Sharing sensitive data in life sciences: an overview of centralized and federated approaches.

Biomedical data are generated and collected from various sources, including medical imaging, laboratory tests and genome sequencing. Sharing these data for research can help address unmet health needs, contribute to scientific breakthroughs, accelerate the development of more effective treatments and inform public health policy. Due to the potential sensitivity of such data, however, privacy concerns have led to policies that restrict data sharing. In addition, sharing sensitive data requires a secure and robust infrastructure with appropriate storage solutions. Here, we examine and compare the centralized and federated data sharing models through the prism of five large-scale and real-world use cases of strategic significance within the European data sharing landscape: the French Health Data Hub, the BBMRI-ERIC Colorectal Cancer Cohort, the federated European Genome-phenome Archive, the Observational Medical Outcomes Partnership/OHDSI network and the EBRAINS Medical Informatics Platform. Our analysis indicates that centralized models facilitate data linkage, harmonization and interoperability, while federated models facilitate scaling up and legal compliance, as the data typically reside on the data generator's premises, allowing for better control of how data are shared. This comparative study thus offers guidance on the selection of the most appropriate sharing strategy for sensitive datasets and provides key insights for informed decision-making in data sharing efforts.

Tectonic trigger to the first major extinction of the Phanerozoic: The early Cambrian Sinsk event.

The Cambrian explosion, one of the most consequential biological revolutions in Earth history, occurred in two phases separated by the Sinsk event, the first major extinction of the Phanerozoic. Trilobite fossil data show that Series 2 strata in the Ross Orogen, Antarctica, and Delamerian Orogen, Australia, record nearly identical and synchronous tectono-sedimentary shifts marking the Sinsk event. These resulted from an abrupt pulse of contractional supracrustal deformation on both continents during the Pararaia janeae trilobite Zone. The Sinsk event extinction was triggered by initial Ross/Delamerian supracrustal contraction along the edge of Gondwana, which caused a cascading series of geodynamic, paleoenvironmental, and biotic changes, including (i) loss of shallow marine carbonate habitats along the Gondwanan margin; (ii) tectonic transformation to extensional tectonics within the Gondwanan interior; (iii) extrusion of the Kalkarindji large igneous province; (iv) release of large volumes of volcanic gasses; and (v) rapid climatic change, including incursions of marine anoxic waters and collapse of shallow marine ecosystems.

Clinical Characterization of Patients Diagnosed with Prostate Cancer and Undergoing Conservative Management: A PIONEER Analysis Based on Big Data.

BACKGROUND: Conservative management is an option for prostate cancer (PCa) patients either with the objective of delaying or even avoiding curative therapy, or to wait until palliative treatment is needed. PIONEER, funded by the European Commission Innovative Medicines Initiative, aims at improving PCa care across Europe through the application of big data analytics. OBJECTIVE: To describe the clinical characteristics and long-term outcomes of PCa patients on conservative management by using an international large network of real-world data. DESIGN, SETTING, AND PARTICIPANTS: From an initial cohort of >100 000 000 adult individuals included in eight databases evaluated during a virtual study-a-thon hosted by PIONEER, we identified newly diagnosed PCa cases (n = 527 311). Among those, we selected patients who did not receive curative or palliative treatment within 6 mo from diagnosis (n = 123 146). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient and disease characteristics were reported. The number of patients who experienced the main study outcomes was quantified for each stratum and the overall cohort. Kaplan-Meier analyses were used to estimate the distribution of time to event data. RESULTS AND LIMITATIONS: The most common comorbidities were hypertension (35-73%), obesity (9.2-54%), and type 2 diabetes (11-28%). The rate of PCa-related symptomatic progression ranged between 2.6% and 6.2%. Hospitalization (12-25%) and emergency department visits (10-14%) were common events during the 1st year of follow-up. The probability of being free from both palliative and curative treatments decreased during follow-up. Limitations include a lack of information on patients and disease characteristics and on treatment intent. CONCLUSIONS: Our results allow us to better understand the current landscape of patients with PCa managed with conservative treatment. PIONEER offers a unique opportunity to characterize the baseline features and outcomes of PCa patients managed conservatively using real-world data. PATIENT SUMMARY: Up to 25% of men with prostate cancer (PCa) managed conservatively experienced hospitalization and emergency department visits within the 1st year after diagnosis; 6% experienced PCa-related symptoms. The probability of receiving therapies for PCa decreased according to time elapsed after the diagnosis.

