Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study.

BACKGROUND: Physical activity has not been objectively measured in prospective cohorts with sufficiently large numbers to reliably detect associations with multiple health outcomes. Technological advances now make this possible. We describe the methods used to collect and analyse accelerometer measured physical activity in over 100,000 participants of the UK Biobank study, and report variation by age, sex, day, time of day, and season. METHODS: Participants were approached by email to wear a wrist-worn accelerometer for seven days that was posted to them. Physical activity information was extracted from 100Hz raw triaxial acceleration data after calibration, removal of gravity and sensor noise, and identification of wear / non-wear episodes. We report age- and sex-specific wear-time compliance and accelerometer measured physical activity, overall and by hour-of-day, week-weekend day and season. RESULTS: 103,712 datasets were received (44.8% response), with a median wear-time of 6.9 days (IQR:6.5-7.0). 96,600 participants (93.3%) provided valid data for physical activity analyses. Vector magnitude, a proxy for overall physical activity, was 7.5% (2.35mg) lower per decade of age (Cohen's d = 0.9). Women had a higher vector magnitude than men, apart from those aged 45-54yrs. There were major differences in vector magnitude by time of day (d = 0.66). Vector magnitude differences between week and weekend days (d = 0.12 for men, d = 0.09 for women) and between seasons (d = 0.27 for men, d = 0.15 for women) were small. CONCLUSIONS: It is feasible to collect and analyse objective physical activity data in large studies. The summary measure of overall physical activity is lower in older participants and age-related differences in activity are most prominent in the afternoon and evening. This work lays the foundation for studies of physical activity and its health consequences. Our summary variables are part of the UK Biobank dataset and can be used by researchers as exposures, confounding factors or outcome variables in future analyses.

Comparison of DNA quantification methodology used in the DNA extraction protocol for the UK Biobank cohort.

BACKGROUND: UK Biobank is a large prospective cohort study in the UK established by the Medical Research Council (MRC) and the Wellcome Trust to enable approved researchers to investigate the role of genetic factors, environmental exposures and lifestyle in the causes of major diseases of late and middle age. A wide range of phenotypic data has been collected at recruitment and has recently been enhanced by the UK Biobank Genotyping Project. All UK Biobank participants (500,000) have been genotyped on either the UK Biobank Axiom® Array or the Affymetrix UK BiLEVE Axiom® Array and the workflow for preparing samples for genotyping is described. The genetic data is hoped to provide further insight into the genetics of disease. All data, including the genetic data, is available for access to approved researchers. Data for two methods of DNA quantification (ultraviolet-visible spectroscopy [UV/Vis]) measured on the Trinean DropSense™ 96 and PicoGreen®) were compared by two laboratories (UK Biobank and Affymetrix). RESULTS: The sample processing workflow established at UK Biobank, for genotyping on the custom Affymetrix Axiom® array, resulted in high quality DNA (average DNA concentration 38.13 ng/µL, average 260/280 absorbance 1.91). The DNA generated high quality genotype data (average call rate 99.48% and pass rate 99.45%). The DNA concentration measured on the Trinean DropSense™ 96 at UK Biobank correlated well with DNA concentration measured by PicoGreen® at Affymetrix (r = 0.85). CONCLUSIONS: The UK Biobank Genotyping Project demonstrated that the high throughput DNA extraction protocol described generates high quality DNA suitable for genotyping on the Affymetrix Axiom array. The correlation between DNA concentration derived from UV/Vis and PicoGreen® quantification methods suggests, in large-scale genetic studies involving two laboratories, it may be possible to remove the DNA quantification step in one laboratory without affecting downstream analyses. This would result in reductions in cost and time to complete the project, allowing generation of genetic data faster and cheaper.

UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age.

Cathie Sudlow and colleagues describe the UK Biobank, a large population-based prospective study, established to allow investigation of the genetic and non-genetic determinants of the diseases of middle and old age.

Understanding the impact of pre-analytic variation in haematological and clinical chemistry analytes on the power of association studies.

BACKGROUND: Errors, introduced through poor assessment of physical measurement or because of inconsistent or inappropriate standard operating procedures for collecting, processing, storing or analysing haematological and biochemistry analytes, have a negative impact on the power of association studies using the collected data. A dataset from UK Biobank was used to evaluate the impact of pre-analytical variability on the power of association studies. METHODS: First, we estimated the proportion of the variance in analyte concentration that may be attributed to delay in processing using variance component analysis. Then, we captured the proportion of heterogeneity between subjects that is due to variability in the rate of degradation of analytes, by fitting a mixed model. Finally, we evaluated the impact of delay in processing on the power of a nested case-control study using a power calculator that we developed and which takes into account uncertainty in outcome and explanatory variables measurements. RESULTS: The results showed that (i) the majority of the analytes investigated in our analysis, were stable over a period of 36 h and (ii) some analytes were unstable and the resulting pre-analytical variation substantially decreased the power of the study, under the settings we investigated. CONCLUSIONS: It is important to specify a limited delay in processing for analytes that are very sensitive to delayed assay. If the rate of degradation of an analyte varies between individuals, any delay introduces a bias which increases with increasing delay. If pre-analytical variation occurring due to delays in sample processing is ignored, it affects adversely the power of the studies that use the data.

