Integrating biomedical research and electronic health records to create knowledge-based biologically meaningful machine-readable embeddings.

In order to advance precision medicine, detailed clinical features ought to be described in a way that leverages current knowledge. Although data collected from biomedical research is expanding at an almost exponential rate, our ability to transform that information into patient care has not kept at pace. A major barrier preventing this transformation is that multi-dimensional data collection and analysis is usually carried out without much understanding of the underlying knowledge structure. Here, in an effort to bridge this gap, Electronic Health Records (EHRs) of individual patients are connected to a heterogeneous knowledge network called Scalable Precision Medicine Oriented Knowledge Engine (SPOKE). Then an unsupervised machine-learning algorithm creates Propagated SPOKE Entry Vectors (PSEVs) that encode the importance of each SPOKE node for any code in the EHRs. We argue that these results, alongside the natural integration of PSEVs into any EHR machine-learning platform, provide a key step toward precision medicine

Latent physiological factors of complex human diseases revealed by independent component analysis of clinarrays

<p>Abstract</p> <p>Background</p> <p>Diagnosis and treatment of patients in the clinical setting is often driven by known symptomatic factors that distinguish one particular condition from another. Treatment based on noticeable symptoms, however, is limited to the types of clinical biomarkers collected, and is prone to overlooking dysfunctions in physiological factors not easily evident to medical practitioners. We used a vector-based representation of patient clinical biomarkers, or clinarrays, to search for latent physiological factors that underlie human diseases directly from clinical laboratory data. Knowledge of these factors could be used to improve assessment of disease severity and help to refine strategies for diagnosis and monitoring disease progression.</p> <p>Results</p> <p>Applying Independent Component Analysis on clinarrays built from patient laboratory measurements revealed both known and novel concomitant physiological factors for asthma, types 1 and 2 diabetes, cystic fibrosis, and Duchenne muscular dystrophy. Serum sodium was found to be the most significant factor for both type 1 and type 2 diabetes, and was also significant in asthma. TSH3, a measure of thyroid function, and blood urea nitrogen, indicative of kidney function, were factors unique to type 1 diabetes respective to type 2 diabetes. Platelet count was significant across all the diseases analyzed.</p> <p>Conclusions</p> <p>The results demonstrate that large-scale analyses of clinical biomarkers using unsupervised methods can offer novel insights into the pathophysiological basis of human disease, and suggest novel clinical utility of established laboratory measurements.</p

The future of laboratory medicine - A 2014 perspective.

Predicting the future is a difficult task. Not surprisingly, there are many examples and assumptions that have proved to be wrong. This review surveys the many predictions, beginning in 1887, about the future of laboratory medicine and its sub-specialties such as clinical chemistry and molecular pathology. It provides a commentary on the accuracy of the predictions and offers opinions on emerging technologies, economic factors and social developments that may play a role in shaping the future of laboratory medicine