Data sharing in neurodegenerative disease research: challenges and learnings from the innovative medicines initiative public-private partnership model.

Efficient data sharing is hampered by an array of organizational, ethical, behavioral, and technical challenges, slowing research progress and reducing the utility of data generated by clinical research studies on neurodegenerative diseases. There is a particular need to address differences between public and private sector environments for research and data sharing, which have varying standards, expectations, motivations, and interests. The Neuronet data sharing Working Group was set up to understand the existing barriers to data sharing in public-private partnership projects, and to provide guidance to overcome these barriers, by convening data sharing experts from diverse projects in the IMI neurodegeneration portfolio. In this policy and practice review, we outline the challenges and learnings of the WG, providing the neurodegeneration community with examples of good practices and recommendations on how to overcome obstacles to data sharing. These obstacles span organizational issues linked to the unique structure of cross-sectoral, collaborative research initiatives, to technical issues that affect the storage, structure and annotations of individual datasets. We also identify sociotechnical hurdles, such as academic recognition and reward systems that disincentivise data sharing, and legal challenges linked to heightened perceptions of data privacy risk, compounded by a lack of clear guidance on GDPR compliance mechanisms for public-private research. Focusing on real-world, neuroimaging and digital biomarker data, we highlight particular challenges and learnings for data sharing, such as data management planning, development of ethical codes of conduct, and harmonization of protocols and curation processes. Cross-cutting solutions and enablers include the principles of transparency, standardization and co-design - from open, accessible metadata catalogs that enhance findability of data, to measures that increase visibility and trust in data reuse.

Gill function in an early arthropod and the widespread adoption of the countercurrent exchange mechanism.

Rising but fluctuating oxygen levels in the Early Palaeozoic provide an environmental context for the radiation of early metazoans, but little is known about how mechanistically early animals satisfied their oxygen requirements. Here we propose that the countercurrent gaseous exchange, a highly efficient respiratory mechanism, was effective in the gills of the Late Ordovician trilobite Triarthrus eatoni. In order to test this, we use computational fluid dynamics to simulate water flow around its gills and show that water velocity decreased distinctly in front of and between the swollen ends, which first encountered the oxygen-charged water, and slowed continuously at the mid-central region, forming a buffer zone with a slight increase of the water volume. In T. eatoni respiratory surface area was maximized by extending filament height and gill shaft length. In comparison with the oxygen capacity of modern fish and crustaceans, a relatively low weight specific area in T. eatoni may indicate its low oxygen uptake, possibly related to a less active life mode. Exceptionally preserved respiratory structures in the Cambrian deuterostome Haikouella are also consistent with a model of countercurrent gaseous exchange, exemplifying the wide adoption of this strategy among early animals.

Developmental and functional controls on enrolment in an ancient, extinct arthropod.

Three-dimensional models reveal how the mechanics of exoskeletal enrolment changed during the development of a model organism for insights into ancient arthropod development, the 429-million-year-old trilobite Aulacopleura koninckii. Changes in the number, size and allocation of segments within the trunk, coupled with the need to maintain effective exoskeletal shielding of soft tissue during enrolment, necessitated a transition in enrolment style about the onset of mature growth. During an earlier growth phase, enrolment was sphaeroidal, with the venter of the trunk fitting exactly against that of the head. In later growth, if lateral exoskeletal encapsulation was to be maintained trunk length proportions did not permit such exact fitting, requiring an alternative, non-sphaeoridal enrolment style. Our study favours the adoption of a posture in later growth in which the posterior trunk extended beyond the front of the head. This change in enrolment accommodated a pattern of notable variation in the number of mature trunk segments, well known to characterize the development of this species. It suggests how an animal whose early segmental development was remarkably precisely controlled was able to realize the marked variation in mature segment number that was related, apparently, to life in a physically challenging, reduced oxygen setting.

