Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Clinical decision-making and secondary findings in systems medicine.

BACKGROUND: Systems medicine is the name for an assemblage of scientific strategies and practices that include bioinformatics approaches to human biology (especially systems biology); "big data" statistical analysis; and medical informatics tools. Whereas personalized and precision medicine involve similar analytical methods applied to genomic and medical record data, systems medicine draws on these as well as other sources of data. Given this distinction, the clinical translation of systems medicine poses a number of important ethical and epistemological challenges for researchers working to generate systems medicine knowledge and clinicians working to apply it. DISCUSSION: This article focuses on three key challenges: First, we will discuss the conflicts in decision-making that can arise when healthcare providers committed to principles of experimental medicine or evidence-based medicine encounter individualized recommendations derived from computer algorithms. We will explore in particular whether controlled experiments, such as comparative effectiveness trials, should mediate the translation of systems medicine, or if instead individualized findings generated through "big data" approaches can be applied directly in clinical decision-making. Second, we will examine the case of the Riyadh Intensive Care Program Mortality Prediction Algorithm, pejoratively referred to as the "death computer," to demonstrate the ethical challenges that can arise when big-data-driven scoring systems are applied in clinical contexts. We argue that the uncritical use of predictive clinical algorithms, including those envisioned for systems medicine, challenge basic understandings of the doctor-patient relationship. Third, we will build on the recent discourse on secondary findings in genomics and imaging to draw attention to the important implications of secondary findings derived from the joint analysis of data from diverse sources, including data recorded by patients in an attempt to realize their "quantified self." This paper examines possible ethical challenges that are likely to be raised as systems medicine to be translated into clinical medicine. These include the epistemological challenges for clinical decision-making, the use of scoring systems optimized by big data techniques and the risk that incidental and secondary findings will significantly increase. While some ethical implications remain still hypothetical we should use the opportunity to prospectively identify challenges to avoid making foreseeable mistakes when systems medicine inevitably arrives in routine care.

[Clinical relevance of imaging techniques in population-based research]. / Klinische Bedeutung bildgebender Verfahren in populationsbasierter Forschung.

Similar to clinical practise, population-based studies with a clinical-epidemiological focus include imaging techniques to identify manifest disease and to assess subclinical disease. Even population-based cross-sectional studies offer various options to address scientific questions of great clinical relevance, including analysis of reference values, prevalence estimates and association analysis. Further potential values of imaging techniques in population-based studies concern additional information on incidental diseases and mortality rate, which make it possible to investigate the association between imaging findings at baseline and subsequent disease. Modern population-based designs ensure a high degree of being representative and can be generally applied to clinical practise and, as a result, may be highly relevant to daily clinical routine. When imaging techniques are integrated within population-based research, problems of quality control may have to be solved, all probands must give informed consent and a decision made on what findings have to be given to the participants.

[Clinicochemical blood values in newborn calves. 2. Repeated studies in the same animals]. / Klinisch-chemische Blutwerte bei neugeborenen Kälbern. 2. Wiederholte Untersuchungen an den gleichen Tieren.

Blood samples taken by venipuncture in calves within 12 hours after delivery and again in the same animals within 5 to 23 days of postnatal life were analyzed for hematocrit and fifteen other biochemical values. The changes of blood values between these two sampling points in each individual calf were investigated by regression analysis. Remarkable individual reactions and effects of the constitution of the animal immediately after delivery on the level and on the changes of the biochemical values could be observed as well as great deviations of some blood values of twin calves too. The scattering of some blood values and their changes in the first days of postnatal life are discussed regarding the maturity of the calves as well as the possible incidence of deficiency states or the setting of a new level for these physiological values.

[Clinico-chemical blood values in newborn calves. 1. Effects of some internal and external conditions]. / Klinisch-chemische Blutwerte bei neugeborenen Kälbern. 1. Einflüsse einiger innerer und äusserer Bedingungen.

In a large dairy cattle herd blood samples taken by venipuncture in newborn calves within 0 to 12 hours after delivery were analysed for hematocrit and fifteen other variables. The time of birth and the time of blood sampling and of first colostrum supply were recorded as well as body weight, sex and breed of the animals. Blood sampling in dairy cows was performed in the course of a herd health programme. The effects of the above-mentioned factors on the blood values of calves were investigated. Comparing the blood values of the pregnant cows with those of their newborn calves led to the result that in calves the measures were higher than (Hkt, Thyroxine), equal to (urea, P, Ca, Zn, Mg, K, Na, TIBC) or below (total protein, albumin, gammaglobulin, cholesterol, coeruloplasmin, Fe, Cu) those of their dams. There was great scattering of the concentrations of Zn, Cu, Mg, Fe, TIBC, total protein, albumin and in hematocrit. Uptake of colostrum caused the concentration of Mg, total protein and gammaglobulin to increase and those of albumin and hematocrit to decrease, leaving the levels of P and blood urea unchanged.

