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.

Alzheimer's disease marker phospho-tau181 is not elevated in the first year after moderate-to-severe TBI.

BACKGROUND: Traumatic brain injury (TBI) is associated with the tauopathies Alzheimer's disease and chronic traumatic encephalopathy. Advanced immunoassays show significant elevations in plasma total tau (t-tau) early post-TBI, but concentrations subsequently normalise rapidly. Tau phosphorylated at serine-181 (p-tau181) is a well-validated Alzheimer's disease marker that could potentially seed progressive neurodegeneration. We tested whether post-traumatic p-tau181 concentrations are elevated and relate to progressive brain atrophy. METHODS: Plasma p-tau181 and other post-traumatic biomarkers, including total-tau (t-tau), neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP), were assessed after moderate-to-severe TBI in the BIO-AX-TBI cohort (first sample mean 2.7 days, second sample within 10 days, then 6 weeks, 6 months and 12 months, n=42). Brain atrophy rates were assessed in aligned serial MRI (n=40). Concentrations were compared patients with and without Alzheimer's disease, with healthy controls. RESULTS: Plasma p-tau181 concentrations were significantly raised in patients with Alzheimer's disease but not after TBI, where concentrations were non-elevated, and remained stable over one year. P-tau181 after TBI was not predictive of brain atrophy rates in either grey or white matter. In contrast, substantial trauma-associated elevations in t-tau, NfL, GFAP and UCH-L1 were seen, with concentrations of NfL and t-tau predictive of brain atrophy rates. CONCLUSIONS: Plasma p-tau181 is not significantly elevated during the first year after moderate-to-severe TBI and levels do not relate to neuroimaging measures of neurodegeneration.

Who are the superheroes? A cross-sectional study on the determinants of good health among Italian older adults.

BACKGROUND: People who reach old age enjoying good physical and mental health can be defined as (health) "superheroes", given their relatively low impact on healthcare expenditure and the desirable model they represent. AIM: To evaluate prevalence and possible determinants of being "physical superheroes" (i.e., free from the ten major chronic conditions, plus obesity), "mental superheroes" (i.e., free from major mental symptoms), and "superheroes" (i.e., both mental and physical superheroes). METHODS: A telephone-based cross-sectional study (LOST in Lombardia) was conducted in November 2020 (i.e., during the COVID-19 pandemic) on a representative sample of 4,400 adults aged ≥ 65 years from Lombardy region, northern Italy. All participants provided both current data and data referring to one year before. RESULTS: Mental and physical superheroes were 59.0% and 17.6%, respectively. Superheroes were 12.8% overall, 15.1% among men, and 11.1% among women; 20.2% among individuals aged 65-69 years, 11.3% among 70-74, 10.0% among 75-79, and 8.3% among ≥ 80 years. Multivariable analysis showed that female sex, higher age, disadvantaged socio-economic status, and physical inactivity (p for trend < 0.001) were inversely related to being superheroes. People not smoking (adjusted odds ratio, aOR = 1.40), alcohol abstainers (aOR = 1.30), and those free from feelings of hopelessness (aOR = 5.92) more frequently met the definition of superheroes. During COVID-19 pandemic, the proportion of superheroes decreased by 16.3%. CONCLUSIONS: Differences in the older adults' health status are largely attributable to their lifestyles but are also likely due to gender, educational, and socio-economic disparities, which should be properly addressed by public health policies.

The Hematocrit Affects the Volume of Plasma Treated With Coupled Plasma Filtration and Adsorption With Predilution.

Coupled plasma filtration and adsorption (CPFA) is an extracorporeal blood purification technique proposed for the treatment of septic-shock. By removing pro- and anti-inflammatory mediators from plasma, CPFA is supposed to have a therapeutic effect on the abnormal inflammatory response seen in this condition. Recently, blood predilution with citrate solution has been adopted to prevent clotting in the CPFA circuit-one of the main problems of the technique. Taking into account the patient's hematocrit, we worked out a formula for the volume of plasma effectively treated by CPFA after predilution. Neglecting this effect, as is commonly done, introduces significant distortions in the estimation of the volume, possibly causing under-treatment. The distortion is stronger when the hematocrit and the predilution fraction are large and weaker when both values shrink. By correctly indicating the daily dose of plasma adsorption received by patients, this formula is essential for assessing the therapeutic efficacy of CPFA and, subsequently, establishing its optimal doses.

A new test and graphical tool to assess the goodness of fit of logistic regression models.