A concentric circles view of health data relations facilitates understanding of sociotechnical challenges for learning health systems and the role of federated data networks.

The ability to use clinical and research data at scale is central to hopes for data-driven medicine. However, in using such data researchers often encounter hurdles-both technical, such as differing data security requirements, and social, such as the terms of informed consent, legal requirements and patient and public trust. Federated or distributed data networks have been proposed and adopted in response to these hurdles. However, to date there has been little consideration of how FDNs respond to both technical and social constraints on data use. In this Perspective we propose an approach to thinking about data in terms that make it easier to navigate the health data space and understand the value of differing approaches to data collection, storage and sharing. We set out a socio-technical model of data systems that we call the "Concentric Circles View" (CCV) of data-relationships. The aim is to enable a consistent understanding of the fit between the local relationships within which data are produced and the extended socio-technical systems that enable their use. The paper suggests this model can help understand and tackle challenges associated with the use of real-world data in the health setting. We use the model to understand not only how but why federated networks may be well placed to address emerging issues and adapt to the evolving needs of health research for patient benefit. We conclude that the CCV provides a useful model with broader application in mapping, understanding, and tackling the major challenges associated with using real world data in the health setting.

Revision of F. R. C. Reeds Ordovician trilobite types from Myanmar (Burma) and western Yunnan Province, China.

The field collections made from Burma (Myanmar) by the Geological Survey of India, and described by F.R.C. Reed more than a century ago, still provide the only ground truthing for an important region of the Ordovician marginal terranes fringing Gondwana. A revision of these faunas is overdue, particularly as it is likely that further collections cannot be made in the northern Shan State in the near future. The specimens, stored in the Geological Survey of India collections in Kolkata, cannot be loaned. Sixteen species are fully revised herein; another twelve species are left under open nomenclature because of inadequacies in the material. Several of Reeds species subsequently became type species of genera that have proved to be widespread: Birmanites Sheng, 1934, Encrinurella Reed, 1915, Neseuretinus Dean, 1967, and Pliomerina Chugaeva, 1956. Reeds Ordovician trilobite collections came from two main areas: northern Shan State (Myanmar), and westernmost Yunnan (China). The Burmese (Myanmar) collections are from the Upper Ordovician (Katian) while Yunnan specimens are from the Middle Ordovician (Darriwilian), though Upper Ordovician trilobites also occur in the area. Both collections are predominantly from clastic strata. Based on a small new Katian collection from Pupiao, we report Neseuretinus birmanicus (Reed, 1906) in common between the northern part of the Shan State and western Yunnan. A few genera (Dionide Barrande, 1847, Phorocephala Lu, 1957, Lonchodomas Angelin, 1854, Nileus Dalman, 1827) are distributed worldwide, and include pelagic (Phorocephala) or deeper benthic (Dionide) taxa. The palaeogeographic comparisons offered by the other taxa are mostly peri-Gondwanan and extend from southwest China westwards (present geography) as far as the Iberian Pennsula. Birmanites is the type genus of a subfamily (Birmanitinae Kobayashi, 1960, revived herein) widely distributed over Ordovician Gondwana, and absent from Laurentia, Baltica and North China/Siberia. Mioptychopyge Zhou, Dean, Yuan Zhou, 1998, probably belongs with the same group and is otherwise known from South China. Parillaenus Jaanusson, 1954, is also peripheral Gondwanan, as is Prionocheilus Rouault, 1847. The Reedocalymeninae Kobayashi, 1951 (Neseuretinus, Reedocalymene Kobayashi, 1951) are similarly diagnostic of periGondwanan sites. However, some genera (Pliomerina, Encrinurella, Ovalocephalus Koroleva, 1959) have been associated with other oriental and Australian occurrences in particular, with outliers in certain terranes in Kazakhstan, i.e. palaeotropical Gondwana.

European Health Data Space-An Opportunity Now to Grasp the Future of Data-Driven Healthcare.

