Runs of homozygosity in killer whale genomes provide a global record of demographic histories.

Runs of homozygosity (ROH) occur when offspring inherit haplotypes that are identical by descent from each parent. Length distributions of ROH are informative about population history; specifically, the probability of inbreeding mediated by mating system and/or population demography. Here, we investigated whether variation in killer whale (Orcinus orca) demographic history is reflected in genome-wide heterozygosity and ROH length distributions, using a global data set of 26 genomes representative of geographic and ecotypic variation in this species, and two F1 admixed individuals with Pacific-Atlantic parentage. We first reconstructed demographic history for each population as changes in effective population size through time using the pairwise sequential Markovian coalescent (PSMC) method. We found a subset of populations declined in effective population size during the Late Pleistocene, while others had more stable demography. Genomes inferred to have undergone ancestral declines in effective population size, were autozygous at hundreds of short ROH (<1 Mb), reflecting high background relatedness due to coalescence of haplotypes deep within the pedigree. In contrast, longer and therefore younger ROH (>1.5 Mb) were found in low latitude populations, and populations of known conservation concern. These include a Scottish killer whale, for which 37.8% of the autosomes were comprised of ROH >1.5 Mb in length. The fate of this population, in which only two adult males have been sighted in the past five years, and zero fecundity over the last two decades, may be inextricably linked to its demographic history and consequential inbreeding depression.

Oceanographic barriers, divergence, and admixture: Phylogeography and taxonomy of two putative subspecies of short-finned pilot whale.

Genomic phylogeography plays an important role in describing evolutionary processes and their geographic, ecological, or cultural drivers. These drivers are often poorly understood in marine environments, which have fewer obvious barriers to mixing than terrestrial environments. Taxonomic uncertainty of some taxa (e.g., cetaceans), due to the difficulty in obtaining morphological data, can hamper our understanding of these processes. One such taxon, the short-finned pilot whale, is recognized as a single global species but includes at least two distinct morphological forms described from stranding and drive hunting in Japan, the "Naisa" and "Shiho" forms. Using samples (n = 735) collected throughout their global range, we examine phylogeographic patterns of divergence by comparing mitogenomes and nuclear SNP loci. Our results suggest three types within the species: an Atlantic Ocean type, a western/central Pacific and Indian Ocean (Naisa) type, and an eastern Pacific Ocean and northern Japan (Shiho) type. mtDNA control region differentiation indicates these three types form two subspecies, separated by the East Pacific Barrier: Shiho short-finned pilot whale, in the eastern Pacific Ocean and northern Japan, and Naisa short-finned pilot whale, throughout the remainder of the species' distribution. Our data further indicate two diverging populations within the Naisa subspecies, in the Atlantic Ocean and western/central Pacific and Indian Oceans, separated by the Benguela Barrier off South Africa. This study reveals a process of divergence and speciation within a globally-distributed, mobile marine predator, and indicates the importance of the East Pacific Barrier to this evolutionary process.

Killer whale genomes reveal a complex history of recurrent admixture and vicariance.

Reconstruction of the demographic and evolutionary history of populations assuming a consensus tree-like relationship can mask more complex scenarios, which are prevalent in nature. An emerging genomic toolset, which has been most comprehensively harnessed in the reconstruction of human evolutionary history, enables molecular ecologists to elucidate complex population histories. Killer whales have limited extrinsic barriers to dispersal and have radiated globally, and are therefore a good candidate model for the application of such tools. Here, we analyse a global data set of killer whale genomes in a rare attempt to elucidate global population structure in a nonhuman species. We identify a pattern of genetic homogenisation at lower latitudes and the greatest differentiation at high latitudes, even between currently sympatric lineages. The processes underlying the major axis of structure include high drift at the edge of species' range, likely associated with founder effects and allelic surfing during postglacial range expansion. Divergence between Antarctic and non-Antarctic lineages is further driven by ancestry segments with up to four-fold older coalescence time than the genome-wide average; relicts of a previous vicariance during an earlier glacial cycle. Our study further underpins that episodic gene flow is ubiquitous in natural populations, and can occur across great distances and after substantial periods of isolation between populations. Thus, understanding the evolutionary history of a species requires comprehensive geographic sampling and genome-wide data to sample the variation in ancestry within individuals.