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.Peer reviewe

Bioinformaatika meetodid personaalses farmakoteraapias

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKogutavate terviseandmete hulk kasvab kiiresti. Tänu neile andmetele on meditsiinilise ravi pakkumisel võimalik senisest enam arvesse võtta individuaalseid bioloogilisi andmeid. See doktoritöö käsitleb mitmeid personaalses meditsiinis esinevaid probleeme ja näitab, et ravi individualiseerimiseks kasutatavad andmed tulevad väga erinevatest allikatest. Inimestevahelised erinevused teevad ravimite metabolismi ennustamise keerukaks, siiski on ravi käigus kogutavad kontsentratsioonimõõtmised ravimiefekti hindamisel heaks allikaks. Me arendasime välja täppisdoseerimise tööriista, mis võimaldab vankomütsiini ravil vastsündinutele määrata ravi tõhustavat personaalseid doose kasutades selleks nende endi ravi käigus kogutud kontsentratsioone. Suurema osa ravimiteraapiate puhul ei ole võimalik pidevalt ravimi kontsentratsioone koguda. Nende ülejäänud ravimite puhul on heaks informatsiooniallikaks geneetika. Paljude ravimimetabolismiga seotud geneetiliste variantide mõju on piisav, et tingida muutuseid ravi läbiviimisel. Me uurisime geneetika ja ravimite kõrvalmõjude omavahelisi seoseid kasutades rahvastikupõhist lähenemist. See toetus Eesti Geenivaramu geeniandmetele ja teistele laiapõhjalistele terviseandmete registritele. Me leidsime ja valideerisime seose, et CTNNA3 geenis olev geenivariant tõstab oksikaamide ravil olevate inimeste jaoks kõrvalmõjude sagedust. Arvutuslik geneetika toetub kvantitatiivsetele meetoditele, millest kõige levinum on ülegenoomne assotsiatsiooni analüüs (GWAS). Sagedasti kasutatav GWASi järelsamm on aega nõudev GWASist ilmnenud p-väärtuste visuaalne hindamine teiste samas genoomi piirkonnas olevate geneetiliste variantide kontekstis. Selle sammu automatiseerimiseks arendasime me kaks tööriista, Manhattan Harvester ja Cropper, mis võimaldavad automaatselt huvipakkuvaid piirkondi tuvastada ja nende headust hinnata.The amount of collected health data is growing fast. Insights from these data allow using biological patient specifics to improve therapy management with further individualization. This thesis addresses problems in multiple sub-fields of personalised medicine and aims to illustrate that data for precision medicine emerges from different sources. Drug metabolism is difficult to predict because individual biological differences. Fortunately, drug concentrations are a good proxy for drug effect. To address the growing need for tools that allow on-line therapy adjustment based on individual concentrations we have developed and externally evaluated a precision dosing tool that allows individualised dosing of vancomycin in neonates. Other than drugs used in therapeutic drug monitoring, most pharmacotherapies can not rely on continuous concentration measurements but for such drugs genetics provides a valuable source of information for individualization. Effects of many genetic variants in drug metabolism pathways are often large enough to require changes in drug prescriptions or schedules. We have applied a population-based approach in testing relations between drug related adverse effects and genomic loci, and found and validated a novel variant in CTNNA3 gene that increases adverse drug effects in patients with oxicam prescriptions. This was done by leveraging the data in Estonian Genome Center and linking these to nation-wide electronic health data registries. Computational genetics relies on quantitative methods for which the most common is the genome-wide association analysis (GWAS). A common GWAS downstream step involves time-consuming visual assessment of the association study p-values in context with other variants in genomic vicinity. In order to streamline this step, we developed, Manhattan Harvester and Cropper, that allow for automated detection of peak areas and assign scores by emulating human evaluators.https://www.ester.ee/record=b524282

Longitudinal multi-dimensional investigation of metabolic and endocrine genetics

Genome-wide association studies (GWASs) in recent decades have revealed the genetic landscape and shared aetiology of common, complex traits across the spectrum of human phenotypes. In this work, I develop and apply statistical tools to interrogate the genetic basis of, and relationships between, metabolic and endocrine traits. I demonstrate that under-explored primary care electronic health records (EHRs), linked to massive biobank projects across the globe, are a valuable source of longitudinal and rare biomarker data for genetics studies. Using EHRs, I find a common missense variant in the APOE gene that is associated with weight-loss in adulthood, which replicates in three global biobanking cohorts of between 125,000 to 475,000 individuals each. While the heritability of weight-change is low ( 700,000 participants across seven global biobanks), to characterise the genetic contributions to these common but poorly understood phenotypes. I find 21 unique genetic loci for infertility, of which only six colocalise with reproductive hormone levels. While there is modest correlation between female infertility and heritable diseases of the reproductive tract, such as endometriosis (rG = 58%) and polycystic ovary syndrome (PCOS) (rG = 40%), I find no evidence for metabolic conditions such as obesity in the genetic aetiology of infertility. I explore these findings further through Mendelian Randomisation analyses to reveal heterogeneity in the genetically predicted causal effects of overall and central obesity on the risk of female reproductive conditions, including infertility, endometriosis, and PCOS, which may be partly genetically mediated by hormone levels. Through a range of genetics-based investigations, I outline the shared and distinct mechanisms of metabolic and endocrine disease in humans

Hedelmällisyyspotentiaalin kehitys ja hoitomuodot sukupuolisen kehityksen variaatioissa sekä viivästyneessä murrosiässä