The May 2022 proposal from the European commission for a 'European health data space' envisages advantages for health from exploiting the growing mass of health data in Europe. However, key stakeholders have identified aspects that demand clarification to ensure success. Data will need to be freed from traditional silos to flow more easily and to cross artificial borders. Wide engagement will be necessary among healthcare professionals, researchers, and the patients and citizens that stand to gain the most but whose trust must be won if they are to allow use or transfer of their data. This paper aims to alert the wider scientific community to the impact the ongoing discussions among lawmakers will have. Based on the literature and the consensus findings of an expert multistakeholder panel organised by the European Alliance for Personalised Medicine (EAPM) in June 2022, it highlights the key issues at the intersection of science and policy, and the potential implications for health research for years, perhaps decades, to come.

Enduring evolutionary embellishment of cloudinids in the Cambrian.

The Ediacaran-Cambrian transition and the following Cambrian Explosion are among the most fundamental events in the evolutionary history of animals. Understanding these events is enhanced when phylogenetic linkages can be established among animal fossils across this interval and their trait evolution monitored. Doing this is challenging because the fossil record of animal lineages that span this transition is sparse, preserved morphologies generally simple and lifestyles in the Ediacaran and Cambrian commonly quite different. Here, we identify derived characters linking some members of an enigmatic animal group, the cloudinids, which first appeared in the Late Ediacaran, to animals with cnidarian affinity from the Cambrian Series 2 and the Miaolingian. Accordingly, we present the first case of an animal lineage represented in the Ediacaran that endured and diversified successfully throughout the Cambrian Explosion by embellishing its overall robustness and structural complexity. Among other features, dichotomous branching, present in some early cloudinids, compares closely with a cnidarian asexual reproduction mode. Tracking this morphological change from Late Ediacaran to the Miaolingian provides a unique glimpse into how a primeval animal group responded during the Cambrian Explosion.

The trilobite upper limb branch is a well-developed gill.

Whether the upper limb branch of Paleozoic "biramous" arthropods, including trilobites, served a respiratory function has been much debated. Here, new imaging of the trilobite Triarthrus eatoni shows that dumbbell-shaped filaments in the upper limb branch are morphologically comparable with gill structures in crustaceans that aerate the hemolymph. In Olenoides serratus, the upper limb's partial articulation to the body via an extended arthrodial membrane is morphologically comparable to the junction of the respiratory book gill of Limulus and differentiates it from the typically robust exopod junction in Chelicerata or Crustacea. Apparently limited mechanical rotation of the upper branch may have protected the respiratory structures. Partial attachment of the upper branch to the body wall may represent an intermediate state in the evolution of limb branch fusion between dorsal attachment to the body wall, as in Radiodonta, and ventral fusion to the limb base, as in extant Euarthropoda.

Common Problems, Common Data Model Solutions: Evidence Generation for Health Technology Assessment.

There is growing interest in using observational data to assess the safety, effectiveness, and cost effectiveness of medical technologies, but operational, technical, and methodological challenges limit its more widespread use. Common data models and federated data networks offer a potential solution to many of these problems. The open-source Observational and Medical Outcomes Partnerships (OMOP) common data model standardises the structure, format, and terminologies of otherwise disparate datasets, enabling the execution of common analytical code across a federated data network in which only code and aggregate results are shared. While common data models are increasingly used in regulatory decision making, relatively little attention has been given to their use in health technology assessment (HTA). We show that the common data model has the potential to facilitate access to relevant data, enable multidatabase studies to enhance statistical power and transfer results across populations and settings to meet the needs of local HTA decision makers, and validate findings. The use of open-source and standardised analytics improves transparency and reduces coding errors, thereby increasing confidence in the results. Further engagement from the HTA community is required to inform the appropriate standards for mapping data to the common data model and to design tools that can support evidence generation and decision making.

Public involvement in the governance of population-level biomedical research: unresolved questions and future directions.