Demography or selection on linked cultural traits or genes? Investigating the driver of low mtDNA diversity in the sperm whale using complementary mitochondrial and nuclear genome analyses.

Mitochondrial DNA has been heavily utilized in phylogeography studies for several decades. However, underlying patterns of demography and phylogeography may be misrepresented due to coalescence stochasticity, selection, variation in mutation rates and cultural hitchhiking (linkage of genetic variation to culturally-transmitted traits affecting fitness). Cultural hitchhiking has been suggested as an explanation for low genetic diversity in species with strong social structures, counteracting even high mobility, abundance and limited barriers to dispersal. One such species is the sperm whale, which shows very limited phylogeographic structure and low mtDNA diversity despite a worldwide distribution and large population. Here, we use analyses of 175 globally distributed mitogenomes and three nuclear genomes to evaluate hypotheses of a population bottleneck/expansion vs. a selective sweep due to cultural hitchhiking or selection on mtDNA as the mechanism contributing to low worldwide mitochondrial diversity in sperm whales. In contrast to mtDNA control region (CR) data, mitogenome haplotypes are largely ocean-specific, with only one of 80 shared between the Atlantic and Pacific. Demographic analyses of nuclear genomes suggest low mtDNA diversity is consistent with a global reduction in population size that ended approximately 125,000 years ago, correlated with the Eemian interglacial. Phylogeographic analysis suggests that extant sperm whales descend from maternal lineages endemic to the Pacific during the period of reduced abundance and have subsequently colonized the Atlantic several times. Results highlight the apparent impact of past climate change, and suggest selection and hitchhiking are not the sole processes responsible for low mtDNA diversity in this highly social species.

Management of Atypical Renal Cell Carcinomas.

OPINION STATEMENT: Non-clear cell renal cell carcinoma (RCC) encompasses a diverse group of diseases, with research yielding different histologic findings and genetic profiles with each distinct subgroup. Simply mirroring the management techniques of clear cell RCC and borrowing from its growing armamentarium of therapeutic agents, while somewhat productive at first, but will ultimately be limiting. Further investigation into the molecular pathogenesis of disease, similarities and differences between specific subtypes, and mechanisms of resistance to therapeutics will help identify new targets, stimulate development of novel agents, and improve clinical trial offerings for non-clear cell RCC (nccRCC). As nccRCC has been largely excluded from past trials, there will be a need for future trials to be designed either to evaluate nccRCC specifically, or to include nccRCC as a prespecified subgroup. Multi-center collaborative trials should be supported, as many of the nccRCC subtypes are rare and remain underrepresented even within the construct of trials that only enroll nccRCC. Given the absence of clear molecular targets at present, patients with metastatic nccRCC should be offered and encouraged enrollment on clinical studies whenever possible.

Platform dependencies in bottom-up hydrogen/deuterium exchange mass spectrometry.

Hydrogen-deuterium exchange mass spectrometry is an important method for protein structure-function analysis. The bottom-up approach uses protein digestion to localize deuteration to higher resolution, and the essential measurement involves centroid mass determinations on a very large set of peptides. In the course of evaluating systems for various projects, we established two (HDX-MS) platforms that consisted of a FT-MS and a high-resolution QTOF mass spectrometer, each with matched front-end fluidic systems. Digests of proteins spanning a 20-110 kDa range were deuterated to equilibrium, and figures-of-merit for a typical bottom-up (HDX-MS) experiment were compared for each platform. The Orbitrap Velos identified 64% more peptides than the 5600 QTOF, with a 42% overlap between the two systems, independent of protein size. Precision in deuterium measurements using the Orbitrap marginally exceeded that of the QTOF, depending on the Orbitrap resolution setting. However, the unique nature of FT-MS data generates situations where deuteration measurements can be inaccurate, because of destructive interference arising from mismatches in elemental mass defects. This is shown through the analysis of the peptides common to both platforms, where deuteration values can be as low as 35% of the expected values, depending on FT-MS resolution, peptide length and charge state. These findings are supported by simulations of Orbitrap transients, and highlight that caution should be exercised in deriving centroid mass values from FT transients that do not support baseline separation of the full isotopic composition.

