Utilization of anonymization techniques to create an external control arm for clinical trial data.

BACKGROUND: Subject-level real-world data (RWD) collected during daily healthcare practices are increasingly used in medical research to assess questions that cannot be addressed in the context of a randomized controlled trial (RCT). A novel application of RWD arises from the need to create external control arms (ECAs) for single-arm RCTs. In the analysis of ECAs against RCT data, there is an evident need to manage and analyze RCT data and RWD in the same technical environment. In the Nordic countries, legal requirements may require that the original subject-level data be anonymized, i.e., modified so that the risk to identify any individual is minimal. The aim of this study was to conduct initial exploration on how well pseudonymized and anonymized RWD perform in the creation of an ECA for an RCT. METHODS: This was a hybrid observational cohort study using clinical data from the control arm of the completed randomized phase II clinical trial (PACIFIC-AF) and RWD cohort from Finnish healthcare data sources. The initial pseudonymized RWD were anonymized within the (k, ε)-anonymity framework (a model for protecting individuals against identification). Propensity score matching and weighting methods were applied to the anonymized and pseudonymized RWD, to balance potential confounders against the RCT data. Descriptive statistics for the potential confounders and overall survival analyses were conducted prior to and after matching and weighting, using both the pseudonymized and anonymized RWD sets. RESULTS: Anonymization affected the baseline characteristics of potential confounders only marginally. The greatest difference was in the prevalence of chronic obstructive pulmonary disease (4.6% vs. 5.4% in the pseudonymized compared to the anonymized data, respectively). Moreover, the overall survival changed in anonymization by only 8% (95% CI 4-22%). Both the pseudonymized and anonymized RWD were able to produce matched ECAs for the RCT data. Anonymization after matching impacted overall survival analysis by 22% (95% CI -21-87%). CONCLUSIONS: Anonymization may be a viable technique for cases where flexible data transfer and sharing are required. As anonymization necessarily affects some aspects of the original data, further research and careful consideration of anonymization strategies are needed.

Multiomics and digital monitoring during lifestyle changes reveal independent dimensions of human biology and health.

We explored opportunities for personalized and predictive health care by collecting serial clinical measurements, health surveys, genomics, proteomics, autoantibodies, metabolomics, and gut microbiome data from 96 individuals who participated in a data-driven health coaching program over a 16-month period with continuous digital monitoring of activity and sleep. We generated a resource of >20,000 biological samples from this study and a compendium of >53 million primary data points for 558,032 distinct features. Multiomics factor analysis revealed distinct and independent molecular factors linked to obesity, diabetes, liver function, cardiovascular disease, inflammation, immunity, exercise, diet, and hormonal effects. For example, ethinyl estradiol, a common oral contraceptive, produced characteristic molecular and physiological effects, including increased levels of inflammation and impact on thyroid, cortisol levels, and pulse, that were distinct from other sources of variability observed in our study. In total, this work illustrates the value of combining deep molecular and digital monitoring of human health. A record of this paper's transparent peer review process is included in the supplemental information.

Genetic Risk Score for Serum 25-Hydroxyvitamin D Concentration Helps to Guide Personalized Vitamin D Supplementation in Healthy Finnish Adults.

BACKGROUND: Genetic factors modify serum 25-hydroxyvitamin D [25(OH)D] concentration and can affect the optimal intake of vitamin D. OBJECTIVES: We aimed to personalize vitamin D supplementation by applying knowledge of genetic factors affecting serum 25(OH)D concentration. METHODS: We performed a genome-wide association study of serum 25(OH)D concentration in the Finnish Health 2011 cohort (n = 3339) using linear regression and applied the results to develop a population-matched genetic risk score (GRS) for serum 25(OH)D. This GRS was used to tailor vitamin D supplementation for 96 participants of a longitudinal Digital Health Revolution (DHR) Study. The GRS, serum 25(OH)D concentrations, and personalized supplementation and dietary advice were electronically returned to participants. Serum 25(OH)D concentrations were assessed using immunoassays and vitamin D intake using FFQs. In data analyses, cross-sectional and repeated-measures statistical tests and models were applied as described in detail elsewhere. RESULTS: GC vitamin D-binding protein and cytochrome P450 family 2 subfamily R polypeptide 1 genes showed genome-wide significant associations with serum 25(OH)D concentration. One single nucleotide polymorphism from each locus (rs4588 and rs10741657) was used to develop the GRS. After returning data to the DHR Study participants, daily vitamin D supplement users increased from 32.6% to 60.2% (P = 6.5 × 10-6) and serum 25(OH)D concentration from 64.4 ± 20.9 nmol/L to 68.5 ± 19.2 nmol/L (P = 0.006) between August and November. Notably, the difference in serum 25(OH)D concentrations between participants with no risk alleles and those with 3 or 4 risk alleles decreased from 20.7 nmol/L to 8.0 nmol/L (P = 0.0063). CONCLUSIONS: We developed and applied a population-matched GRS to identify individuals genetically predisposed to low serum 25(OH)D concentration. We show how the electronic return of individual genetic risk, serum 25(OH)D concentrations, and factors affecting vitamin D status can be used to tailor vitamin D supplementation. This model could be applied to other populations and countries.