Population-level biomedical research offers new opportunities to improve population health, but also raises new challenges to traditional systems of research governance and ethical oversight. Partly in response to these challenges, various models of public involvement in research are being introduced. Yet, the ways in which public involvement should meet governance challenges are not well understood. We conducted a qualitative study with 36 experts and stakeholders using the World Café method to identify key governance challenges and explore how public involvement can meet these challenges. This brief report discusses four cross-cutting themes from the study: the need to move beyond individual consent; issues in benefit and data sharing; the challenge of delineating and understanding publics; and the goal of clarifying justifications for public involvement. The report aims to provide a starting point for making sense of the relationship between public involvement and the governance of population-level biomedical research, showing connections, potential solutions and issues arising at their intersection. We suggest that, in population-level biomedical research, there is a pressing need for a shift away from conventional governance frameworks focused on the individual and towards a focus on collectives, as well as to foreground ethical issues around social justice and develop ways to address cultural diversity, value pluralism and competing stakeholder interests. There are many unresolved questions around how this shift could be realised, but these unresolved questions should form the basis for developing justificatory accounts and frameworks for suitable collective models of public involvement in population-level biomedical research governance.

Opioid use, postoperative complications, and implant survival after unicompartmental versus total knee replacement: a population-based network study.

BACKGROUND: There is uncertainty around whether to use unicompartmental knee replacement (UKR) or total knee replacement (TKR) for individuals with osteoarthritis confined to a single compartment of the knee. We aimed to emulate the design of the Total or Partial Knee Arthroplasty Trial (TOPKAT) using routinely collected data to assess whether the efficacy results reported in the trial translate into effectiveness in routine practice, and to assess comparative safety. METHODS: We did a population-based network study using data from four US and one UK health-care database, part of the Observational Health Data Sciences and Informatics network. The inclusion criteria were the same as those for TOPKAT; briefly, we identified patients aged at least 40 years with osteoarthritis who had undergone UKR or TKR and who had available data for at least one year prior to surgery. Patients were excluded if they had evidence of previous knee arthroplasty, knee fracture, knee surgery (except diagnostic), rheumatoid arthritis, infammatory arthropathies, or septic arthritis. Opioid use from 91-365 days after surgery, as a proxy for persistent pain, was assessed for all participants in all databases. Postoperative complications (ie, venous thromboembolism, infection, readmission, and mortality) were assessed over the 60 days after surgery and implant survival (as measured by revision procedures) was assessed over the 5 years after surgery. Outcomes were assessed in all databases, except for readmission, which was assessed in three of the databases, and mortality, which was assessed in two of the databases. Propensity score matched Cox proportional hazards models were fitted for each outcome. Calibrated hazard ratios (cHRs) were generated for each database to account for observed differences in control outcomes, and cHRs were then combined using meta-analysis. FINDINGS: 33 867 individuals who received UKR and 557 831 individuals who received TKR between Jan 1, 2005, and April 30, 2018, were eligible for matching. 32 379 with UKR and 250 377 with TKR were propensity score matched and informed the analyses. UKR was associated with a reduced risk of postoperative opioid use (cHR from meta-analysis 0·81, 95% CI 0·73-0·90) and a reduced risk of venous thromboembolism (0·62, 0·36-0·95), whereas no difference was seen for infection (0·85, 0·51-1·37) and readmission (0·79, 0·47-1·25). Evidence was insufficient to conclude whether there was a reduction in risk of mortality. UKR was also associated with an increased risk of revision (1·64, 1·40-1·94). INTERPRETATION: UKR was associated with a reduced risk of postoperative opioid use compared with TKR, which might indicate a reduced risk of persistent pain after surgery. UKR was associated with a lower risk of venous thromboembolism but an increased risk of revision compared with TKR. These findings can help to inform shared decision making for individuals eligible for knee replacement surgery. FUNDING: EU/European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (2) Joint Undertaking (EHDEN).

Ecologically Driven Ultrastructural and Hydrodynamic Designs in Stomatopod Cuticles.

