Enrollment Lessons from a Biological Assignment Study of Marrow Transplantation versus Standard Care for Adolescents and Young Adults with Sickle Cell Disease: Considerations for Future Gene and Cellular Therapy Trials.

We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies.

Validation pipeline for machine learning algorithm assessment for multiple vendors.

A standardized objective evaluation method is needed to compare machine learning (ML) algorithms as these tools become available for clinical use. Therefore, we designed, built, and tested an evaluation pipeline with the goal of normalizing performance measurement of independently developed algorithms, using a common test dataset of our clinical imaging. Three vendor applications for detecting solid, part-solid, and groundglass lung nodules in chest CT examinations were assessed in this retrospective study using our data-preprocessing and algorithm assessment chain. The pipeline included tools for image cohort creation and de-identification; report and image annotation for ground-truth labeling; server partitioning to receive vendor "black box" algorithms and to enable model testing on our internal clinical data (100 chest CTs with 243 nodules) from within our security firewall; model validation and result visualization; and performance assessment calculating algorithm recall, precision, and receiver operating characteristic curves (ROC). Algorithm true positives, false positives, false negatives, recall, and precision for detecting lung nodules were as follows: Vendor-1 (194, 23, 49, 0.80, 0.89); Vendor-2 (182, 270, 61, 0.75, 0.40); Vendor-3 (75, 120, 168, 0.32, 0.39). The AUCs for detection of solid (0.61-0.74), groundglass (0.66-0.86) and part-solid (0.52-0.86) nodules varied between the three vendors. Our ML model validation pipeline enabled testing of multi-vendor algorithms within the institutional firewall. Wide variations in algorithm performance for detection as well as classification of lung nodules justifies the premise for a standardized objective ML algorithm evaluation process.

Clinical risks and healthcare utilization of hematopoietic cell transplantation for sickle cell disease in the USA using merged databases.

Advances in allogeneic hematopoietic cell transplantation for sickle cell disease have improved outcomes, but there is limited analysis of healthcare utilization in this setting. We hypothesized that, compared to late transplantation, early transplantation (at age <10 years) improves outcomes and decreases healthcare utilization. We performed a retrospective study of children transplanted for sickle cell disease in the USA during 2000-2013 using two large databases. Univariate and Cox models were used to estimate associations of demographics, sickle cell disease severity, and transplant-related variables with mortality and chronic graft-versus-host disease, while Wilcoxon, Kruskal-Wallis, or linear trend tests were applied for the estimates of healthcare utilization. Among 161 patients with a 2-year overall survival rate of 90% (95% confidence interval [CI] 85-95%) mortality was significantly higher in those who underwent late transplantation versus early (hazard ratio (HR) 21, 95% CI 2.8-160.8, P=0.003) and unrelated compared to matched sibling donor transplantation (HR 5.9, 95% CI 1.7-20.2, P=0.005). Chronic graftversus host disease was significantly more frequent among those translanted late (HR 1.9, 95% CI 1.0-3.5, P=0.034) and those who received an unrelated graft (HR 2.5, 95% CI 1.2-5.4; P=0.017). Merged data for 176 patients showed that the median total adjusted transplant cost per patient was $467,747 (range: $344,029-$799,219). Healthcare utilization was lower among recipients of matched sibling donor grafts and those with low severity disease compared to those with other types of donor and disease severity types (P<0.001 and P=0.022, respectively); no association was demonstrated with late transplantation (P=0.775). Among patients with 2-year pre- and post-transplant data (n=41), early transplantation was associated with significant reductions in admissions (P<0.001), length of stay (P<0.001), and cost (P=0.008). Early transplant outcomes need to be studied prospectively in young children without severe disease and an available matched sibling to provide conclusive evidence for the superiority of this approach. Reduced post-transplant healthcare utilization inpatient care indicates that transplantation may provide a sustained decrease in healthcare costs over time.

Spatially-dense 3D facial asymmetry assessment in both typical and disordered growth.

Mild facial asymmetries are common in typical growth patterns. Therefore, detection of disordered facial growth patterns in individuals characterized by asymmetries is preferably accomplished by reference to the typical variation found in the general population rather than to some ideal of perfect symmetry, which rarely exists. This presents a challenge in developing an asymmetry assessment tool that is applicable, without modification, to detect both mild and severe facial asymmetries. In this paper we use concepts from geometric morphometrics to obtain robust and spatially-dense asymmetry assessments using a superimposition protocol for comparison of a face with its mirror image. Spatially-dense localization of asymmetries was achieved using an anthropometric mask consisting of uniformly sampled quasi-landmarks that were automatically indicated on 3D facial images. Robustness, in the sense of an unbiased analysis under increasing asymmetry, was ensured by an adaptive, robust, least-squares superimposition. The degree of overall asymmetry in an individual was scored using a root-mean-squared-error, and the proportion was scored using a novel relative significant asymmetry percentage. This protocol was applied to a database of 3D facial images from 359 young healthy individuals and three individuals with disordered facial growth. Typical asymmetry statistics were derived and were mainly located on, but not limited to, the lower two-thirds of the face in males and females. The asymmetry in males was more extensive and of a greater magnitude than in females. This protocol and proposed scoring of asymmetry with accompanying reference statistics will be useful for the detection and quantification of facial asymmetry in future studies.

