Protecting patient privacy when sharing patient-level data from clinical trials

Abstract Background Greater transparency and, in particular, sharing of patient-level data for further scientific research is an increasingly important topic for the pharmaceutical industry and other organisations who sponsor and conduct clinical trials as well as generally in the interests of patients participating in studies. A concern remains, however, over how to appropriately prepare and share clinical trial data with third party researchers, whilst maintaining patient confidentiality. Clinical trial datasets contain very detailed information on each participant. Risk to patient privacy can be mitigated by data reduction techniques. However, retention of data utility is important in order to allow meaningful scientific research. In addition, for clinical trial data, an excessive application of such techniques may pose a public health risk if misleading results are produced. After considering existing guidance, this article makes recommendations with the aim of promoting an approach that balances data utility and privacy risk and is applicable across clinical trial data holders. Discussion Our key recommendations are as follows: 1. Data anonymisation/de-identification: Data holders are responsible for generating de-identified datasets which are intended to offer increased protection for patient privacy through masking or generalisation of direct and some indirect identifiers. 2. Controlled access to data, including use of a data sharing agreement: A legally binding data sharing agreement should be in place, including agreements not to download or further share data and not to attempt to seek to identify patients. Appropriate levels of security should be used for transferring data or providing access; one solution is use of a secure ‘locked box’ system which provides additional safeguards. Summary This article provides recommendations on best practices to de-identify/anonymise clinical trial data for sharing with third-party researchers, as well as controlled access to data and data sharing agreements. The recommendations are applicable to all clinical trial data holders. Further work will be needed to identify and evaluate competing possibilities as regulations, attitudes to risk and technologies evolve

Type 2 polysaccharide storage myopathy in Quarter Horses is a novel glycogen storage disease causing exertional rhabdomyolysis

Background: Both type 1 (PSSM1) and type 2 polysaccharide storage myopathy (PSSM2) are characterised by aggregates of abnormal polysaccharide in skeletal muscle. Whereas the genetic basis for PSSM1 is known (R309H GYS1), the cause of PSSM2 in Quarter Horses (PSSM2-QH) is unknown and glycogen concentrations not defined. Objectives: To characterise the histopathological and biochemical features of PSSM2-QH and determine if an associated monogenic variant exists in genes known to cause glycogenosis. Study design: Retrospective case control. Methods: Sixty-four PSSM2-QH, 30 PSSM1-QH and 185 control-QH were identified from a biopsy repository and clinical data, histopathology scores (0–3), glycogen concentrations and selected glycolytic enzyme activities compared. Coding sequences of 12 genes associated with muscle glycogenoses were identified from whole genome sequences and compared between seven PSSM2-QH and five control-QH. Results: Exertional rhabdomyolysis in PSSM2-QH occurred predominantly in barrel racing and working cow/roping performance types and improved with regular exercise and a low starch/fat-supplemented diet. Histopathological scores, including the amount of amylase-resistant polysaccharide (PSSM2-QH 1.4 ± 0.6, PSSM1-QH 2.1 ± 0.3, control-QH 0 ± 0, p \u3c 0.001), and glycogen concentrations (PSSM2-QH 129 ± 62, PSSM1-QH 175 ± 9, control-QH 80 ± 27 mmol/kg, p \u3c 0.0001) were intermediate in PSSM2-QH with significant differences among groups. In PSSM2-QH, abnormal polysaccharide had a less filamentous ultrastructure than PSSM1-QH and phosphorylase and phosphofructokinase activities were normal. Seventeen of 30 PSSM2-QH with available pedigrees descended from one of three stallions within four generations. Of the 29 predicted high or moderate impact genetic variants identified in candidate genes, none were present in only PSSM2-QH and absent in control-QH

Investigating subantarctic ¹⁴C ages of different peat components: site and sample selection for developing robust age models in dynamic landscapes

Precise radiocarbon (¹⁴C) dating of sedimentary sequences is important for developing robust chronologies of environmental change, but sampling of suitable components can be challenging in highly dynamic landscapes. Here we investigate radiocarbon determinations of different peat size fractions from six peat sites, representing a range of geomorphological contexts on the South Atlantic subantarctic islands of the Falklands and South Georgia. To investigate the most suitable fraction for dating, 112 measurements were obtained from three components within selected horizons: a fine fraction 0.2 mm, and bulk material. We find site selection is critical, with locations surrounded by high-ground and/or relatively slowly accumulating sites more susceptible to the translocation of older carbon. Importantly, in locations with reduced potential for redeposition of material, our results show that there is no significant or systematic difference between ages derived from bulk material, fine or coarse (plant macrofossil) material, providing confidence in the resulting age model. Crucially, in areas comprising complex terrain with extreme relief, we recommend dating macrofossils or bulk carbon rather than a fine fraction, or employing comprehensive dating of multiple sedimentary fractions to determine the most reliable fraction(s) for developing a robust chronological framework

Evidence for increased expression of the Amundsen Sea Low over the South Atlantic during the late Holocene

