====== Skin Autofluorescence ======

Skin [[https://en.wikipedia.org/wiki/Autofluorescence|autofluorescence]] (SAF) ([[sections|section]]: [[physical state]]) was measured in adult [[start|Lifelines]] participants during [[1A Visit 1]] (n = ~84.000, n = ~76,000 after rigorous quality control). 

===== Background =====
SAF was measured in Lifelines participants using the [[https://www.diagnoptics.com/nl/age-reader|AGE Reader]], a noninvasive instrument to determine the accumulation of [[https://en.wikipedia.org/wiki/Advanced_glycation_end-product|Advanced Glycation Endproducts]] (AGEs) in the skin of the forearm.\\
Increased AGE levels are associated with ageing and development of several chronic diseases such as diabetes, renal insufficiency, and cardiovascular disease.AGEs are glycated proteins or lipids as a result of exposure to sugars (the [[https://en.wikipedia.org/wiki/Maillard_reaction|Maillard reaction]]). The presence of AGEs increases the level of SAF, and indeed SAF levels are increased in patients with diabetes, renal failure and in patients with vascular complications. Moreover, SAF is strongly related to the progression of coronary heart disease and mortality, independently of traditional risk factors.\\
In general, SAF-derived AGE values appear to be good predictors of long-term vascular complications in diabetes and in other conditions associated with AGE accumulation((Mulder DJ et al. (2006). Skin autofluorescence, a novel marker for glycemic and oxidative stress-derived advanced glycation endproducts: an overview of current clinical studies, evidence, and limitations. Diabetes Technology & Therapeutics 8(5):523-535))((Bos DC et al. (2011) Diabetes Technology & Therapeutics 13(7):773-779)).\\

===== Validation =====
The AGE Reader was validated against skin biopsies. Skin autofluorescence (SAF) was measured in 46 diabetic patients and 46 control subjects, skin biopsies were obtained from 43 participants (n=13 type 1 diabetes, n=18 type 2 diabetes, n=12 controls). Skin fluorescence was measured at the arm and lower leg. Skin biopsies were obtained at the same site of the arm, and analysed for collagen-linked fluorescence (CLF) and specific AGE: pentosidine, NΣ-(carboxymethyl)-lysine (CML) and NΣ-(carboxyethyl)lysine (CEL)((Meerwaldt R. et al. (2004) Simple non-invasive assessment of advanced glycation endproduct accumulation. Diabetologia 47:1324-1330)).\\
Reliability was tested in 5 nursing students, aged 20 to 21. AF was measured using the triple measurments setting with three measurments of approximately 20 sec on three different lower arm sites. Cronbach’s alpha=0.974. Conclusion: reliability is very high((Deltsidou, A. et al. (2017). Reliability analysis of Finometer and AGE-Reader devices in a clinical research trial, International Journal of Reliability and Safety 11(1/2): 78–96)\\
The correlation between SAF and AGEs is influenced by skin color, and this must be taken into account in the calculation of the results((Koetsier M. et al. (2019) Skin color independent assessment of ageing using skin autofluorescence. Optics Express 18, 14416-14429)).

===== Protocol & Quality Control =====
In adult Lifelines participants, three measurements were made on the volar side of the forearm, 10 cm below the elbow, at room temperature. The average of these three values (or the median in case of 1 deviant value) is released for analyses.\\
Measurements were made with an AGE-reader by illuminating a skin surface of approximately 4 cm², guarded against surrounding light, using an excitation light source with a wavelength between 300 and 420 nm (peak intensity at ~ 370 nm) for 10 seconds. Emission light and reflected excitation light from the skin are measured with an internal spectrometer in the range 300–600 nm.\\
SAF is calculated by dividing the average emitted light intensity per nanometre in the range of 420–600 nm by the average excited light intensity per nanometre in the range 300–420 nm and multiplied by 100. SAF levels are expressed in arbitrary units and will increase or decrease per arbitrary unit (AU)((Van Waateringe RP et al. (2016) Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study. Eur J Clin Invest. 46(5): 481-490)).\\

Ca 9% of the measurements at [[1A visit 2|baseline]] were excluded for use in analyses after quality control. Reasons for exclusion were:
  * Use of sunscreen by participants on the day of measurement;
  * Calibration errors (i.e. dates on which all measurements of a single AGE-reader were deviant);
  * Substantial deviations in repeated measures within 1 participant.
Details about the quality control of AGE-reader results can be obtained from Lifelines (research@lifelines.nl, on request).

===== Publications using Lifelines data =====

  - van Waateringe et al. (2016) Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study. European Journal of Clinical Invertigation 46(5): 481-490
  - van Waateringe et al. (2017) Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is associated with the metabolic syndrome and its individual components. Diabetology & Metabolic Symdrome 9(1): 42
  - van Waateringe et al. (2017) The association between various smoking behaviors, cotinine biomarkers and skin autofluorescence, a marker for advanced glycation end product accumulation. Plos ONE 12(6): e0179330
  - Fokkens et al. (2018) Skin autofluorescence improves the Finnish Diabetes Risk Score in the detection of diabetes in a large population-based cohort: The LifeLines Cohort Study. Diabetes & Metabolism 44(5): 424-430
  - van Waaterine et al. (2018) Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to the number of pregnancies. Journal of Diabetes 10(11): 899-901
  - van Waateringe et al. (2019) Skin autofluorescence predicts incident type 2 diabetes, cardiovascular disease and mortality in the general population. Diabetologia 62(2): 269-280 

===== Variables =====

| **Questions English**  | **Questions Dutch**       | **Variable**  | **Assessment**   | **Age**  |
| Skin cream used        | Creme gebruikt            | ARCREME       | [[1A Visit 1|]]  | 18+      |
| Suncream used          | Zonnebrandcreme gebruikt  | ARZON         | [[1A Visit 1|]]  | 18+      |
| Skin Autofluorescence  | AgeReader SAF             | SAF           | [[1A Visit 1|]]  | 18+      |
| Reflection             | AgeReader Reflectie       | UVREFLECT     | [[1A Visit 1|]]  | 18+      |