Comparison of solution-based exome capture methods for next generation sequencing.

BACKGROUND: Techniques enabling targeted re-sequencing of the protein coding sequences of the human genome on next generation sequencing instruments are of great interest. We conducted a systematic comparison of the solution-based exome capture kits provided by Agilent and Roche NimbleGen. A control DNA sample was captured with all four capture methods and prepared for Illumina GAII sequencing. Sequence data from additional samples prepared with the same protocols were also used in the comparison. RESULTS: We developed a bioinformatics pipeline for quality control, short read alignment, variant identification and annotation of the sequence data. In our analysis, a larger percentage of the high quality reads from the NimbleGen captures than from the Agilent captures aligned to the capture target regions. High GC content of the target sequence was associated with poor capture success in all exome enrichment methods. Comparison of mean allele balances for heterozygous variants indicated a tendency to have more reference bases than variant bases in the heterozygous variant positions within the target regions in all methods. There was virtually no difference in the genotype concordance compared to genotypes derived from SNP arrays. A minimum of 11× coverage was required to make a heterozygote genotype call with 99% accuracy when compared to common SNPs on genome-wide association arrays. CONCLUSIONS: Libraries captured with NimbleGen kits aligned more accurately to the target regions. The updated NimbleGen kit most efficiently covered the exome with a minimum coverage of 20×, yet none of the kits captured all the Consensus Coding Sequence annotated exons.

Robust denoising of electrophoresis and mass spectrometry signals with minimum description length principle.

The need for high-throughput assays in molecular biology places increasing requirements on the applied signal processing and modelling methods. In order to be able to extract useful information from the measurements, the removal of undesirable signal characteristics such as random noise is required. This can be done in a quite elegant and efficient way by the minimum description length (MDL) principle, which treats and separates 'noise' from the useful information as that part in the data that cannot be compressed. In its current form the MDL denoising method assumes the Gaussian noise model but does not require any ad hoc parameter settings. It provides a basis for high-speed automated processing systems without requiring continual user interventions to validate the results as in the conventional signal processing methods. Our analysis of the denoising problem in mass spectrometry, capillary electrophoresis genotyping, and sequencing signals suggests that the MDL denoising method produces robust and intuitively appealing results sometimes even in situations where competing approaches perform poorly.

Segmental duplications flank the multiple sclerosis locus on chromosome 17q.

Large chromosomal rearrangements, duplications, and inversions are relatively common in mammalian genomes. Here we report interesting features of DNA strands flanking a Multiple Sclerosis (MS) susceptibility locus on Chromosome 17q24. During the positional cloning process of this 3-Mb locus, several markers showed a radiation hybrid clone retention rate above the average (1.8-fold), suggestive for the existence of duplicated sequences in this region. FISH studies demonstrated multiple signals with three of the tested regional BACs, and 24 BACs out of 187 showed evidence for duplication in shotgun sequence comparisons of the 17q22-q24 region. Specifically, the MS haplotype region proved to be flanked by palindromic sequence stretches and by long segmental intrachromosomal duplications in which highly homologous DNA sequences (>96% identity) are present at both ends of the haplotype. Moreover, the 3-Mb DNA segment, flanked by the duplications, is inverted in the mouse genome when compared with the orientation in human and chimp. The segmental duplication architecture surrounding the MS locus raises the possibility that a nonallelic homologous recombination between duplications could affect the biological activity of the regional genes, perhaps even contributing to the genetic background of MS.