The Amundsen Sea Low (ASL) plays a major role in the climate and environment of Antarctica and the Southern Ocean, including surface air temperature and sea ice concentration changes. Unfortunately, a relative dearth of observational data across the Amundsen and Bellingshausen seas prior to the satellite era (post-1979) limits our understanding of the past behaviour and impact of the ASL. The limited proxy evidence for changes in the ASL are primarily restricted to the Antarctic where ice core evidence suggests a deepening of the atmospheric pressure system during the late Holocene. However, no data have previously been reported from the northern side of the ASL. Here we report a high-resolution, multi-proxy study of a 5000-year-long peat record from the Falkland Islands, a location sensitive to contemporary ASL dynamics which modulates northerly and westerly airflow across the southwestern South Atlantic sector of the Southern Ocean. In combination with climate reanalysis, we find a marked period of wetter, colder conditions most likely the result of enhanced southerly airflow between 5000 and 2500 years ago, suggesting limited ASL influence over the region. After 2500 years ago, drier and warmer conditions were established, implying more westerly airflow and the increased projection of the ASL onto the South Atlantic. The possible role of the equatorial Pacific via atmospheric teleconnections in driving this change is discussed. Our results are in agreement with Antarctic ice core records and fjord sediments from the southern South American coast, and suggest that the Falkland Islands provide a valuable location for reconstructing high southern latitude atmospheric circulation changes on multi-decadal to millennial timescales

Anomalous mid-twentieth century atmospheric circulation change over the South Atlantic compared to the last 6000 years

Determining the timing and impact of anthropogenic climate change in data-sparse regions is a considerable challenge. Arguably, nowhere is this more difficult than the Antarctic Peninsula and the subantarctic South Atlantic where observational records are relatively short but where high rates of warming have been experienced since records began. Here we interrogate recently developed monthly-resolved observational datasets from the Falkland Islands and South Georgia, and extend the records back using climate-sensitive peat growth over the past 6000 years. Investigating the subantarctic climate data with ERA-Interim and Twentieth Century Reanalysis, we find that a stepped increase in precipitation across the 1940s is related to a change in synoptic atmospheric circulation: a westward migration of quasi-permanent positive pressure anomalies in the South Atlantic has brought the subantarctic islands under the increased influence of meridional airflow associated with the Amundsen Sea Low. Analysis of three comprehensively multi-dated (using 14C and 137Cs) peat sequences across the two islands demonstrates unprecedented growth rates since the mid-twentieth century relative to the last 6000 years. Comparison to observational and reconstructed sea surface temperatures suggests this change is linked to a warming tropical Pacific Ocean. Our results imply 'modern' South Atlantic atmospheric circulation has not been under this configuration for millennia

A 250-year periodicity in Southern Hemisphere westerly winds over the last 2600 years

Middle Holocene cultures have been widely studied around the Eastern-Mediterranean basin in the last 30 years and past cultural activities have been commonly linked with regional climate changes. However, in many cases such linkage is equivocal, in part due to existing climatic evidence that has been derived from areas outside the distribution of ancient settlements, leading to uncertainty from complex spatial heterogeneity in both climate and demography. A few high-resolution well-dated paleoclimate records were recently established using speleothems in the Central and Eastern-Mediterranean basin, however, the scarcity of such records in the western part of the Mediterranean prevents us from correlating past climate evolutions across the basin and deciphering climate–culture relation at fine timescales. Here we report the first decadal-resolved Mid-Holocene climate proxy records from the Western-Mediterranean basin based on the stable carbon and oxygen isotopes analyses of two U/Th dated stalagmites from the Gueldaman GLD1 Cave in Northern Algeria. Comparison of our records with those from Italy and Israel reveals synchronous (multi) centennial dry phases centered at ca. 5600, ca. 5200 and ca. 4200 yr BP across the Mediterranean basin. New calibrated radiocarbon dating constrains reasonably well the age of rich anthropogenic deposits (e.g., faunal remains, pottery, charcoal) excavated inside the cave, which allows the comparison between in situ evidence of human occupation and of climate change. This approach shows that the timing of a prolonged drought at ca. 4400–3800 yr BP blankets the onset of cave abandonment shortly after ca. 4403 cal yr BP, supporting the hypothesis that a climate anomaly may have played a role in this cultural disruption

Redating the earliest evidence of the mid-Holocene relative sea-level highstand in Australia and implications for global sea-level rise.

Reconstructing past sea levels can help constrain uncertainties surrounding the rate of change, magnitude, and impacts of the projected increase through the 21st century. Of significance is the mid-Holocene relative sea-level highstand in tectonically stable and remote (far-field) locations from major ice sheets. The east coast of Australia provides an excellent arena in which to investigate changes in relative sea level during the Holocene. Considerable debate surrounds both the peak level and timing of the east coast highstand. The southeast Australian site of Bulli Beach provides the earliest evidence for the establishment of a highstand in the Southern Hemisphere, although questions have been raised about the pretreatment and type of material that was radiocarbon dated for the development of the regional sea-level curve. Here we undertake a detailed morpho- and chronostratigraphic study at Bulli Beach to better constrain the timing of the Holocene highstand in eastern Australia. In contrast to wood and charcoal samples that may provide anomalously old ages, probably due to inbuilt age, we find that short-lived terrestrial plant macrofossils provide a robust chronological framework. Bayesian modelling of the ages provide improved dating of the earliest evidence for a highstand at 6,880±50 cal BP, approximately a millennium later than previously reported. Our results from Bulli now closely align with other sea-level reconstructions along the east coast of Australia, and provide evidence for a synchronous relative sea-level highstand that extends from the Gulf of Carpentaria to Tasmania. Our refined age appears to be coincident with major ice mass loss from Northern Hemisphere and Antarctic ice sheets, supporting previous studies that suggest these may have played a role in the relative sea-level highstand. Further work is now needed to investigate the environmental impacts of regional sea levels, and refine the timing of the subsequent sea-level fall in the Holocene and its influence on coastal evolution