Evolution of the MHC-DQB exon 2 in marine and terrestrial mammals.

On the basis of a general low polymorphism, several studies suggest that balancing selection in the class II major histocompatibility complex (MHC) is weaker in marine mammals as compared with terrestrial mammals. We investigated such differential selection among Cetacea, Artiodactyla, and Primates at exon 2 of MHC-DQB gene by contrasting indicators of molecular evolution such as occurrence of transpecific polymorphisms, patterns of phylogenetic branch lengths by codon position, rates of nonsynonymous and synonymous substitutions as well as accumulation of variable sites on the sampling of alleles. These indicators were compared between the DQB and the mitochondrial cytochrome b gene (cytb) as a reference of neutral expectations and differences between molecular clocks resulting from life history and historical demography. All indicators showed that the influence of balancing selection on the DQB is more variable and overall weaker for cetaceans. In our sampling, ziphiids, the sperm whale, monodontids and the finless porpoise formed a group with lower DQB polymorphism, while mysticetes exhibited a higher DQB variation similar to that of terrestrial mammals as well as higher occurrence of transpecific polymorphisms. Different dolphins appeared in the two groups. Larger variation of selection on the cetacean DQB could be related to greater stochasticity in their historical demography and thus, to a greater complexity of the general ecology and disease processes of these animals.

Intervention in childbirth: should we allow women to choose?

The issue of whether women should be able to choose to give birth by caesarean section in the absence of pregnancy complications remains a controversial topic. To explore the issues and allow the public the opportunity to voice their views, academics at Bournemouth University organised a public debate on the pros and cons of allowing women free choice with regard to intervention. Two teams, each with a well-known user representative, an experienced practitioner and an academic, debated the motion: "This house believes that women should be able to choose caesarean section on demand." This paper reports the debate and the public vote on the motion.

Quantification by droplet digital PCR and species identification by metabarcoding of environmental (e)DNA from Blainville's beaked whales, with assisted localization from an acoustic array.

Detection and identification of species, subspecies or stocks of whales, dolphins and porpoises at sea remain challenging, particularly for cryptic or elusive species like beaked whales (Family: Ziphiidae). Here we investigated the potential for using an acoustically assisted sampling design to collect environmental (e)DNA from beaked whales on the U.S. Navy's Atlantic Undersea Test and Evaluation Center (AUTEC) in The Bahamas. During 12 days of August 2019, we conducted 9 small-boat surveys and collected 56 samples of seawater (paired subsamples of 1L each, including controls) using both a spatial collection design in the absence of visual confirmation of whales, and a serial collection design in the proximity of whales at the surface. There were 7 sightings of whales, including 11 Blainville's beaked whales (Mesoplodon densirostris). All whales were located initially with the assistance of information from a bottom-mounted acoustic array available on the AUTEC range. Quantification by droplet digital (dd)PCR from the four spatial design collections showed no samples of eDNA above the threshold of detection and none of these 20 samples yielded amplicons for conventional or next-generation sequencing. Quantification of the 31 samples from four serial collections identified 11 likely positive detections. eDNA barcoding by conventional sequencing and eDNA metabarcoding by next-generation sequencing confirmed species identification for 9 samples from three of the four serial collections. We further resolved five intra-specific variants (i.e., haplotypes), two of which showed an exact match to previously published haplotypes and three that have not been reported previously to the international repository, GenBank. A minimum spanning network of the five eDNA haplotypes, with all other published haplotypes of Blainville's beaked whales, suggested the potential for further resolution of differences between oceanic populations.

