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For the goal of individualized medicine, it is critical to have clinical phenotypes at hand which represent the individual pathophysiology. However, for most of the utilized phenotypes, two individuals with the same phenotype assignment may differ strongly in their underlying biological traits. In this paper, we propose a definition for individualization and a corresponding statistical operationalization, delivering thereby a statistical framework in which the usefulness of a variable in the meaningful differentiation of individuals with the same phenotype can be assessed. Based on this framework, we develop a statistical workflow to derive individualized phenotypes, demonstrating that under specific statistical constraints the prediction error of prediction scores contains information about hidden biological traits not represented in the modeled phenotype of interest, allowing thereby internal differentiation of individuals with the same assigned phenotypic manifestation. We applied our procedure to data of the population-based Study of Health in Pomerania to construct a refined definition of obesity, demonstrating the utility of the definition in prospective survival analyses. Summarizing, we propose a framework for the individualization of phenotypes aiding personalized medicine by shifting the focus in the assessment of prediction models from the model fit to the informational content of the prediction error.
Periodontitis is one of the most prevalent oral diseases worldwide and is caused by multifactorial interactions between host and oral bacteria. Altered cellular metabolism of host and microbes releases a number of intermediary end products known as metabolites. There is an increasing interest in identifying metabolites from oral fluids such as saliva to widen the understanding of the complex pathogenesis of periodontitis. It is believed that some metabolites might serve as indicators toward early detection and screening of periodontitis and perhaps even for monitoring its prognosis in the future. Because contemporary periodontal screening methods are deficient, there is an urgent need for novel approaches in periodontal screening procedures. To this end, we associated oral parameters (clinical attachment level, periodontal probing depth, supragingival plaque, supragingival calculus, number of missing teeth, and removable denture) with a large set of salivary metabolites (n = 284) obtained by mass spectrometry among a subsample (n = 909) of nondiabetic participants from the Study of Health in Pomerania (SHIP-Trend-0). Linear regression analyses were performed in age-stratified groups and adjusted for potential confounders. A multifaceted image of associated metabolites (n = 107) was revealed with considerable differences according to age groups. In the young (20 to 39 y) and middle-aged (40 to 59 y) groups, metabolites were predominantly associated with periodontal variables, whereas among the older subjects (≥60 y), tooth loss was strongly associated with metabolite levels. Metabolites associated with periodontal variables were clearly linked to tissue destruction, host defense mechanisms, and bacterial metabolism. Across all age groups, the bacterial metabolite phenylacetate was significantly associated with periodontal variables. Our results revealed alterations of the salivary metabolome in association with age and oral health status. Among our comprehensive panel of metabolites, periodontitis was significantly associated with the bacterial metabolite phenylacetate, a promising substance for further biomarker research.
Background: Abdominal obesity is a major driver for adverse medical conditions. While an interaction between adipose tissue and thyroid function is thought to exist, to our knowledge, no study has examined the effect of thyroid-stimulating hormone (TSH) on visceral adipose tissue (VAT) in a population-based context. Objective: We determined an association between serum TSH levels and VAT. Methods: A sample of 1,021 female and 956 male adults aged 20-79 years was drawn from registry offices in the cross-sectional, population-based Study of Health in Pomerania Trend (SHIP Trend) in Northeast Germany from 2008 to 2012. Our main exposure was serum TSH levels. Our main outcome was VAT measured using magnetic resonance imaging. The possibly mediating role of leptin on the TSH-VAT association was also assessed. Results: A total of 1,719 participants (87.9%) had serum TSH levels within the reference range. The mean volume of VAT was 5.33 liters for men and 2.83 liters for women. No association between TSH and VAT (β = 0.06, 95% CI: -0.02, 0.14) was observed, and there were no differences detected between sexes. VAT was strongly associated with leptin with a greater effect in women than in men. Leptin was strongly associated with TSH. Conclusions: No association between TSH and VAT was observed. Other biomarkers such as leptin may play a role in the relationship between thyroid function and metabolic risk.
Background: Hyperthyroidism is known to induce a hypercoagulable state. It stimulates plasma levels of procoagulative factors and reduces fibrinolytic activity. So far most of the data have been derived from patients with endogenous hyperthyroidism with a wide variability in the underlying pathogenesis and severity of the disease. Objectives: In this study we experimentally induced thyrotoxicosis in healthy volunteers to explore the effects of thyroxine excess on the plasma proteome. Using a shotgun proteomics approach, the abundance of plasma proteins was monitored before, during and after thyrotoxicosis. Methods: Sixteen healthy male subjects were sampled at baseline, 4 and 8 weeks under 250 µg/day thyroxine p.o., as well as 4 and 8 weeks after stopping the application. Plasma proteins were analyzed after depletion of 6 high-abundance proteins (MARS6) by LC-ESI-MS/MS mass spectrometry. Mass spectrometric raw data were processed using a label-free, intensity-based workflow. Subsequently, the linear dependence between protein abundances and fT<sub>4</sub> levels were calculated using a Pearson correlation. Results: All subjects developed biochemical thyrotoxicosis, and this effect was reversed within the first 4 weeks of follow-up. None of the volunteers noticed any subjective symptoms. Levels of 10 proteins involved in the coagulation cascade specifically correlated with fT<sub>4</sub>, supporting an influence of thyroid hormone levels on blood coagulation even at nonpathological levels. Conclusions: The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.