A prognostic model is well calibrated when it accurately predicts event rates. This is first determined by testing for goodness of fit with the development dataset. All existing tests and graphic tools designed for the purpose suffer several drawbacks, related mainly to the subgrouping of observations or to heavy dependence on arbitrary parameters. We propose a statistical test and a graphical method to assess the goodness of fit of logistic regression models, obtained through an extension of similar techniques developed for external validation. We analytically computed and numerically verified the distribution of the underlying statistic. Simulations on a set of realistic scenarios show that this test and the well-known Hosmer-Lemeshow approach have similar type I error rates. The main advantage of this new approach is that the relationship between model predictions and outcome rates across the range of probabilities can be represented in the calibration belt plot, together with its statistical confidence. By readily spotting any deviations from the perfect fit, this new graphical tool is designed to identify, during the process of model development, poorly modeled variables that call for further investigation. This is illustrated through an example based on real data.

Judging quality of current septic shock definitions and criteria.

Septic shock definitions are being revisited. We assess the feasibility, reliability, and validity characteristics of the current definitions and criteria of septic shock. Septic shock is conceptualised as cardiovascular dysfunction, tissue perfusion and cellular abnormalities caused by infection. Currently, for feasibility, septic shock is identified at the bedside by using either hypotension or a proxy for tissue perfusion/cellular abnormalities (e.g., hyperlactatemia). We propose that concurrent presence of cardiovascular dysfunction and perfusion/cellular abnormalities could improve validity of septic shock diagnosis, as we are more likely to identify a patient population with all elements of the illness concept. This epidemiological refinement should not affect clinical care and may aid study design to identify illness-specific biomarkers and interventions.

A new calibration test and a reappraisal of the calibration belt for the assessment of prediction models based on dichotomous outcomes.

Calibration is one of the main properties that must be accomplished by any predictive model. Overcoming the limitations of many approaches developed so far, a study has recently proposed the calibration belt as a graphical tool to identify ranges of probability where a model based on dichotomous outcomes miscalibrates. In this new approach, the relation between the logits of the probability predicted by a model and of the event rates observed in a sample is represented by a polynomial function, whose coefficients are fitted and its degree is fixed by a series of likelihood-ratio tests. We propose here a test associated with the calibration belt and show how the algorithm to select the polynomial degree affects the distribution of the test statistic. We calculate its exact distribution and confirm its validity via a numerical simulation. Starting from this distribution, we finally reappraise the procedure to construct the calibration belt and illustrate an application in the medical context.

[The SIAARTI consensus document on the management of patients with end-stage chronic organ failure. From evidence-based medicine to knowledge-based medicine]. / Da una medicina basata sulle evidenze a una medicina basata sulle conoscenze.

The management of patients with end-stage chronic organ failure is an increasingly important topic, since the extraordinary medical and technological advances have significantly reduced mortality and improved quality of life with prolonged survival of end-stage diseases. What should be the plan of care for these patients? Who should bear the responsibility for care? With what targets? These are crucial questions, to which modern medicine should provide convincing answers. The authors of the document explicitly resisted the temptation to draw up guidelines, showing that it is possible to customize medical intervention on the individual patient, keeping it tightly linked to the available knowledge. This is the most relevant aspect of the document: it goes beyond the classical concept of evidence-based medicine choosing to refer to the most dynamic knowledge-based medicine approach.

Diagnosis of sepsis in the emergency department: a real-world analysis from Lombardy, Italy.

Early identification of sepsis is particularly important in the emergency department (ED). However, data on the diagnosis of sepsis in the ED are scanty, especially within the Italian context. To quantify sepsis incidence and recognition in the ED from Lombardy, Italy, we used EUOL data from the Regional Emergency Agency for the years 2017-2022. Sepsis was identified based on the ED discharge diagnosis; recognized sepsis cases were those assigned to a high-priority code at triage, while unrecognized ones were those assigned to a low priority code. Odds ratios (ORs) for sepsis recognition according to various patient characteristics were estimated using multivariable mixed-effects logistic regression models. The rate of sepsis diagnosis in ED was 1.9 per 1000 (6626 patients) in 2017 and increased to 3.4 per 1000 in 2022 (11,508 patients). In 2022, 67% of sepsis cases were correctly identified. Death in the ED was more frequent in patients with recognized sepsis (10.4%) than in those with unrecognized sepsis (2.3%). The probability of sepsis being recognized at ED admission was higher in men (multivariable OR: 1.06), in individuals with advanced age (OR: 1.71 for age ≥ 90 years vs < 60), and in those with access to the second (OR: 1.48) and third ED level (OR: 1.87). Conversely, it was lower in patients arriving at the ED through autonomous transportation (OR: 0.36). This large real-world analysis indicates an increase in sepsis cases referred to the ED in recent years. About one-third of sepsis cases are not correctly identified at triage, although more severe cases appear to be promptly recognized.