Differences of sexual development (DSDs) are a wide range of congenital conditions that affect the development of chromosomal, gonadal, or anatomic sex. Fertility is strongly reduced in most DSDs. However, congenital hypogonadotropic hypogonadism (CHH) is an example of a DSD where male infertility is treatable. To induce puberty in CHH boys, virilization can be achieved with testosterone, but testicular maturation and induction of spermatogenesis require treatment with gonadotropins. Treatment with gonadotropins in infancy may have beneficial effects on testicular function and genital development, but the efficiency of this intervention is unknown. Constitutional delay of growth and puberty (CDGP) is a self-limited condition and the most common reason for delayed puberty. Watchful waiting and reassurance are generally an adequate approach. For boys who seek medical intervention, low-dose androgen or aromatase inhibitor can be used for puberty-promoting treatment. However, the risks and benefits of manipulating the reproductive axis during early puberty and the possible effects on fertility potential should be studied further. Study I described the timing of diagnosis and treatment in DSD patients treated in a single pediatric tertiary center between 2004 and 2014. The most common diagnoses were Turner syndrome (TS) (19.8 %, diagnosed at the mean age of 4.7 ± 5.5 years), Klinefelter syndrome (KS) (14.5 %, 6.8 ± 6.2 years) and bilateral cryptorchidism (23.1 %). Very few patients with 46,XY DSD (7 %) or 46,XX DSD (21 %) had a molecular genetic diagnosis. The Nordic consensus statement on treatment of undescended testis, released in 2007, recommends surgical treatment before the age of one year. After 2007, the age at operation in bilateral cryptorchidism declined from 54.5 ± 43.0 months to 41.1 ± 45.3 months (p = 0.0001) but did not reach recommended levels yet. In Study II the aim was to assess the long-term effects of r-hFSH treatment in prepubertal CHH boys with a known molecular diagnosis. In five prepubertal CHH boys, priming treatment with r-hFSH doubled the testicular volume (from a mean ± SD of 0.9 ± 0.9 mL to 1.9 ± 1.7 mL; p < 0.05) and increased inhibin B (from 15 ± 5 ng/L to 85 ± 40 ng/L; p < 0.05) as desired, even though three of them received testosterone simultaneously. In three of the boys, puberty was successfully induced with hCG after the priming treatment, and testicular volume increased further (from 2.1 ± 2.3 mL to 8.6 ± 1.7 mL). All three boys treated with hCG developed sperm, even though two of them had initially extremely small testis size (0.3 mL). Study III investigated the outcome of r-hFSH treatment given in infancy. Five infant CHH boys treated with r-hFSH and testosterone showed increase in inhibin B and penile length during the treatment (inhibin B from 76 ± 18 ng/l to 176 ± 80 ng/l, p = 0.04 and penile length by 81 ± 50 %, p = 0.04). Unexpectedly, two boys with robust inhibin B responses in infancy demonstrated in peripuberty low inhibin B values that did not differ from the untreated CHH controls. Study IV assessed whether treating CDGP in boys with letrozole (Lz) or conventional low-dose testosterone (T) had differing effects on developing seminiferous epithelium. Anti-Müllerian hormone (AMH) declined similarly in both groups. Between 0 and 3 months, the changes in gonadotropin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of inhibin B (FSH vs inhibin B, r = 0.55, p = 0.002; LH vs inhibin B, r = 0.72, p < 0.0001), but not with the changes in AMH (p = NS). Serum Lz levels (range, 124-1262 nmol/L) in these children were largely explained by the Lz dose per weight (at 3 months r = 0.62, p = 0.01; at 6 months r = 0.52, p = 0.05). Lz levels did not associate with changes in indices of hypothalamus-pituitary-gonadal-axis activity or Sertoli cell markers (in all, p = NS). In summary, the findings in Study I suggest that of the most common DSDs in our data, TS and KS are diagnosed relatively