Objective assessment of vaginal surgical skills.

OBJECTIVE: To develop and validate an instrument to assess surgical skills during vaginal surgery. STUDY DESIGN: Trainees from 2 institutions were directly assessed in the operating room by supervising surgeons while performing a vaginal hysterectomy using the new Vaginal Surgical Skills Index, global rating scale, and visual analogue scale. Trainees were assessed again by the same surgeons 4 weeks after the live surgery and by a blinded outside reviewer using a videotape of the case. Internal consistency, interrater and intrarater reliability, and construct validity were evaluated. RESULTS: Two hundred twelve evaluations were analyzed on 76 surgeries from 27 trainees. There was good internal consistency, interrater, and intrarater reliability. Vaginal Surgical Skills Index scores correlated with global rating score and visual analog scale scores. Increasing Vaginal Surgical Skills Index scores significantly correlated with year of training and surgical volume with an estimated increase in score of 0.3 per hysterectomy performed. CONCLUSION: The Vaginal Surgical Skills Index is a feasible, reliable, and valid instrument to assess vaginal surgical skills.

A prospective assessment of overactive bladder symptoms in a cohort of elderly women who underwent transvaginal surgery for advanced pelvic organ prolapse.

OBJECTIVE: The objective of this study was to evaluate the impact of transvaginal prolapse surgery on overactive bladder symptoms in elderly women. STUDY DESIGN: Women (> or = 65 years old) with stage III or IV prolapse who enrolled in a prospective study that compared vaginal reconstructive surgery (n = 39) to obliterative surgery (n = 26) and who underwent preoperative urodynamics are the subjects of this study. The women completed the Pelvic Floor Distress Inventory at baseline and again 6 months and 12 months after surgery. Postoperative changes in symptoms of urinary urgency, frequency, and urge urinary incontinence were assessed. The association between a baseline urodynamic diagnosis of detrusor overactivity and pre- and postoperative overactive bladder symptoms was also determined. RESULTS: Data were analyzed from 65 subjects with a mean age of 75.3 years (range, 65.5-87.0 years). Detrusor overactivity was documented in 25% of subjects. There was no difference in the proportion of baseline urge incontinence (P = .38), urinary frequency (P = .53), or urgency (P = .76) in comparing women with and without detrusor overactivity. Surgery resulted in a significant reduction of urgency and frequency symptoms 6 months after surgery and a similar significant reduction in urgency and urge incontinence at 1 year after surgery. Overall, a clinically and statistically significant improvement in the irritative subscale of the Pelvic Floor Distress Inventory was noted at 6 months (18.3%; P < .0001) and 12 months (17.6%; P < .0001) after surgery. In our cohort, performance of a mid urethral sling, a bladder neck sling, or a Kelly plication was not associated with a reduction in postoperative symptoms of urgency, frequency, or urge incontinence (P = .48). Likewise, there was no difference in postoperative symptom reduction (urgency, frequency, or urge incontinence) between women who received reconstructive surgery vs women who had obliterative surgery (P = .84). CONCLUSION: Vaginal surgery for stage III or IV pelvic organ prolapse significantly reduces overactive bladder symptoms in elderly women. In our cohort, symptom reduction was unrelated to the type of vaginal surgery (obliterative vs reconstructive) or the inclusion of a procedure to treat stress incontinence. Furthermore, preoperative urodynamic findings did not correlate with the presence or absence of overactive bladder symptoms.

Outcomes of preimplantation genetic diagnosis therapy in treatment of beta-thalassemia: A retrospective analysis.

Thalassemia is one of the most common single-gene disorders that can be cured by hematopoietic stem cell transplantation (HCT) from a human leukocyte antigen (HLA)-identical sibling donor. In families that have an affected child, preimplantation genetic diagnosis (PGD) can be used to select an unaffected, HLA-identical embryo. In brief, this procedure requires in vitro fertilization, oocyte retrieval, fertilization, and blastomere biopsy for identification of unaffected HLA-identical embryos. After delivery, umbilical cord blood from the sibling donor is collected for HCT. The objective of this study was to determine the outcomes of families using PGD therapy for cure of beta-thalassemia and to review the limitations of PGD therapy. Families affected with beta-thalassemia who attempted PGD therapy were retrospectively identified and reviewed for indication, attempted cycles, successful pregnancy, and transplantation outcomes. Eight identified families affected by thalassemia underwent PGD. The diagnosis of their affected children included six cases of beta-thalassemia major and two cases of transfusion-dependent hemoglobin E-beta-thalassemia patients. A total of 14 cycles of PGD were attempted, ranging from one to four attempts per family. Following successful identification of HLA-identical cells, two pregnancies occurred, of which one resulted in engraftment of a beta-thalassemia child. PGD therapy offers the possibility of recruiting a suitable donor for HCT, yet is limited by financial cost due to labor-intensive techniques, low probability of obtaining an HLA-matched unaffected embryo, variable implantation capacity, and significant emotional impact. Improvements in PGD therapy's efficacy and cost will make this a more viable option for affected families.