Assessing the heterogeneity of the impact of COVID-19 incidence on all-cause excess mortality among healthcare districts in Lombardy, Italy, to evaluate the local response to the pandemic: an ecological study.

OBJECTIVES: The fragmentation of the response to the COVID-19 pandemic at national, regional and local levels is a possible source of variability in the impact of the pandemic on society. This study aims to assess how much of this variability affected the burden of COVID-19, measured in terms of all-cause 2020 excess mortality. DESIGN: Ecological retrospective study. SETTING: Lombardy region of Italy, 2015-2020. OUTCOME MEASURES: We evaluated the relationship between the intensity of the epidemics and excess mortality, assessing the heterogeneity of this relationship across the 91 districts after adjusting for relevant confounders. RESULTS: The epidemic intensity was quantified as the COVID-19 hospitalisations per 1000 inhabitants. Five confounders were identified through a directed acyclic graph: age distribution, population density, pro-capita gross domestic product, restriction policy and population mobility.Analyses were based on a negative binomial regression model with district-specific random effects. We found a strong, positive association between COVID-19 hospitalisations and 2020 excess mortality (p<0.001), estimating that an increase of one hospitalised COVID-19 patient per 1000 inhabitants resulted in a 15.5% increase in excess mortality. After adjusting for confounders, no district differed in terms of COVID-19-unrelated excess mortality from the average district. Minimal heterogeneity emerged in the district-specific relationships between COVID-19 hospitalisations and excess mortality (6 confidence intervals out of 91 did not cover the null value). CONCLUSIONS: The homogeneous effect of the COVID-19 spread on the excess mortality in the Lombardy districts suggests that, despite the unprecedented conditions, the pandemic reactions did not result in health disparities in the region.

A Model Predicting the 6-Month Disability of Patients With Traumatic Brain Injury to Assess the Quality of Care in Intensive Care Units: Results from the CREACTIVE Study.

Assessing quality of care is essential for improving the management of patients experiencing traumatic brain injury (TBI). This study aimed at devising a rigorous framework to evaluate the quality of TBI care provided by intensive care units (ICUs) and applying it to the Collaborative Research on Acute Traumatic Brain Injury in Intensive Care Medicine in Europe (CREACTIVE) consortium, which involved 83 ICUs from seven countries. The performance of the centers was assessed in terms of patients' outcomes, as measured by the 6-month Glasgow Outcome Scale-Extended (GOS-E). To account for the between-center differences in the characteristics of the admitted patients, we developed a multinomial logistic regression model estimating the probability of a four-level categorization of the GOS-E: good recovery (GR), moderate disability (MD), severe disability (SD), and death or vegetative state (D/VS). A total of 5928 patients admitted to the participating ICUs between March 2014 and March 2019 were analyzed. The model included 11 predictors and demonstrated good discrimination (area under the receiver operating characteristic [ROC] curve in the validation set for GR: 0.836, MD: 0.802, SD: 0.706, D/VS: 0.890) and calibration, both overall (Hosmer-Lemeshow test p value: 0.87) and in several subgroups, defined by prognostically relevant variables. The model was used as a benchmark for assessing quality of care by comparing the observed number of patients experiencing GR, MD, SD, and D/VS to the corresponding numbers expected in each category by the model, computing observed/expected (O/E) ratios. The four center-specific ratios were assembled with polar representations and used to provide a multidimensional assessment of the ICUs, overcoming the loss of information consequent to the traditional dichotomizations of the outcome in TBI research. The proposed framework can help in identifying strengths and weaknesses of current TBI care, triggering the changes that are necessary to improve patient outcomes.

The Fenice project to evaluate and improve the quality of healthcare in high-dependency care units: results after the first year.

High-Dependency care Units (HDUs) have been introduced worldwide as intermediate wards between Intensive Care Units (ICUs) and general wards. Performing a comparative assessment of the quality of care in HDU is challenging because there are no uniform standards and heterogeneity among centers is wide. The Fenice network promoted a prospective cohort study to assess the quality of care provided by HDUs in Italy. This work aims at describing the structural characteristics and admitted patients of Italian HDUs. All Italian HDUs affiliated to emergency departments were eligible to participate in the study. Participating centers reported detailed structural information and prospectively collected data on all admitted adult patients. Patients' data are presented overall and analyzed to evaluate the heterogeneity across the participating centers. A total of 12 HDUs participated in the study and enrolled 3670 patients. Patients were aged 68 years on average, had multiple comorbidities and were on major chronic therapies. Several admitted patients had at least one organ failure (39%). Mortality in HDU was 8.4%, raising to 16.6% in hospital. While most patients were transferred to general wards, a small proportion required ICU transfer (3.9%) and a large group was discharged directly home from the HDU (31%). The expertise of HDUs in managing complex and fragile patients is supported by both the available equipment and the characteristics of admitted patients. The limited proportion of patients transferred to ICUs supports the hypothesis of preventing of ICU admissions. The heterogeneity of HDU admissions requires further research to define meaningful patients' outcomes to be used by quality-of-care assessment programs.