Context: 3,5-Diiodo-<smlcap>L</smlcap>-thyronine (3,5-T<sub>2</sub>) is a thyroid hormone metabolite which exhibited versatile effects in rodent models, including the prevention of insulin resistance or hepatic steatosis typically forced by a high-fat diet. With respect to euthyroid humans, we recently observed a putative link between serum 3,5-T<sub>2</sub> and glucose but not lipid metabolism. Objective: The aim of the present study was to widely screen the urine metabolome for associations with serum 3,5-T<sub>2</sub> concentrations in healthy individuals. Study Design and Methods: Urine metabolites of 715 euthyroid participants of the population-based Study of Health in Pomerania (SHIP-TREND) were analyzed by <sup>1</sup>H-NMR spectroscopy. Multinomial logistic and multivariate linear regression models were used to detect associations between urine metabolites and serum 3,5-T<sub>2</sub> concentrations. Results: Serum 3,5-T<sub>2</sub> concentrations were positively associated with urinary levels of trigonelline, pyroglutamate, acetone and hippurate. In detail, the odds for intermediate or suppressed serum 3,5-T<sub>2</sub> concentrations doubled owing to a 1-standard deviation (SD) decrease in urine trigonelline levels, or increased by 29-50% in relation to a 1-SD decrease in urine pyroglutamate, acetone and hippurate levels. Conclusion: Our findings in humans confirmed the metabolic effects of circulating 3,5-T<sub>2</sub> on glucose and lipid metabolism, oxidative stress and enhanced drug metabolism as postulated before based on interventional pharmacological studies in rodents. Of note, 3,5-T<sub>2</sub> exhibited a unique urinary metabolic profile distinct from previously published results for the classical thyroid hormones.
Background: Chronic kidney disease (CKD) and low serum total testosterone (TT) concentrations are independent predictors of mortality risk in the general population, but their combined potential for improved mortality risk stratification is unknown. Methods: We used data of 1,822 men from the population-based Study of Health in Pomerania followed- up for 9.9 years (median). The direct effects of kidney dysfunction (estimated glomerular filtration rate <60 ml/min/ 1.73 m<sup>2</sup>), albuminuria (urinary albumin-creatinine ratio ≧2.5 mg/mmol) and their combination (CKD) on all-cause and cardiovascular mortality were analyzed using multivariable Cox regression models. Serum TT concentrations below the age-specific 10th percentile (by decades) were considered low and were used for further risk stratification. Results: Kidney dysfunction (hazard ratio, HR, 1.40; 95% confidence interval, CI, 1.02–1.92), albuminuria (HR, 1.38; 95% CI, 1.06–1.79), and CKD (HR, 1.42; 95% CI, 1.09–1.84) were associated with increased all-cause mortality risk, while only kidney dysfunction (HR, 2.01; 95% CI, 1.21–3.34) was associated with increased cardiovascular mortality risk after multivariable adjustment. Men with kidney dysfunction and low TT concentrations were identified as high-risk individuals showing a more than 2-fold increased all-cause mortality risk (HR, 2.52; 95% CI, 1.08–5.85). Added to multivariable models, nonsignificant interaction terms suggest that kidney dysfunction and low TT are primarily additive rather than synergistic mortality risk factors. Conclusion: In the case of early loss of kidney function, measured TT concentrations might help to detect high-risk individuals for potential therapeutic interventions and to improve mortality risk assessment and outcome.