Ecological pressures and varied feeding behaviors in a multitude of organisms have necessitated the drive for adaptation. One such change is seen in the feeding appendages of stomatopods, a group of highly predatory marine crustaceans. Stomatopods include "spearers," who ambush and snare soft bodied prey, and "smashers," who bludgeon hard-shelled prey with a heavily mineralized club. The regional substructural complexity of the stomatopod dactyl club from the smashing predator Odontodactylus scyllarus represents a model system in the study of impact tolerant biominerals. The club consists of a highly mineralized impact region, a characteristic Bouligand architecture (common to arthropods), and a unique section of the club, the striated region, composed of highly aligned sheets of mineralized fibers. Detailed ultrastructural investigations of the striated region within O. scyllarus and a related species of spearing stomatopod, Lysiosquillina maculate show consistent organization of mineral and organic, but distinct differences in macro-scale architecture. Evidence is provided for the function and substructural exaptation of the striated region, which facilitated redeployment of a raptorial feeding appendage as a biological hammer. Moreover, given the need to accelerate underwater and "grab" or "smash" their prey, the spearer and smasher appendages are specifically designed with a significantly reduced drag force.

Real world big data for clinical research and drug development.

The objective of this paper is to identify the extent to which real world data (RWD) is being utilized, or could be utilized, at scale in drug development. Through screening peer-reviewed literature, we have cited specific examples where RWD can be used for biomarker discovery or validation, gaining a new understanding of a disease or disease associations, discovering new markers for patient stratification and targeted therapies, new markers for identifying persons with a disease, and pharmacovigilance. None of the papers meeting our criteria was specifically geared toward novel targets or indications in the biopharmaceutical sector; the majority were focused on the area of public health, often sponsored by universities, insurance providers or in combination with public health bodies such as national insurers. The field is still in an early phase of practical application, and is being harnessed broadly where it serves the most direct need in public health applications in early, rare and novel disease incidents. However, these exemplars provide a valuable contribution to insights on the use of RWD to create novel, faster and less invasive approaches to advance disease understanding and biomarker discovery. We believe that pharma needs to invest in making better use of Electronic Health Records and the need for more precompetitive collaboration to grow the scale of this 'big denominator' capability, especially given the needs of precision medicine research.

Positional specification in the segmental growth pattern of an early arthropod.

In many arthropods, there is a change in relative segment size during post-embryonic development, but how segment differential growth is produced is little known. A new dataset of the highest quality specimens of the 429 Myr old trilobite Aulacopleura koninckii provides an unparalleled opportunity to investigate segment growth dynamics and its control in an early arthropod. Morphometric analysis across nine post-embryonic stages revealed a growth gradient in the trunk of A. koninckii. We contrastively tested different growth models referable to two distinct hypotheses of growth control for the developing trunk: (i) a segment-specific control, with individual segments having differential autonomous growth progression, and (ii) a regional control, with segment growth depending on their relative position along the main axis. We show that the trunk growth pattern of A. koninckii was consistent with a regional growth control producing a continuous growth gradient that was stable across all developmental stages investigated. The specific posterior-to-anterior decaying shape of the growth gradient suggests it deriving from the linear transduction of a graded signal, similar to those commonly provided by morphogens. A growth control depending on a form of positional specification, possibly realized through the linear interpretation of a graded signal, may represent the primitive condition for arthropod differential growth along the main body axis, from which the diverse and generally more complex forms of growth control in subsequent arthropods have evolved.

Developmental trait evolution in trilobites.

We performed a tree-based analysis of trilobite postembryonic development in a sample of 60 species for which quantitative data on segmentation and growth increments between putative successive instars are available, and that spans much of the temporal, phylogenetic, and habitat range of the group. Three developmental traits were investigated: the developmental mode of trunk segmentation, the average per-molt growth rate, and the conformity to a constant per-molt growth rate (Dyar's rule), for which an original metric was devised. Growth rates are within the normal range with respect to other arthropods and show overall conformity to Dyar's rule. Randomization tests indicate statistically significant phylogenetic signal for growth in early juveniles but not in later stages. Among five evolutionary models fit via maximum likelihood, one in which growth rates vary independently among species, analogous to Brownian motion on a star phylogeny, is the best supported in all ontogenetic stages, although a model with a single, stationary peak to which growth rates are attracted also garners nontrivial support. These results are not consistent with unbounded, Brownian-motion-like evolutionary dynamics, but instead suggest the influence of an adaptive zone. Our results suggest that developmental traits in trilobites were relatively labile during evolutionary history.