Parent and emergency physician comfort with a system of on-line emergency-focused medical summaries for infants with significant cardiac disease.

Surveys were developed and administered to assess parental comfort with emergency care for children with special health care needs (CSHCN) with cardiac disease and the impact of a web-based database of emergency-focused clinical summaries (emergency information forms-EIF) called Midwest Emergency Medical Services for Children Information System (MEMSCIS) on parental attitudes regarding emergency care of their CSHCN. We hypothesized that MEMSCIS would improve the parent and provider outlook regarding emergencies of young children with heart disease in a randomized controlled trial. Children under age 2 were enrolled in MEMSCIS by study nurses associated with pediatric cardiac centers in a metropolitan area. Parents were surveyed at enrollment and 1 year on a 5-Point Likert Scale. Validity and reliability of the survey were evaluated. Study nurses formulated the emergency-focused summaries with cardiologists. One-hundred-seventy parent subjects, 94 study and 76 control, were surveyed at baseline and 1 year. Parents felt that hospital personnel were well-prepared for emergencies of their children and this improved from baseline 4.07 ± 1.03 to 1 year 4.24 ± 1.04 in study parents who had an EIF for their child and participated in the program (p = 0.0114) but not control parents. Parents perceived an improved comfort level by pre-hospital (p = 0.0256) and hospital (p = 0.0031) emergency personnel related to the MEMSCIS program. The MEMSCIS Program with its emergency-focused web-based clinical summary improved comfort levels for study parents. We speculate that the program facilitated normalization for parents even if the EIF was not used in an emergency during the study. The MEMSCIS program helps to prepare the family and the emergency system for care of CSHCN outside of the medical home.

Tracking bacterial lineages in complex and dynamic environments with applications for growth control and persistence.

As bacteria transition from exponential to stationary phase, they change substantially in size, morphology, growth and expression profiles. These responses also vary between individual cells, but it has proved difficult to track cell lineages along the growth curve to determine the progression of events or correlations between how individual cells enter and exit dormancy. Here, we developed a platform for tracking more than 105 parallel cell lineages in dense and changing cultures, independently validating that the imaged cells closely track batch populations. Initial applications show that for both Escherichia coli and Bacillus subtilis, growth changes from an 'adder' mode in exponential phase to mixed 'adder-timers' entering stationary phase, and then a near-perfect 'sizer' upon exit-creating broadly distributed cell sizes in stationary phase but rapidly returning to narrowly distributed sizes upon exit. Furthermore, cells that undergo more divisions when entering stationary phase suffer reduced survival after long periods of dormancy but are the only cells observed that persist following antibiotic treatment.

Long-term outcomes of pediatric laparoscopic needled-assisted inguinal hernia repair: A 10-year experience.

PURPOSE: Laparoscopic inguinal hernia repair (LIHR) has gained wide acceptance over the past decade, although studies with longer term follow-up are lacking. We present one of the largest cohorts of children undergoing laparoscopic needle-assisted repair (LNAR) with long-term follow-up. METHODS: A clinical quality database was maintained for children ≤14 years of age who underwent laparoscopic needle-assisted repair between 2009 and 2017 with review of follow-up through 2019. De-identified data was reviewed. RESULTS: 1023 patients with 1457 LNAR were included during the 10-year period. Mean age at surgery was 2.56 years (2 days to14 years). The overall hernia recurrence rate was 0.75% (11/1457). A total of four postoperative hydroceles required intervention. Preterm infant repair done <60w post conceptional age had a significantly lower recurrence rate (0.63%) than other patients (0.82%) (p < 0.01). 64.2% of patients had clinical follow-up over a period of 11 years with a mean follow-up of 5.97 years. CONCLUSION: We present a large cohort study of consecutive pediatric laparoscopic hernia repairs followed over an 11-year period. LNAR is safe and effective for term and preterm patients with similar complication rates to other techniques, including open repair. Additionally, our results suggest that preterm infants may have superior outcomes with this method. LEVEL OF EVIDENCE: Level III - Retrospective Comparative Study.