Das Immunsystem hat die Aufgabe körperfremde von körpereigenen Strukturen zu unterscheiden. Es gewährt dem Organismus die spezifische Abwehr gegenüber krankheitsauslösenden Strukturen (Bakterien, Viren, Gifte). In seiner Komplexität führen Fehlfunktionen des Immunsystems zu verschiedenen Erkrankungen. Richtet sich die Immunantwort gegen körpereigene Strukturen und versagt die Unterscheidung zwischen Eigen und Fremd, so spricht man von Autoimmunerkrankungen. Die vorliegende Arbeit beschäftigte sich mit der Epidemiologie von (1) Allergien und (2) Autoimmunerkrankungen der Schilddrüse (AIT). (1) Parodontitis und Allergien HINTERGRUND: Parodontitis ist eine unter Erwachsenen weit verbreitete lokale, orale Infektion, die systemische Auswirkungen hat. In der Ätiologie von Allergien wird seit den 80iger Jahren die sogenannte Hygiene-Hypothese diskutiert. Diese besagt, dass Infektionen im Kindesalter präventiv auf die Entstehung von Allergien wirken. In der vorliegenden Studie wurde der Zusammenhang zwischen Parodontitis und allergischen Erkrankungen (Heuschnupfen, Hausstauballergie und Asthma) in der Allgemeinbevölkerung Vorpommerns und einem Diabetes mellitus Typ 1 Patientenkollektiv untersucht. METHODEN: Für die erste Analyse wurden Daten von 2837 Männern und Frauen im Alter zwischen 20 und 59 Jahren aus der bevölkerungsrepräsentativen „Study of Health in Pomerania“ (SHIP) herangezogen. Das Diabetes mellitus Typ 1 Patientenkollektiv beinhaltete 170 Patienten im Alter zwischen 17 und 80 Jahren. Der Attachmentverlust (AV) wurde gemessen und das Ausmaß der Parodontitis mittels des Prozentsatzes an Fläche mit einem AV über 3mm erfasst (gesunder Parodontalstatus, geringer AV, moderater AV, schwerwiegender AV). ERGEBNISSE: In SHIP berichteten 326 Personen Heuschnupfen, 111 Personen eine Hausstauballergie und 114 Personen waren von Asthma betroffen. In dem untersuchten Diabetes mellitus Typ 1 Patientenkollektiv litten 22 Patienten an mindestens einer der drei allergischen Erkrankungen. In SHIP wurde nach Kontrolle für ausgewählte Konfounder ein inverser Zusammenhang zwischen dem Schweregrad der Parodontitis und dem Vorhandensein von Heuschnupfen sowie Hausstauballergie gefunden. Mit steigendem AV nahm die Wahrscheinlichkeit für Heuschnupfen (ptrend<0,05) und Hausstauballergie (ptrend<0,05) ab. Hinsichtlich Asthma zeigte sich kein signifikanter Trend (ptrend=0,11), jedoch konnte auch hier mit steigendem AV eine gleichzeitige Abnahme der Wahrscheinlichkeit für das Auftreten von Asthma beobachtet werden. Die Analysen im Diabetes mellitus Typ 1 Patientenkollektiv bestätigten diese Ergebnisse. Auch hier nahm die Wahrscheinlichkeit für das Auftreten einer Allergie mit zunehmenden AV ab. FAZIT: Sowohl in der Allgemeinbevölkerung Vorpommerns als auch in Diabetes mellitus Typ 1 Patienten wurde eine inverse Assoziation zwischen dem Parodontalstatus und allergischen Erkrankungen dargelegt. Diese Ergebnisse befürworten die Hygiene-Hypothese. (2) Anzahl an Schwangerschaften und AIT HINTERGRUND: Frauen sind häufiger von AIT betroffen als Männer. Darüber hinaus ist bekannt, dass das Risiko für einen AIT während der Schwangerschaft und in der Post-Partum-Periode steigt. Das Ziel der Analysen war es, die Assoziation zwischen der Anzahl an Schwangerschaften und AIT zu untersuchen. METHODEN: Daten von 2837 Frauen im Alter zwischen 20 und 79 Jahren aus der bevölkerungsrepräsentativen „Study of Health in Pomerania“ (SHIP) wurden analysiert. Serum Anti-Thyreoperoxidase-Antikörper (anti-TPO) und Thyrotropin Titer wurden bestimmt. Weiterhin wurde eine Schilddrüsensonographie durchgeführt. Eine AIT lag beim gleichzeitigen Vorliegen eines echoarmen Schilddrüsenmusters und eines positiven anti-TPO Titers (>200 IU/ml) vor. ERGEBNISSE: Multivariable Zusammenhangsanalysen zeigten, dass die Chance für eine AIT (OR 4,7 [95%-KI 1,4-15,6], p<0,05) bei Frauen mit mindestens einer Schwangerschaft im Vergleich zu Frauen, die niemals schwanger waren, erhöht war. Ähnliche Ergebnisse zeigten sich auch für ein echoarmes Schilddrüsenmuster (OR 1,7 [95%-KI 1,0-2,8], p<0,05) und positive anti-TPO Werte (OR 1,9 [95%-KI 1,0-3,3], p<0,05). FAZIT: In der untersuchten Studienpopulation stieg das Risiko für eine AIT mit dem Durchleben der ersten Schwangerschaft an.