Whiplash injuries in Finland: the situation 3 years later.

The aim of this study was to define the influence of whiplash injuries on the perceived condition of health 3 years after injury. We evaluated remaining symptoms and the use of health services. Insurance companies provided reports and medical certificates from traffic accidents in Finland in 1998, for those injured who had agreed to take part in the study. Participants in the 1-year follow-up study answered a self-report questionnaire. Three years after the whiplash-causing accident, 11.8% of participants reported that injury symptoms had caused their health to deteriorate significantly as compared with before the accident. Neck pain was the most common single symptom, reported by 14.6% of respondents. The severity of the initial symptoms according to the WAD classification is reflected in the subject's self-perception of health after 3 years. A remarkable 10-17% of respondents still used health services regularly because of the symptoms. Although some of the injured had improved in the long term, some reported that their health condition was worse after 3 years than at the 1-year follow-up. The percentage of respondents reporting a significant health deterioration remains unchanged 3 years after the whiplash injury. These findings illuminate the importance of early recognition of risk factors for long-term disability and the primary treatment and rehabilitation procedures.

The possibility to use simple validated questionnaires to predict long-term health problems after whiplash injury.

STUDY DESIGN: A prospective follow-up study. OBJECTIVES: To evaluate the relation of the state of health before the accident and the significance of the symptoms reported soon after the injury to the situation 3 years after the injury. To evaluate the possibility of using simple validated questionnaires to predict long-term health problems after the injury. SUMMARY OF BACKGROUND DATA: A whiplash injury is generally benign in its natural course. However, some of the patients have diverse and prolonged symptoms. Although several prognostic factors have been suggested for the poor recovery, in most cases the factors leading to prolonged disability remain unclear. METHODS: In collaboration with traffic insurance companies, we gathered information of neck injuries that occurred in traffic accidents in Finland in 1998. After the insurance company received a notification of a neck injury and consent from the injured party to participate in the study, they sent the information to the research team. The first inquiry was sent to the patients as soon as possible. One- and three-year follow-up questionnaires were posted to those who responded to the first inquiry. A total of 144 persons returned the 3-year follow-up questionnaires and form the material of this study. RESULTS A poor state of health or frequent neck pain or headache before the accident did not have any significant relation to the poor outcome 3 years after the accident. The extent of neck pain and lower back pain reported soon after the accident was significantly associated to a poor outcome in the follow-up. The Neck Disability Index questionnaire was significantly related to the poor outcome after 3 years. CONCLUSIONS: The subjective experience of a notably decreased level of activity because of the neck pain when supplemented by the enhanced score of Neck Disability Index questionnaire predicts well poor outcome in long-term follow-up and can be used as a tool to identify persons who are at risk to suffer long-term health problems after whiplash injury.

Whiplash injuries in Finland--the possibility of some sociodemographic and psychosocial factors to predict the outcome after one year.

PURPOSE: The aim of our study was to evaluate if there was any relation between the change experienced in the condition of health or the length of the reported sick leaves after one year of whiplash injury and different sociodemographic and psychosocial factors. METHOD: Our study design is a prospective 1-year-follow-up study. The material was collected in the year 1998 from neck injuries that had been caused by traffic accidents. The insurance companies sent a notice of the accident with medical certificate to the research team. After this we sent questionnaires to the injured and after one year of the accident a new inquiry was done. One hundred and eighty-two persons returned the 1-year-follow-up questionnaire which formed the material of this study. RESULTS: The persons who had the lowest basic education and people over 60 years of age had more health problems after one year of the accident. The other sociodemographic and psychosocial factors had only limited prognostic value when we evaluated the experienced change of health one year after the whiplash injury. Only 71 persons reported that they had been on sick leave because of the whiplash injury and of them only 21 reported sick leave over 1 month. CONCLUSIONS: Several sociodemographic and psychosocial factors can have relation to the deterioration of health experienced after whiplash injury but in this prospective study they proved to have only limited prognostic value in the long term symptoms with the exception of the education.