Hydra: software for tailored processing of H/D exchange data from MS or tandem MS analyses.

BACKGROUND: Hydrogen/deuterium exchange mass spectrometry (H/DX-MS) experiments implemented to characterize protein interaction and protein folding generate large quantities of data. Organizing, processing and visualizing data requires an automated solution, particularly when accommodating new tandem mass spectrometry modes for H/DX measurement. We sought to develop software that offers flexibility in defining workflows so as to support exploratory treatments of H/DX-MS data, with a particular focus on the analysis of very large protein systems and the mining of tandem mass spectrometry data. RESULTS: We present a software package ("Hydra") that supports both traditional and exploratory treatments of H/DX-MS data. Hydra's software architecture tolerates flexible data analysis procedures by allowing the addition of new algorithms without significant change to the underlying code base. Convenient user interfaces ease the organization of raw data files and input of peptide data. After executing a user-defined workflow, extracted deuterium incorporation values can be visualized in tabular and graphical formats. Hydra also automates the extraction and visualization of deuterium distribution values. Manual validation and assessment of results is aided by an interface that aligns extracted ion chromatograms and mass spectra, while providing a means of rapidly reprocessing the data following manual adjustment. A unique feature of Hydra is the automated processing of tandem mass spectrometry data, demonstrated on a large test data set in which 40,000 deuterium incorporation values were extracted from replicate analysis of approximately 1000 fragment ions in one hour using a typical PC. CONCLUSION: The customizable workflows and user-friendly interfaces of Hydra removes a significant bottleneck in processing and visualizing H/DX-MS data and helps the researcher spend more time executing new experiments and interpreting results. This increased efficiency will encourage the analysis of larger protein systems. The ability to accommodate the tandem MS dimension supports alternative data collection and analysis strategies, as well as higher resolution localization of deuteration where permitted by the fragmentation mechanism.

A worldwide perspective on the population structure and genetic diversity of bottlenose dolphins (Tursiops truncatus) in New Zealand.

Bottlenose dolphins (Tursiops truncatus) occupy a wide range of coastal and pelagic habitats throughout tropical and temperate waters worldwide. In some regions, "inshore" and "offshore" forms or ecotypes differ genetically and morphologically, despite no obvious boundaries to interchange. Around New Zealand, bottlenose dolphins inhabit 3 coastal regions: Northland, Marlborough Sounds, and Fiordland. Previous demographic studies showed no interchange of individuals among these populations. Here, we describe the genetic structure and diversity of these populations using skin samples collected with a remote biopsy dart. Analysis of the molecular variance from mitochondrial DNA (mtDNA) control region sequences (n = 193) showed considerable differentiation among populations (F(ST) = 0.17, Phi(ST) = 0.21, P < 0.001) suggesting little or no female gene flow or interchange. All 3 populations showed higher mtDNA diversity than expected given their small population sizes and isolation. To explain the source of this variation, 22 control region haplotypes from New Zealand were compared with 108 haplotypes worldwide representing 586 individuals from 19 populations and including both inshore and offshore ecotypes as described in the Western North Atlantic. All haplotypes found in the Pacific, regardless of population habitat use (i.e., coastal or pelagic), are more divergent from populations described as inshore ecotype in the Western North Atlantic than from populations described as offshore ecotype. Analysis of gene flow indicated long-distance dispersal among coastal and pelagic populations worldwide (except for those haplotypes described as inshore ecotype in the Western North Atlantic), suggesting that these populations are interconnected on an evolutionary timescale. This finding suggests that habitat specialization has occurred independently in different ocean basins, perhaps with Tursiops aduncus filling the ecological niche of the inshore ecotype in some coastal regions of the Indian and Western Pacific Oceans.

Single-cell microscopy of suspension cultures using a microfluidics-assisted cell screening platform.