late, and that treatment of bilateral cryptorchidism was influenced by international guidelines. It is feasible that age at diagnosis in patients with TS and KS and the age at operation of bilateral cryptorchidism could serve as indices for monitoring the diagnostic effectiveness and management of DSD patients within and between different tertiary centers providing DSD care. In Study II we showed that spermatogenesis can be induced with gonadotropins even in adolescent CHH boys with extremely small testes, also despite low-dose testosterone treatment given in early puberty. Study III suggests that although infant CHH boys reacted well to r-hFSH treatment in terms of increasing inhibin B levels, the effects may be transient in long-term follow-up. In Study IV, treatment-induced gonadotropin stimulus was unable to counteract the androgen-mediated decrease in AMH in early puberty, while changes in inhibin B levels were associated with changes in gonadotropin levels. Similar AMH decline in both treatment groups implied that there were no adverse effects on the developing seminiferous epithelium. In addition, since a fixed dose of Lz produced the desired puberty-promoting effect in all boys despite variable serum Lz, more research is needed to determine the lowest effective dose per weight.Tässä väitöskirjassa pyritään kuvaamaan tapoja tutkia ja turvata hedelmällisyyspotentiaalia lapsilla ja nuorilla, joilla on sukupuolisen kehityksen variaatio (difference of sex development, DSD) tai viivästynyt murrosikä. Suurimmassa osassa DSD-diagnooseja hedelmällisyys on selvästi alentunut. Viivästyneenä murrosikänä usein ilmenevä synnynnäinen hypogonadotrooppinen hypogonadismi (CHH) on kuitenkin esimerkki DSD:stä, jossa miehen infertiliteettiä pystytään hoitamaan. Yleisimmin viivästynyt murrosikä johtuu itsestään rajoittuvasta konstitutionaalisesta viivästyneestä puberteetista (CDGP), jonka hoidoksi riittää yleensä seuranta. Pieniannoksista testosteronihoitoa tai aromataasi-inhibiittorihoitoa voidaan käyttää potilaan niin toivoessa murrosiän edistämiseen, mutta näiden lisääntymisakselia manipuloivien hoitojen riskit ja hyödyt, sekä vaikutukset hedelmällisyyspotentiaaliin tulee punnita tarkkaan. Osatyössä I arvioitiin diagnoosin ja hoidon ajoitusta yhden keskuksen 10 vuoden aikana hoidettujen DSD-potilaiden hedelmällisyyspotentiaaliin vaikuttavina tekijöinä. Yleisimmistä DSD-diagnooseista Turnerin- ja Klinefelterin syndrooma diagnosoitiin suhteellisen myöhään ja molemminpuolisen piilokiveksisyyden leikkausikään tarkastelujaksolla vaikuttivat uusitut kansainväliset hoitosuositukset. Näitä diagnoosi- ja leikkausikiä voisi hyödyntää mittareina, joilla monitoroitaisiin DSD-potilaiden diagnostiikan ja hoidon tehokkuutta. Osatöissä II ja III tarkasteltiin follikkelia stimuloiva hormoni (r-hFSH) -hoidon vaikutusta CHH-potilaiden hedelmällisyyspotentiaaliin. Viidellä pojalla imeväisiässä annettu r-hFSH-hoito nosti kivesten Sertolin solujen erittämän inhibiini B:n tasoja toivotulla tavalla, mutta kolmelta pojalta saaduissa murrosikää edeltävissä seurantamittauksissa inhibiini B ei eronnut hoitamattomista kontrolleista. Viidellä esimurrosikäisellä CHH-pojalla inhibiini B ja kivestilavuus suurenivat r-hFSH-hoidon aikana. Tämän jälkeen murrosikä käynnistettiin koriongonadotropiini-hormonilla (hCG) kolmella pojista ja huolimatta kivesten pienestä lähtötilavuudesta he pystyivät tuottamaan siittiöitä. Osatyössä IV tarkasteltiin kivesten erittämän AMH:n tasoja 30:llä CDGP-pojalla, joita oli hoidettu testosteronilla tai aromataasi-inhibiittori letrotsolilla. Samankaltainen AMH-lasku molemmissa hoitoryhmissä viittasi siihen, että hoidoilla ei ollut haitallisia vaikutuksia kehittyvään siementiehytepiteeliin kiveksissä. Koska vakioitu letrotsoliannos edisti murrosikää toivotulla tavalla kaikilla pojilla riippumatta vaihtelevista seerumin letrotsolipitoisuuksista, lisää tutkimusta tarvitaan pienimmän mahdollisen tehokkaan letrotsoliannoksen määrittelemiseksi