Imaging in population science: cardiovascular magnetic resonance in 100,000 participants of UK Biobank - rationale, challenges and approaches.

UK Biobank is a prospective cohort study with 500,000 participants aged 40 to 69. Recently an enhanced imaging study received funding. Cardiovascular magnetic resonance (CMR) will be part of a multi-organ, multi-modality imaging visit in 3-4 dedicated UK Biobank imaging centres that will acquire and store imaging data from 100,000 participants (subject to successful piloting). In each of UK Biobank's dedicated bespoke imaging centres, it is proposed that 15-20 participants will undergo a 2 to 3 hour visit per day, seven days a week over a period of 5-6 years. The imaging modalities will include brain MRI at 3 Tesla, CMR and abdominal MRI at 1.5 Tesla, carotid ultrasound and DEXA scans using carefully selected protocols. We reviewed the rationale, challenges and proposed approaches for concise phenotyping using CMR on such a large scale. Here, we discuss the benefits of this imaging study and review existing and planned population based cardiovascular imaging in prospective cohort studies. We will evaluate the CMR protocol, feasibility, process optimisation and costs. Procedures for incidental findings, quality control and data processing and analysis are also presented. As is the case for all other data in the UK Biobank resource, this database of images and related information will be made available through UK Biobank's Access Procedures to researchers (irrespective of their country of origin and whether they are academic or commercial) for health-related research that is in the public interest.

Effects of the UK Biobank collection protocol on potential biomarkers in saliva.

BACKGROUND: The UK Biobank (UKB) is a national epidemiological study of the health of 500 000 people, aged 40-69 years, who completed health-related tests and a questionnaire and gave samples of blood and urine. Salivas collected from 120 000 of these subjects were transported at 4°C and were placed in ultra-low temperature archives at up to 24 h after collection. The present study assessed how changes in saliva composition under UKB conditions influence a range of potential biomarkers resulting from holding saliva at 4°C for 24 h. METHODS: Unstimulated whole-mouth saliva samples were collected from 23 volunteers aged 45-69 years. Salivas were split into aliquots some of which were immediately frozen at -80°C, whereas others were stored at 4°C for 24 h and then frozen at -80°C, mimicking the UKB protocol. RESULTS: Assessment of mRNA by real-time polymerase chain reaction revealed no difference between samples that were analysed after the UKB protocol and those that were immediately preserved. Immunochemical analysis showed some loss of ß-Actin under UKB conditions, whereas other salivary proteins including cytokines and C-reactive protein appeared to be unaffected. Cortisol and showed no reduction by UKB conditions, but salivary nitrite was reduced by 30%. The oral microbiome, as revealed by sequencing 16S rRNA genes, showed variations between subjects, but paired samples within subjects were very similar. CONCLUSIONS: Our results suggest that many salivary components remain little affected under UKB collection and handling protocols, suggesting that the resource of 120 000 samples held in storage will be useful for phenotyping subjects and revealing potential prognostic disease biomarkers.

New models for large prospective studies: is there a better way?

Large prospective cohort studies are critical for identifying etiologic factors for disease, but they require substantial long-term research investment. Such studies can be conducted as multisite consortia of academic medical centers, combinations of smaller ongoing studies, or a single large site such as a dominant regional health-care provider. Still another strategy relies upon centralized conduct of most or all aspects, recruiting through multiple temporary assessment centers. This is the approach used by a large-scale national resource in the United Kingdom known as the "UK Biobank," which completed recruitment/examination of 503,000 participants between 2007 and 2010 within budget and ahead of schedule. A key lesson from UK Biobank and similar studies is that large studies are not simply small studies made large but, rather, require fundamentally different approaches in which "process" expertise is as important as scientific rigor. Embedding recruitment in a structure that facilitates outcome determination, utilizing comprehensive and flexible information technology, automating biospecimen processing, ensuring broad consent, and establishing essentially autonomous leadership with appropriate oversight are all critical to success. Whether and how these approaches may be transportable to the United States remain to be explored, but their success in studies such as UK Biobank makes a compelling case for such explorations to begin.

Current standards for the storage of human samples in biobanks.

Biobanks are diverse in their design and purpose; the idea of fully harmonizing historical and future biobanks is unaffordable and unfeasible. Biobanks should focus their efforts instead on developing and maintaining high-quality collections of samples capable of providing a wide range of biological information using processes that minimize introduced variability. A full data audit trail on sample processing, archiving, and quality control procedures should also be provided. This should enable the data derived from biobanks to contribute as part of wider collaborative efforts with other similar resources.

The UK Biobank sample handling and storage validation studies.