Studies that rely on fluorescence imaging of nonadherent cells that are cultured in suspension, such as Escherichia coli, are often hampered by trade-offs that must be made between data throughput and imaging resolution. We developed a platform for microfluidics-assisted cell screening (MACS) that overcomes this trade-off by temporarily immobilizing suspension cells within a microfluidics chip. This enables high-throughput and automated single-cell microscopy for a wide range of cell types and sizes. As cells can be rapidly sampled directly from a suspension culture, MACS bypasses the need for sample preparation, and therefore allows measurements without perturbing the native cell physiology. The setup can also be integrated with complex growth chambers, and can be used to enrich or sort the imaged cells. Furthermore, MACS facilitates the visualization of individual cytoplasmic fluorescent proteins (FPs) in E. coli, allowing low-abundance proteins to be counted using standard total internal reflection fluorescence (TIRF) microscopy. Finally, MACS can be used to impart mechanical pressure for assessing the structural integrity of individual cells and their response to mechanical perturbations, or to make cells take up chemicals that otherwise would not pass through the membrane. This protocol describes the assembly of electronic control circuitry, the construction of liquid-handling components and the creation of the MACS microfluidics chip. The operation of MACS is described, and automation software is provided to integrate MACS control with image acquisition. Finally, we provide instructions for extending MACS using an external growth chamber (1 d) and for how to sort rare cells of interest.

A microvascular compartment model validated using 11C-methylglucose liver PET in pigs.

The standard compartment model (CM) is widely used to analyse dynamic PET data. The CM is fitted to time-activity curves to estimate rate constants that describe the transport of a tracer between well-mixed compartments. The aim of this study was to develop and validate a more realistic microvascular compartment model (MCM) that includes capillary tracer concentration gradients, backflux from cells into the perfused capillaries and multiple re-uptakes during the passage through a capillary. The MCM incorporates only parameters with clear physiological meaning, it is easy to implement, and it does not require numerical solution. We compared the MCM and CM for the analysis of 3 min dynamic PET data of pig livers (N = 5) following injection of 11C-methylglucose. During PET scans, the tracer concentrations in blood were measured in the abdominal aorta, portal vein and liver vein by manual sampling. We found that the MCM outperformed the CM and that dynamic PET data include information which cannot be extracted using standard CM. The MCM fitted dynamic PET data better than the CM (Akaike values were 46 ± 4 for best MCM fits, and 82 ± 8 for best CM fits; mean ± standard deviation) and extracted physiologically reasonable parameter estimates such as blood perfusion that were in agreement with independent measurements. The difference between model-independent perfusion estimates and the best MCM perfusion estimates was -0.01 ± 0.05 ml/ml/min, whereas the difference was 0.30 ± 0.13 ml/ml/min using the CM. In addition, the MCM predicted the time course of concentrations in the liver vein, a prediction fundamentally unobtainable using the CM as it does not return tracer backflux from cells to capillary blood. The results demonstrate the benefit of using models that include more physiology and that models including concentration gradients should be preferred when analysing the blood-cell exchange of any tracer in any capillary bed.

Federated optimisation of kinetic analysis problems.

Positron Emission Tomography (PET) data is intrinsically dynamic, and kinetic analysis of dynamic PET data can substantially augment the information provided by static PET reconstructions. Yet despite the insights into disease that kinetic analysis offers, it is not used clinically and seldom used in research beyond the preclinical stage. The utility of PET kinetic analysis is hampered by several factors including spatial inconsistency within regions of homogeneous tissue and relative computational expense when fitting complex models to individual voxels. Even with sophisticated algorithms inconsistencies can arise because local optima frequently have narrow basins of convergence, are surrounded by relatively flat (uninformative) regions, have relatively low-gradient valley floors, or combinations thereof. Based on the observation that cost functions for individual voxels frequently bear some resemblance to each-other, this paper proposes the federated optimisation of the individual kinetic analysis problems within a given image. This approach shares parameters proposed during optimisation with other, similar voxels. Federated optimisation exploits the redundancy typical of large medical images to improve the optimisation residuals, computational efficiency and, to a limited extent, image consistency. This is achieved without restricting the formulation of the kinetic model, resorting to an explicit regularisation parameter, or limiting the resolution at which parameters are computed.