[The register GiViTI about the use of the drug Xigris® in the Italian intensive care units]. / Il registro GiViTI sull'utilizzo del farmaco Xigris® nelle Terapie Intensive italiane.

INTRODUCTION: The Register was aimed at monitoring the use, possible side effects, and clinical effectiveness of Xigris® - drotrecogin alfa (activated) - for the treatment of severe sepsis in Italian intensive care units (ICUs). METHODS: Data collection was performed using an online web form or a specific electronic module of the software Margherita, available only for the ICUs adhering to the GiViTI. Drug purchase information available for each center was used to identify and stimulate collaboration of non-compliant centers. Several countermeasures were taken to have the largest participation. RESULTS: We analyzed data from 1001 patients treated in 161 ICUs between July 2003 and September 2007, corresponding to 70% of all the patients who received the drug in that period. The off-label use of the drug was frequent: 15.6% of cases before and 27.3% after the label change with the introduction of timing restrictions. Treatment was temporarily interrupted in 10%, and definitely stopped in 25% of cases, after the occurrence of adverse events, the most frequent being bleeding. Severe bleeding occurred in 3.8% of patients. Multivariable analysis, which allowed an adjusted comparison with a control group, showed that treatment increased mortality among elective-surgery patients (OR 2.79, 95%CI 1.31-5.97). DISCUSSION: The results of this study and other evidences led the European Medicines Agency (EMA) to require a confirmatory trial in 2007. In October 2011 Ely-Lilly, the producer of the drug, announced the worldwide withdrawal from the market of Xigris®, on the basis of the negative results of the confirmatory trial. CONCLUSIONS: The availability of purchase information is essential to carry out post-marketing drug surveillance studies, since it allows to identify and contact non-compliant centers. Actually, a representative sample of treated patients provides reliable information on the use, efficacy, and safety of the drug in daily clinical practice that could positively influence healthcare policies.

Cerebral Metabolic Dysfunction at the Acute Phase of Traumatic Brain Injury Correlates with Long-Term Tissue Loss.

Following traumatic brain injury (TBI), cerebral metabolic dysfunction, characterized by an elevated cerebral microdialysis (CMD) lactate/pyruvate (LP) ratio, is associated with poor outcome. However, the exact pathophysiological mechanisms underlying this association are not entirely established. In this pre-planned analysis of the BIOmarkers of AXonal injury after Traumatic Brain Injury (BIO-AX-TBI) prospective study, we investigated any associations of LP ratio with brain structure volume change rates at 1 year. Fourteen subjects underwent acute-phase (0-96 h post-TBI) CMD monitoring and had longitudinal magnetic resonance imaging (MRI) quantification of brain volume loss between the subacute phase (14 days to 6 weeks) and 1 year after TBI, recalculated as an annual rate. On average, CMD showed an elevated (>25) LP ratio (31 [interquartile range (IQR) 24-34]), indicating acute cerebral metabolic dysfunction. Annualized whole brain and total gray matter (GM) volume change rates were abnormally reduced (-3.2% [-9.3 to -2.2] and -1.9% [-4.4 to 1.7], respectively). Reduced annualized total GM volume correlated significantly with elevated CMD LP ratio (Spearman's ρ = -0.68, p-value = 0.01) and low CMD glucose (ρ = 0.66, p-value = 0.01). After adjusting for age, admission Glasgow Coma Scale (GCS) score and CT Marshall score, CMD LP ratio remained strongly associated with 1-year total GM volume change rate (p < 0.001; multi-variable analysis). No relationship was found between WM volume changes and CMD metabolites. We demonstrate a strong association between acute post-traumatic cerebral metabolic dysfunction and 1-year gray matter atrophy, reinforcing the role of CMD LP ratio as an early biomarker of poor long-term recovery after TBI.

Strategies to convert hospital beds for COVID-19 patients to minimize emergency department overcrowding.

