacy of simple training protocol in patients after mild traumatic brain injury.

Mild Traumatic Brain Injury (mTBI) is the most common type of craniocerebral injury. Proper management appears to be a key factor in preventing post-concussion syndrome. The aim of this prospective study was to evaluate the effect and safety of selected training protocol in patients after mTBI. This was a prospective study that included 25 patients with mTBI and 25 matched healthy controls. Assessments were performed in two sessions and included a post-concussion symptoms questionnaire, battery of neurocognitive tests, and magnetic resonance with tractography. Participants were divided into two groups: a passive subgroup with no specific recommendations and an active subgroup with simple physical and cognitive training. The training program with slightly higher initial physical and cognitive loads was well tolerated and was harmless according to the noninferiority test. The tractography showed overall temporal posttraumatic changes in the brain. The predictive model was able to distinguish between patients and controls in the first (AUC=0.807) and second (AUC=0.652) sessions. In general, tractography had an overall predictive dominance of measures. The results from our study objectively point to the safety of our chosen training protocol, simultaneously with the signs of slight benefits in specific cognitive domains. The study also showed the capability of machine learning and predictive models in mTBI patient recognition.

Comparing the volume of vascular intersection of two femoral neck fracture fixation implants using an In silico technique.

Three dimensional (3D) µCT angiograms of 9 cadaveric proximal femora were produced. Three segmented volumes-porous or cancellous bone, filled or cortical bone, and intraosseous vasculature-were converted to surface files. 3D in silico models of the fixation systems were sized and implanted in silico without visibility of the vascular maps. The volume of vasculature that overlapped with the devices was determined. The ratio of the vascular intersection to the comparator device was calculated, and the mean ratio was determined. A paired design, noninferiority test was used to compare the devices. Results indicate both significant (P < 0.001) superiority and noninferiority of the hip screw with an integrated antirotation screw when compared with a dynamic hip screw and antirotation screw for the volume of vasculature that overlapped with each device in the femoral neck. Combining established methods of vascular visualization with newer methods enables an implant's impact on vascular intersection to be assessed in silico. This methodology suggests that when used for femoral neck fracture management, the new device intersects fewer blood vessels than the comparator. Comparative clinical studies are needed to investigate whether these findings correlate with the incidence of avascular necrosis and clinical outcomes.

AB-453068-4 BENCH EVALUATION OF OVERLAPPING LESION STEAM POP RATES

Sequentially delivered, overlapping radiofrequency (RF) ablation lesions pose a risk of creating steam pops due to heat stacking. The relationship between inter-lesion distance and heat stacking is presently unknown. Therefore, the smallest inter-lesion distance for safe therapy delivery needs to be determined. The study objective was to quantify steam pop rates when creating sequential, adjacent, potentially overlapping RF ablation lesions at various inter-lesion distances in a non-perfused bovine cardiac tissue model with the intention of identifying the safest minimum inter-lesion distance. In a saline filled tank at clinically relevant conductivity and temperature, a TactiCath SE RF ablation catheter created sets of 2 lesions on isolated, non-perfused bovine right ventricular tissue. At 15g force and 40W, successive 10s lesions were created (transition time less than 1s between lesions) at center-to-center distances of 1, 2, 3, 4, 5, and 10 mm, and steam pop frequency was determined. If a steam pop occurred during the first 10s lesion prior to the drag, the trial was excluded and repeated. Using pilot data, it was determined a minimum of 49 samples at each inter-lesion distance would provide a robust sample size for statistical analysis. Steam pop rate at an inter-lesion distance of 10mm was used as the control for analysis as there was no lesion overlap at this center-to-center distance. Steam pop rates at 1 and 2 mm were significantly greater (p=0.002 and p<0.001) than at 10mm. Using a 2-proportions, 2-sample non-inferiority (NI) test, with a NI margin of 20%, statistical equivalence was claimed between steam pop rates at 10mm and 5mm (p=0.009), 4mm (p=0.005), 3mm (p=0.003). Lesions spaced closer than 3mm apart have a greater risk of resulting in steam pops. Therefore, a minimum of 3mm inter-lesion distance would be recommended as it has shown to have a similar steam pop rate to focal lesions.