Telemedicine-Enabled Clinical Trial of Metformin in Patients With Prostate Cancer.

PURPOSE: Clinical trials are critical to informing cancer care but often are hampered by slow accrual and lack of generalizability because of poor geographic accessibility. We tested the feasibility of replacing onsite study visits with telemedicine visits in a prospective clinical trial. METHODS: Castration-naïve patients with prostate cancer and a rising serum prostate-specific antigen after definitive local therapy were eligible. Patients were required to have a single onsite visit for enrollment. Study treatment consisted of oral metformin 850 mg daily for 1 month followed by 850 mg twice daily for 5 months. Telehealth video visits (televisits) were conducted monthly by using a Health Insurance Portability and Accountability Act-compliant smartphone application. The primary objective was to determine the feasibility of telemedicine-enabled study visits. Secondary objectives were defining safety, anticancer activity, quality of life, and patient satisfaction. RESULTS: Fifteen patients with a median age of 68 years (range, 57 to 83 years) and median one-way driving time to the study center of 71 minutes (range, 12 to 147 minutes) were enrolled. The patients completed 84 eligible televisits (completion rate, 100%; 95% CI, 0.80 to 1). Diarrhea was the most common adverse event but was limited to grade 1 in severity; a single patient experienced grade ≥ 3 adverse events. Seven patients (46.7%; 95% CI, 24.8% to 69.9%) had a ≤ 20% increase in prostate-specific antigen relative to baseline. Patients agreed or strongly agreed that they would participate in a telemedicine-enabled clinical trial in the future. CONCLUSION: To our knowledge, this interventional oncology clinical trial is the first to be conducted through telemedicine. Telemedicine-enabled trials are feasible and may overcome geographic barriers to trial participation. Metformin was generally well tolerated but associated with modest anticancer activity.

Web-Based Tool to Facilitate Shared Decision Making With Regard to Neoadjuvant Chemotherapy Use in Muscle-Invasive Bladder Cancer.

PURPOSE: Level 1 evidence supports the use of neoadjuvant chemotherapy (NAC) for the treatment of muscle-invasive bladder cancer (MIBC), but observational data demonstrate that this approach is underused. A barrier to shared decision making is difficulty in predicting and communicating survival estimates after cystectomy with or without NAC. METHODS: We included patients with MIBC from the National Cancer Database treated with cystectomy. A state-transition model was constructed for calculating 5-year death risk using baseline patient-, tumor-, and facility-level variables. Internal-external cross-validation by geographic region was performed. The effect of NAC was integrated using a literature-derived hazard ratio. Bladder cancer-specific and other-cause mortality was estimated from all-cause mortality rates from US life tables. From the state-transition model, a Web-based tool was developed and pilot usability testing performed. RESULTS: A total of 9,824 patients with MIBC who underwent cystectomy were eligible for inclusion. Median overall survival was 39.6 months (95% CI, 37.4 to 42.4 months). Increasing age, higher clinical T stage, higher comorbidity index, and black race were associated with shorter survival. Private insurance, higher income, and cystectomy at a high-volume facility were associated with longer survival. The prediction model was well calibrated across geographic regions, with observed-to-predicted 5-year death risks ranging from 0.85 to 1.17. Absolute risk reductions with NAC varied from 8.6% to 10.1%. The Web-based tool allowed input of the predictor variables and a user-defined hazard ratio associated with the effect of NAC to generate individualized survival estimates. The tool demonstrated good usability with clinicians. CONCLUSION: A Web-based tool was developed to individualize outcome prediction and communication in patients with MIBC treated with cystectomy with or without NAC to facilitate shared decision making.