[Observations on the maturity of stillborn calves]. / Bemerkungen zum Reifegrad totgeborener Kälber.

Organ weight and trace element analyses were performed on 75 stillborn calves from the same dairy cow herd. The elements Fe, Mn, Zn and Cu were measured in the livers of 66 of the calves. The calves ranged in age from 259 to 299 days of gestation, and in weight from 18 to 58 kg. Based on the quotients of organ and other body parts, stage of growth of the humerus and age, the animals were grouped as either preterm (P), term but light (TL), and term with appropriate weight (TA) calves. In P group calves the heart, lungs, liver, kidneys, thymus, spleen and thyroid glands were relatively heavy. In the TL group calves the brain, heart, lungs and thyroid glands were relatively heavy whereas the spleen and thymus were comparatively light. The liver Fe and Zn values were lower in this group than in the other 2 groups.

[Trace element supply of newborn calves. Effect of the mother and of the genetic makeup, sex and degree of maturity of the newborn]. / Spurenelementausstattung neugeborener Kälber. Einflüsse des Muttertieres sowie von genetischer Konstruktion, Geschlecht und Reifegrad des Neugeborenen.

Stillborn calves of a large dairy cattle herd were used for investigations of trace element (Fe, Zn, Cu, Mn) content of the liver and heart muscle. Trace element content varied markedly in the liver and in the heart muscle too but in the heart muscle with a smaller degree. Calves from heifers had a greater trace element content in the liver and heart muscle than those from cows. Premature calves had small amounts of Mn and Cu in their livers and small but term calves had less Fe and Zn in their livers. Single calves from cows had a greater amount of trace elements in the liver and heart muscle than twin calves.

[Trace elements in the liver and myocardium of stillborn dairy calves]. / Spurenelemente in der Leber und im Herzmuskel totgeborener Kälber des Milchrindes.

Trace element analyses were performed on the livers of 52 and the heart muscle of 19 stillborn dairy calves. All calves originated from one herd and ranged in age from 260 days of gestation up to one day old. In the liver the trace element concentrations (mg/kg fresh weight) were as follows: Fe: 181.3 +/- 173.5; Zn: 74.6 +/- 37.7; Cu: 98.1 +/- 42.6; Mn: 1.4 +/- 0.36 and in the heart: Fe: 54.1 +/- 10.6; Zn: 16.3 +/- 3.8; Cu: 2.5 +/- 0.99; Mn: 0.42 +/- 0.07. Calves from heifers had lower Cu values. The relationship between trace element concentration and content and liver and heart weight is discussed, as are aspects of bioavailability and storage mechanisms as well as clinical signs of trace metal deficiencies.

[Birth weight and measurements of various body parts of stillborn calves of a large dairy cattle herd]. / Geburtsmassen und Masse einiger Körperteile totgeborener Kälber einer grossen Milchrindherde.

Stillborn calves (80 animals) originating from one dairy herd were used for studies on allometric measures in newborn calves. In the first approach some factors were neglected and only the effect of the calves' sex was considered. Differences in mean birthweight between male and female calves were reflected in organ and other body constituent weights too, but with different relations between them. Enlarged thyroid glands could be observed in both sexes but more often in female calves meaning that there is no correlation between thyroid size and body weight. Strong correlations of bones, muscles and outer body measures and looser ones of internal organs (thymus, liver, lung, kidneys, spleen) and endocrine glands (adrenal glands) with body weight were found especially in male calves. In some calves the sometimes enlarged liver looked like a fatty liver with its pale yellowish appearance and crumbly consistency.

[Birth injuries in calves and perinatal calf losses in a large dairy herd]. / Geburtsschäden an Kälbern und perinatale Kälberverluste in einer grossen Milchrindherde.

Post-mortem examinations were carried out on 65 calves which were stillborn or died within 24 hours of birth. All calves came from a large dairy unit with about one thousand cattle of the Schwarzbuntes Milchrind breed. To evaluate the perinatal losses, the farm records of parturitions from 1985-1990 were used. The calves had gross damage of the CNS, the musculature, subcutaneous tissue and internal organs such as lung and intestines. It may be assumed that a lesser degree of similar damage would also be present in the surviving calves. The level of perinatal losses is determined particularly by deaths following prolonged parturition due to foetal oversize in heifers and young cows, but also by the birth of immature calves of low weight after pregnancy of normal or decreased duration and by twin pregnancies with high total calf mass and relative immaturity of the calves.