Overstated conclusions of a non-inferiority trial testing immunogenicity and safety of homologous and heterologous booster - authors' reply.

Overstated conclusions of a non-inferiority trial testing immunogenicity and safety of homologous and heterologous booster - authors' reply.

Overstated conclusions of a non-inferiority trial testing immunogenicity and safety of homologous and heterologous booster vaccination.

Overstated conclusions of a non-inferiority trial testing immunogenicity and safety of homologous and heterologous booster vaccination.

On approximate robust confidence distributions

A confidence distribution is a complete tool for making frequentist inference for a parameter of interest based on an assumed parametric model. Indeed, it provides point estimates, along with confidence intervals, allows to define rejection regions for testing unilateral and bilateral hypotheses, to assign measures of evidence or levels of confidence to prespecified regions of the parameter space, and to compare the parameter of interest with other parameters from other studies. The aim is to discuss robust confidence distributions derived from unbiased M-estimating functions, which provide bounded-influence inference for a parameter of interest, when the assumed central model is just an approximate parametric model or in the presence of deviant values in the observed data. Paralleling likelihood-based results and extending results available for robust scoring rules, two methods are proposed for deriving robust confidence distributions: the first one uses the asymptotic theory of robust pivotal quantities and the second one is based on simulation methods. An application and a simulation study are illustrated in the context of non-inferiority and superiority testing.

A confirmatory basket design considering non-inferiority and superiority testing

ABSTRACT For multiple rare diseases as defined by a common biomarker signature, or a disease with multiple disease subtypes of low frequency, it is often possible to provide confirmatory evidence for these disease or subtypes (baskets) as a combined group. A novel drug, as a second generation, may have marginal improvement in efficacy overall but superior efficacy in some baskets. In this situation, it is appealing to test hypotheses of both non-inferiority overall and superiority on certain baskets. The challenge is designing a confirmatory study efficient to address multiple questions in one trial. A two-stage adaptive design is proposed to test the non-inferiority hypothesis at the interim stage, followed by pruning and pooling before testing a superiority hypothesis at the final stage. Such a design enables an efficient and novel registration pathway, including an early claim of non-inferiority followed by a potential label extension with superiority on certain baskets and an improved benefit-risk profile demonstrated by longer term efficacy and safety data. Operating characteristics of this design are examined by simulation studies, and its appealing features make it ready for use in a confirmatory setting, especially in emerging markets, where both the need and the possibility for efficient use of resources may be the greatest.

Artificial Intelligence as Supporting Reader in Breast Screening: A Novel Workflow to Preserve Quality and Reduce Workload.

To evaluate the effectiveness of a new strategy for using artificial intelligence (AI) as supporting reader for the detection of breast cancer in mammography-based double reading screening practice. Large-scale multi-site, multi-vendor data were used to retrospectively evaluate a new paradigm of AI-supported reading. Here, the AI served as the second reader only if it agrees with the recall/no-recall decision of the first human reader. Otherwise, a second human reader made an assessment followed by the standard clinical workflow. The data included 280 594 cases from 180 542 female participants screened for breast cancer at seven screening sites in two countries and using equipment from four hardware vendors. The statistical analysis included non-inferiority and superiority testing of cancer screening performance and evaluation of the reduction in workload, measured as arbitration rate and number of cases requiring second human reading. Artificial intelligence as a supporting reader was found to be superior or noninferior on all screening metrics compared with human double reading while reducing the number of cases requiring second human reading by up to 87% (245 395/280 594). Compared with AI as an independent reader, the number of cases referred to arbitration was reduced from 13% (35 199/280 594) to 2% (5056/280 594). The simulation indicates that the proposed workflow retains screening performance of human double reading while substantially reducing the workload. Further research should study the impact on the second human reader because they would only assess cases in which the AI prediction and first human reader disagree.