BACKGROUND: and aims UK Biobank is a large prospective study in the United Kingdom to investigate the role of genetic factors, environmental exposures and lifestyle in the causes of major diseases of late and middle age. It involves the collection of blood and urine from 500 000 individuals aged between 40 and 69 years. How the samples are collected, processed and stored will have a major impact on the future scientific usefulness of the UK Biobank resource. A series of validation studies was recommended to test the robustness of the draft sample handling and storage protocol. METHODS: Samples of blood and urine were collected from 40 healthy volunteers and either processed immediately according to the protocol or maintained at specified temperatures (4 degrees C for all tubes with the exception of vacutainers containing acid citrate dextrose that were maintained at 18 degrees C) for 12, 24 or 36 h prior to processing. A further sample was maintained for 24 h at 4 degrees C, processed and the aliquots frozen at -80 degrees C for 20 days and then thawed under controlled conditions. The stability of the samples was compared for the different times in a wide variety of assays. RESULTS: The samples maintained at 4 degrees C were stable for at least 24 h after collection for a wide range of assays. Small but significant changes were observed in metabonomic studies in samples maintained at 4 degrees C for 36 h. There was no degradation of the samples for a range of biochemical assays after short-term freezing and thawing under controlled conditions. Whole blood maintained at 18 degrees C for 24 h in vacutainers containing acid citrate dextrose is suitable for viral immortalization techniques. CONCLUSIONS: The validation studies reported in this supplement provide justification for the sample handling and storage procedures adopted in the UK Biobank project.

Design and implementation of a high-throughput biological sample processing facility using modern manufacturing principles.

BACKGROUND: UK Biobank is a prospective study that is collecting biological samples and health and lifestyle data from 500 000 volunteer participants over a 4-year period. These data will be used to facilitate biological and medical research. METHODS: Modern manufacturing principles were used to direct the development of the sample processing facility and automated systems. RESULTS: A fit for purpose facility comprising technology, systems, dedicated process, infrastructure and an appropriate staff structure has been implemented that will deliver and maintain a resource that will support the long-term goals of the UK Biobank study. CONCLUSIONS: Modern manufacturing principles are appropriate for use in the development of a high throughput biological sample processing facility.

The UK Biobank sample handling and storage protocol for the collection, processing and archiving of human blood and urine.

BACKGROUND: UK Biobank is a large prospective study in the UK to investigate the role of genetic factors, environmental exposures and lifestyle in the causes of major diseases of late and middle age. Extensive data and biological samples are being collected from 500,000 participants aged between 40 and 69 years. The biological samples that are collected and how they are processed and stored will have a major impact on the future scientific usefulness of the UK Biobank resource. AIMS: The aim of the UK Biobank sample handling and storage protocol is to specify methods for the collection and storage of participant samples that give maximum scientific return within the available budget. Processing or storage methods that, as far as can be predicted, will preclude current or future assays have been avoided. METHODS: The protocol was developed through a review of the literature on sample handling and processing, wide consultation within the academic community and peer review. Protocol development addressed which samples should be collected, how and when they should be processed and how the processed samples should be stored to ensure their long-term integrity. The recommended protocol was extensively tested in a series of validation studies. UK Biobank collects about 45 ml blood and 9 ml of urine with minimal local processing from each participant using the vacutainer system. A variety of preservatives, anti-coagulants and clot accelerators is used appropriate to the expected end use of the samples. Collection of other material (hair, nails, saliva and faeces) was also considered but rejected for the full cohort. Blood and urine samples from participants are transported overnight by commercial courier to a central laboratory where they are processed and aliquots of urine, plasma, serum, white cells and red cells stored in ultra-low temperature archives. Aliquots of whole blood are also stored for potential future production of immortalized cell lines. A standard panel of haematology assays is completed on whole blood from all participants, since such assays need to be conducted on fresh samples (whereas other assays can be done on stored samples). By the end of the recruitment phase, 15 million sample aliquots will be stored in two geographically separate archives: 9.5 million in a -80 degrees C automated archive and 5.5 million in a manual liquid nitrogen archive at -180 degrees C. Because of the size of the study and the numbers of samples obtained from participants, the protocol stipulates a highly automated approach for the processing and storage of samples. Implementation of the processes, technology, systems and facilities has followed best practices used in manufacturing industry to reduce project risk and to build in quality and robustness. The data produced from sample collection, processing and storage are highly complex and are managed by a commercially available LIMS system fully integrated with the entire process. CONCLUSION: The sample handling and storage protocol adopted by UK Biobank provides quality assured and validated methods that are feasible within the available funding and reflect the size and aims of the project. Experience from recruiting and processing the first 40,000 participants to the study demonstrates that the adopted methods and technologies are fit-for-purpose and robust.

UK Biobank: from concept to reality.

The UK Biobank is a major UK collaborative research project to recruit and follow longitudinally the health of 500,000 volunteers aged between 40-69 years. It will provide important biological samples and environmental exposure data. As such, it will constitute a resource for many future investigations of the separate and combined effects of genetic, environmental and lifestyle factors on human morbidity, mortality and health.

Delivering the power of discovery in large pharmaceutical organizations.

Increasing the output from discovery is currently a major objective for the pharmaceutical industry aimed at reversing recent downward trends in productivity. Although significant attention has been focused on innovative assay and process technologies, these only address specific points in the discovery process. Little effort has been made to manage the multiple interconnected steps within discovery effectively. This manifests itself in low utilization rates of component elements and low expectations of delivery to any agreed timescale.