Background: The shortage of hospital beds for COVID-19 patients has been one critical cause of Emergency Department (ED) overcrowding. Purpose: We aimed at elaborating a strategy of conversion of hospital beds, from non-COVID-19 to COVID-19 care, minimizing both ED overcrowding and the number of beds eventually converted. Research Design: Observational retrospective study. Study Sample: We considered the centralized database of all ED admissions in the Lombardy region of Italy during the second "COVID-19 wave" (October to December 2020). Data collection and Analysis: We analyzed all admissions to 82 EDs. We devised a family of Monte Carlo simulations to evaluate the performance of hospital beds' conversion strategies triggered by ED crowding of COVID-19 patients, determining a critical number of beds to be converted when passing an ED-specific crowding threshold. Results: Our results suggest that the maximum number of patients waiting for hospitalization could have been decreased by 70% with the proposed strategy. Such a reduction would have been achieved by converting 30% more hospital beds than the total number converted in the region. Conclusions: The disproportion between reduction in ED crowding and additionally converted beds suggests that a wide margin to improve the efficiency of the conversions exists. The proposed simulation apparatus can be easily generalized to study management policies synchronizing ED output and in-hospital bed availability.

Investigating the characteristics and correlates of systemic inflammation after traumatic brain injury: the TBI-BraINFLAMM study.

INTRODUCTION: A significant environmental risk factor for neurodegenerative disease is traumatic brain injury (TBI). However, it is not clear how TBI results in ongoing chronic neurodegeneration. Animal studies show that systemic inflammation is signalled to the brain. This can result in sustained and aggressive microglial activation, which in turn is associated with widespread neurodegeneration. We aim to evaluate systemic inflammation as a mediator of ongoing neurodegeneration after TBI. METHODS AND ANALYSIS: TBI-braINFLAMM will combine data already collected from two large prospective TBI studies. The CREACTIVE study, a broad consortium which enrolled >8000 patients with TBI to have CT scans and blood samples in the hyperacute period, has data available from 854 patients. The BIO-AX-TBI study recruited 311 patients to have acute CT scans, longitudinal blood samples and longitudinal MRI brain scans. The BIO-AX-TBI study also has data from 102 healthy and 24 non-TBI trauma controls, comprising blood samples (both control groups) and MRI scans (healthy controls only). All blood samples from BIO-AX-TBI and CREACTIVE have already been tested for neuronal injury markers (GFAP, tau and NfL), and CREACTIVE blood samples have been tested for inflammatory cytokines. We will additionally test inflammatory cytokine levels from the already collected longitudinal blood samples in the BIO-AX-TBI study, as well as matched microdialysate and blood samples taken during the acute period from a subgroup of patients with TBI (n=18).We will use this unique dataset to characterise post-TBI systemic inflammation, and its relationships with injury severity and ongoing neurodegeneration. ETHICS AND DISSEMINATION: Ethical approval for this study has been granted by the London-Camberwell St Giles Research Ethics Committee (17/LO/2066). Results will be submitted for publication in peer-review journals, presented at conferences and inform the design of larger observational and experimental medicine studies assessing the role and management of post-TBI systemic inflammation.

Prognostic value of respiratory parameters for COVID-19 patients in the emergency department: results from the EC-COVID study.

While several studies have evaluated the prognostic weight of respiratory parameters in patients with COVID-19, few have focused on patients' clinical conditions at the first emergency department (ED) assessment. We analyzed a large cohort of ED patients recruited within the EC-COVID study over the year 2020, and assessed the association between key bedside respiratory parameters measured in room air (pO2, pCO2, pH, and respiratory rate [RR]) and hospital mortality, after adjusting for key confounding factors. Analyses were based on a multivariable logistic Generalized Additive Model (GAM). After excluding patients who did not perform a blood gas analysis (BGA) test in room air or with incomplete BGA results, a total of 2458 patients were considered in the analyses. Most patients were hospitalized on ED discharge (72.0%); hospital mortality was 14.3%. Strong, negative associations with hospital mortality emerged for pO2, pCO2 and pH (p-values: < 0.001, < 0.001 and 0.014), while a significant, positive association was observed for RR (p-value < 0.001). Associations were quantified with nonlinear functions, learned from the data. No cross-parameter interaction was significant (all p-values were larger than 0.10), suggesting a progressive, independent effect on the outcome as the value of each parameter departed from normality. Our results collide with the hypothesized existence of patterns of breathing parameters with specific prognostic weight in the early stages of the disease.

Centre for Statistical and Methodological Excellence (CESAME): A Consortium Initiative for Improving Methodology in Randomised Clinical Trials.

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials.