University of Groningen Albuminuria: more than a renal risk marker? van den Belt, Sophie Mariëlle

Albuminuria: more than a renal risk marker?

van den Belt, Sophie Mariëlle

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Publication date: 2018

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van den Belt, S. M. (2018). Albuminuria: more than a renal risk marker? About the prevalence, measurement, and treatment of albuminuria in children. Rijksuniversiteit Groningen.

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518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Prevalence and distribution of (micro)

albuminuria in toddlers

Authors sĂůĞŶƟŶĂ'ƌĂĐĐŚŝ1*_{͕^ŽƉŚŝĞD͘ǀĂŶĚĞŶĞůƚ}2_{Ύ͕>ĞĂŶŶĞ<͘<ƺƉĞƌƐ}3_͕ǀĂ ŽƌƉĞůĞŝũŶ3_{͕ŝĐŬĚĞĞĞƵǁ}2_{͕,ŝĚĚŽ:͘>ĂŵďĞƌƐ,ĞĞƌƐƉŝŶŬ}2 ĸůŝĂƟŽŶƐ 1_{ĞƉĂƌƚŵĞŶƚŽĨWĞĚŝĂƚƌŝĐEĞƉŚƌŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ} 'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 2_{ĞƉĂƌƚŵĞŶƚŽĨůŝŶŝĐĂůWŚĂƌŵĂĐLJĂŶĚWŚĂƌŵĂĐŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂů} ĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕dŚĞEĞƚŚĞƌůĂŶĚƐ 3_{ĞƉĂƌƚŵĞŶƚŽĨƉŝĚĞŵŝŽůŽŐLJ͕hŶŝǀĞƌƐŝƚLJDĞĚŝĐĂůĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ͕} dŚĞEĞƚŚĞƌůĂŶĚƐ ΎŽƚŚĂƵƚŚŽƌƐĐŽŶƚƌŝďƵƚĞĚĞƋƵĂůůLJƚŽƚŚĞŵĂŶƵƐĐƌŝƉƚ EĞƉŚƌŽůŽŐLJŝĂůLJƐŝƐdƌĂŶƐƉůĂŶƚĂƟŽŶ͕ϮϬϭϲ͖ϯϭ;ϭϬͿ͗ϭϲϴϲͲϭϲϵϮ

2

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Abstract

Background DŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĐŽŵŵŽŶŝŶƚŚĞŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶǁŝƚŚĂƉƌĞǀĂůĞŶĐĞŽĨΕϳй ĂŶĚŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚŝŶĚŝĐĂƚŽƌŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬƐ͘tŚĞƚŚĞƌĂůďƵŵŝŶƵƌŝĂ ŝƐĂĐƋƵŝƌĞĚĚƵƌŝŶŐůŝĨĞ;ĂƐĂƌĞƐƵůƚŽĨŚLJƉĞƌƚĞŶƐŝŽŶͬĚŝĂďĞƚĞƐͿŽƌŝƐĐŽŶŐĞŶŝƚĂůĂŶĚĂůƌĞĂĚLJ ƉƌĞƐĞŶƚĂƚďŝƌƚŚŝƐƵŶŬŶŽǁŶ͘tĞƐƚƵĚŝĞĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ ĂŶĚĐŽŵƉĂƌĞĚƚŚĞĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂǁŝƚŚƚŚĂƚŽĨƚŚĞŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶ͘ /ŶĂĚĚŝƟŽŶ͕ǁĞůŽŽŬĞĚĨŽƌƉŽƐƐŝďůĞĂƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂŶĚĂŶƚĞŶĂƚĂů͕ ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐ͘ Methods dŚĞƵƌŝŶĂƌLJĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶ;h_ͿǁĂƐŵĞĂƐƵƌĞĚŝŶϭϯϱϮĐŚŝůĚƌĞŶĂŶĚƚŚĞƵƌŝŶĂƌLJ ĂůďƵŵŝŶ͗ĐƌĞĂƟŶŝŶĞƌĂƟŽ;h_ZͿŝŶϭϮϴϴĐŚŝůĚƌĞŶĨƌŽŵƚŚĞ'ƌŽŶŝŶŐĞŶdžƉĞƌƚĞŶƚĞƌĨŽƌ<ŝĚƐ ǁŝƚŚKďĞƐŝƚLJ;'<KͿƌĞŶƚŚĞĐŽŚŽƌƚ;ĂŐĞƌĂŶŐĞϮϬͲϰϬŵŽŶƚŚƐͿ͘ůďƵŵŝŶƵƌŝĂĚŝƐƚƌŝďƵƟŽŶ ǁĂƐĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞĂůďƵŵŝŶƵƌŝĂĚŝƐƚƌŝďƵƟŽŶŝŶϰϬϴϱϰƉĂƌƟĐŝƉĂŶƚƐŽĨƚŚĞŐĞŶĞƌĂů ĂĚƵůƚĐŽŚŽƌƚŽĨƚŚĞWƌĞǀĞŶƟŽŶŽĨZĞŶĂůĂŶĚsĂƐĐƵůĂƌŶĚ^ƚĂŐĞŝƐĞĂƐĞ;WZsEͿƐƚƵĚLJ͘ ƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶĂůďƵŵŝŶƵƌŝĂ;ĞdžƉƌĞƐƐĞĚĂƐh_ĂŶĚh_ZͿĂŶĚĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂů ĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐǁĞƌĞƚĞƐƚĞĚǁŝƚŚůŝŶĞĂƌƌĞŐƌĞƐƐŝŽŶĂŶĂůLJƐŝƐ͘ Results dŚĞŵĞĚŝĂŶh_ŝŶƚŚĞ'<KƐƚƵĚLJǁĂƐϮ͘ϯŵŐͬ>;ϱth_-95th_{ƉĞƌĐĞŶƟůĞƐ͗Ϯ͘ϭͲϮϱ͘ϱͿĂŶĚŝŶ} ƚŚĞWZsEƐƚƵĚLJϲ͘ϬŵŐͬ>;Ϯ͘ϯͲϮϴ͘ϲͿ;WĚŝƐƚƌŝďƵƟŽŶĐŽŵƉĂƌŝƐŽŶϬ͘ϬϱϯͿ͘WƌĞǀĂůĞŶĐĞŽĨ h_шϮϬŵŐͬ>ǁĂƐϲ͘ϵйŝŶ'<KĂŶĚϳ͘ϴйŝŶWZsE;WсϬ͘ϭϵϱͿ͘dŚĞƉƌĞǀĂůĞŶĐĞŽĨh_Z шϯϬŵŐͬŐŝŶƚŚĞ'<KƐƚƵĚLJǁĂƐϮϯ͘ϰй͘h_ĂŶĚh_ZǁĞƌĞůŽǁĞƌŝŶďŽLJƐ͘h_ǁĂƐŶŽƚ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚŽƚŚĞƌĚĞƚĞƌŵŝŶĂŶƚƐ͕ďƵƚh_ZǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŐĞĂŶĚŐĞƐƚĂƟŽŶĂů ĚŝĂďĞƚĞƐ͘ Conclusions dŚĞĚŝƐƚƌŝďƵƟŽŶŽĨh_ĂŶĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨh_хϮϬŵŐͬ>ŝŶƚŽĚĚůĞƌƐĂŶĚŝŶƚŚĞLJŽƵŶŐ ŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶĂƌĞĐŽŵƉĂƌĂďůĞ͘dŚĞƐĞĮŶĚŝŶŐƐƐƵŐŐĞƐƚƚŚĂƚŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐĂĐŽŶŐĞŶŝƚĂůĐŽŶĚŝƟŽŶƚŚĂƚŵĂLJƉƌĞĚŝƐƉŽƐĞƚŽĂŚŝŐŚĞƌĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬůĂƚĞƌŝŶůŝĨĞ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

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Introduction

DŝůĚ ƚŽ ŵŽĚĞƌĂƚĞ ŝŶĐƌĞĂƐĞ ŽĨ ƵƌŝŶĂƌLJ ĂůďƵŵŝŶ ŚĂƐ Ă ŚŝŐŚ ƉƌĞǀĂůĞŶĐĞ ŝŶ ƉĂƟĞŶƚƐ ǁŝƚŚ ĚŝĂďĞƚĞƐ ŵĞůůŝƚƵƐ͕ ŚLJƉĞƌƚĞŶƐŝŽŶ ĂŶĚ ĐŚƌŽŶŝĐ ŬŝĚŶĞLJ ĚŝƐĞĂƐĞ͘1,2 _{This so-called} ͚ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͛ĂƉƉĞĂƌƐƚŽďĞĂƌŝƐŬŵĂƌŬĞƌĨŽƌƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐ ůĂƚĞƌŝŶůŝĨĞ͘3,4 /ƚŚĂƐďĞĞŶĚŝƐĐƵƐƐĞĚǁŚĞƚŚĞƌƚŚĞƐĞŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂůĞǀĞůƐĂƌĞĂĐŽŶƐĞƋƵĞŶĐĞ ŽĨƌĞŶĂůĚŝƐĞĂƐĞŽƌŝĨĂůďƵŵŝŶƵƌŝĂŝƚƐĞůĨŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚƌŝƐŬĨĂĐƚŽƌĨŽƌƌĞŶĂůĂŶĚͬŽƌ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘/ŶƚĞƌĞƐƟŶŐŝŶƚŚŝƐĐŽŶƚĞdžƚŝƐƚŚĞĮŶĚŝŶŐƚŚĂƚĂƉƉĂƌĞŶƚůLJ͚ŚĞĂůƚŚLJ͛ ŝŶĚŝǀŝĚƵĂůƐǁŝƚŚŽƵƚƌĞŶĂůĚŝƐĞĂƐĞ͕ĚŝĂďĞƚĞƐ͕ŽƌŚLJƉĞƌƚĞŶƐŝŽŶĂůƐŽƐŚŽǁĂŚŝŐŚƉƌĞǀĂůĞŶĐĞ ŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͕ǀĂƌLJŝŶŐĨƌŽŵϱ͘ϱƚŽϲ͘ϲй͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĂůƐŽĂƉƌĞĚŝĐƚŽƌĨŽƌ ĨƵƚƵƌĞĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘5-8_{dŚĞƐĞĮŶĚŝŶŐƐĂƉƉĞĂƌƚŽƐƵƉƉŽƌƚƚŚĞƐƵŐŐĞƐƟŽŶƚŚĂƚ} ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝƐĂŶŝŶĚĞƉĞŶĚĞŶƚƌŝƐŬĨĂĐƚŽƌͲĂŶĚĐŽƵůĚŵĂLJďĞĞǀĞŶďĞĂĐĂƵƐĞͲĨŽƌ ƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐ͘ dŚĞƉƵƚĂƟǀĞŵĞĐŚĂŶŝƐŵŽĨƐƵĐŚĂĐĂƵƐĂůƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶĞdžĐĞƐƐŝǀĞĂůďƵŵŝŶ ůĞĂŬĂŶĚƌĞŶĂůͬĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞĐŽƵůĚďĞĂŶĞŶĚŽƚŚĞůŝĂůĚLJƐĨƵŶĐƟŽŶ͕ƐƵĐŚĂƐ ŐůLJĐŽĐĂůLJdžůŽƐƐ͘9_{dŚŝƐĚLJƐĨƵŶĐƟŽŶ͚ĂůůŽǁƐ͛ĂůďƵŵŝŶƚŽĞƐĐĂƉĞƚŚĞǀĂƐĐƵůĂƌƐƉĂĐĞĂŶĚ} ŝŶĚƵĐĞƐƐƵďĞŶĚŽƚŚĞůŝĂůǀĂƐĐƵůĂƌůŽǁͲŐƌĂĚĞŝŶŇĂŵŵĂƟŽŶ͕ǁŝƚŚƚŚĞƵůƟŵĂƚĞĐŽŶƐĞƋƵĞŶĐĞ ŽĨǁŝĚĞƐƉƌĞĂĚŽƌŐĂŶĚĂŵĂŐĞ͘10_{dŚĞĐĂƵƐĞŽĨƚŚŝƐĞŶĚŽƚŚĞůŝĂůĚLJƐĨƵŶĐƟŽŶͲĂŶĚƚŚƵƐŽĨ} ƚŚĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂͲŝƐƵŶŬŶŽǁŶďƵƚŝƚŵŝŐŚƚďĞĐŽŶŐĞŶŝƚĂů͕ŵĞĂŶŝŶŐƚŚĂƚĚŝīĞƌĞŶƚ ŝŶĚŝǀŝĚƵĂůƐĂƌĞďŽƌŶǁŝƚŚĂůĂƌŐĞǀĂƌŝĂďŝůŝƚLJŝŶǀĂƐĐƵůĂƌĨƵŶĐƟŽŶĂŶĚƚŚĞƌĞĨŽƌĞǀĂƌLJŝŶŐ ĐŽŶƐƟƚƵƟŽŶĂůƵƌŝŶĞĂůďƵŵŝŶĞdžĐƌĞƟŽŶƐ͘/ŶĚĞĞĚ͕ŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶĞdžĐƌĞƟŽŶŝƐŽďƐĞƌǀĞĚ ŝŶŶĞǁďŽƌŶƐĂŶĚƚŽĚĚůĞƌƐŝŶƐŵĂůůƐƚƵĚŝĞƐŵĞĂƐƵƌŝŶŐůĂďŽƌĂƚŽƌLJƌĞĨĞƌĞŶĐĞǀĂůƵĞƐ͘11 _This ŽďƐĞƌǀĂƟŽŶŝƐƐƵƉƉŽƌƚĞĚďLJĞdžƉĞƌŝŵĞŶƚĂůƐƚƵĚŝĞƐĚĞŵŽŶƐƚƌĂƟŶŐĂůĂƌŐĞǀĂƌŝĂďŝůŝƚLJŝŶ ĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶŝŶƌĂƚƐĂƚďŝƌƚŚ͘dŚĞƐĞĚĂƚĂĂůƐŽƐŚŽǁƚŚĂƚƚŚĞƌĂƚƐǁŝƚŚƚŚĞƉŽŽƌĞƐƚ ĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶǁĞƌĞƚŚĞŵŽƐƚƐƵƐĐĞƉƟďůĞƚŽƌĞŶĂůĚĂŵĂŐĞ͘12_{dŚŝƐĐŽƵůĚŝŵƉůLJ} ƚŚĂƚƐŽŵĞŝŶĚŝǀŝĚƵĂůƐŚĂǀĞĂůƌĞĂĚLJĂƚďŝƌƚŚŚŝŐŚůĞǀĞůƐŽĨĂůďƵŵŝŶƵƌŝĂ͕ĂƐĂƌĞƐƵůƚŽĨ ŝŶďŽƌŶŝŵƉĂŝƌĞĚĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶ͕ǁŚŝĐŚŽŶƚŚĞůŽŶŐƚĞƌŵůĞĂĚƐƚŽĂŚŝŐŚĞƌƌĞŶĂů ĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌƌŝƐŬ͘13 dŚĞĂŝŵŽĨƚŚĞĐƵƌƌĞŶƚƐƚƵĚLJǁĂƐƚŽĚĞƐĐƌŝďĞƚŚĞĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂĂŶĚƚŚĞ ƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶǀĞƌLJLJŽƵŶŐĐŚŝůĚƌĞŶ͘&ƵƌƚŚĞƌŵŽƌĞ͕ǁĞŝŶƚĞŶĚĞĚƚŽ ŝĚĞŶƟĨLJĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐƚŚĂƚĐŽƵůĚĞdžƉůĂŝŶĚŝīĞƌĞŶĐĞƐďĞƚǁĞĞŶ ĐŚŝůĚƌĞŶ͘&ŽƌƚŚŝƐƉƵƌƉŽƐĞ͕ǁĞŝŶǀĞƐƟŐĂƚĞĚĂůĂƌŐĞĐŽŚŽƌƚŽĨƚŽĚĚůĞƌƐŽĨƚŚĞŐĞŶĞƌĂůƵƚĐŚ ƉŽƉƵůĂƟŽŶ;'ƌŽŶŝŶŐĞŶdžƉĞƌƚĞŶƚĞƌĨŽƌ<ŝĚƐǁŝƚŚKďĞƐŝƚLJ͖'<KͿ͘dŚĞƐĞĚĂƚĂǁĞƌĞ ĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞĚĂƚĂĨƌŽŵƚŚĞŐĞŶĞƌĂůĂĚƵůƚƵƚĐŚƉŽƉƵůĂƟŽŶŽĨƚŚĞWƌĞǀĞŶƟŽŶŽĨ ZĞŶĂůĂŶĚsĂƐĐƵůĂƌŶĚƐƚĂŐĞŝƐĞĂƐĞ;WZsEͿĐŽŚŽƌƚ͘

Methods

dŚŝƐƐƚƵĚLJǁĂƐĞŵďĞĚĚĞĚŝŶƚŚĞ'<KͲƌĞŶƚŚĞƐƚƵĚLJ͕ĂƉŽƉƵůĂƟŽŶͲďĂƐĞĚƉƌŽƐƉĞĐƟǀĞ ďŝƌƚŚĐŽŚŽƌƚƐƚƵĚLJŽĨĐŚŝůĚƌĞŶďŽƌŶďĞƚǁĞĞŶƉƌŝůϮϬϬϲĂŶĚƉƌŝůϮϬϬϳŝŶƌĞŶƚŚĞ͕Ă

2

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 26PDF page: 26PDF page: 26PDF page: 26 26 ŶŽƌƚŚĞƌŶƵƚĐŚƉƌŽǀŝŶĐĞ͘dŚĞƉƌŝŵĂƌLJŐŽĂůŽĨƚŚŝƐĐŽŚŽƌƚǁĂƐƚŽŝŶǀĞƐƟŐĂƚĞŽǀĞƌǁĞŝŐŚƚ ƌŝƐŬĨĂĐƚŽƌƐĨƌŽŵďŝƌƚŚƚŚƌŽƵŐŚŽƵƚĐŚŝůĚŚŽŽĚ͘ĞƚĂŝůƐĂďŽƵƚƚŚŝƐĐŽŚŽƌƚŚĂǀĞďĞĞŶ ƉƌĞǀŝŽƵƐůLJĚĞƐĐƌŝďĞĚĂŶĚĂƌĞƌĞŐŝƐƚĞƌĞĚĂƚǁǁǁ͘ďŝƌƚŚĐŽŚŽƌƚƐ͘ŶĞƚ͘14_{dŚĞƐƚƵĚLJǁĂƐ} ĂƉƉƌŽǀĞĚďLJƚŚĞůŽĐĂůDĞĚŝĐĂůZĞƐĞĂƌĐŚĂŶĚƚŚŝĐƐŽŵŵŝƩĞĞ͘ůůŵŽƚŚĞƌƐŚĂĚƐŝŐŶĞĚ ĂŶŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚĨŽƌŵ͘ /ŶƚŚĞƌĞĐƌƵŝƚŵĞŶƚƉĞƌŝŽĚďĞƚǁĞĞŶƉƌŝůϮϬϬϲĂŶĚƉƌŝůϮϬϬϳ͕ϰϳϳϴĞůŝŐŝďůĞĐŚŝůĚƌĞŶ ǁĞƌĞďŽƌŶ͘KĨƚŚĞŵ͕ϮϴϳϰƉĂƌĞŶƚͲĐŚŝůĚƉĂŝƌƐŚĂǀĞĞǀĞƌƉĂƌƟĐŝƉĂƚĞĚĂĐƟǀĞůLJŝŶƚŚĞĐŽŚŽƌƚ͘ ƚďŝƌƚŚ͕ƚŚĞŽďƐƚĞƚƌŝĐŝĂŶƐ͕ŵŝĚǁŝǀĞƐŽƌŐĞŶĞƌĂůƉƌĂĐƟƟŽŶĞƌƐƚŽŽŬĂŶƵŵďŝůŝĐĂůĐŽƌĚďůŽŽĚ ƐĂŵƉůĞƚŚĂƚǁĂƐƉƌŽĐĞƐƐĞĚĂŶĚƐƚŽƌĞĚĨŽƌĨƵƚƵƌĞĂŶĂůLJƐŝƐ͘/ŶĂĚĚŝƟŽŶ͕ƉůĂĐĞŶƚĂǁĞŝŐŚƚ ǁĂƐŵĞĂƐƵƌĞĚĂŶĚĚĂƚĂŽŶƉƌĞŐŶĂŶĐLJĂŶĚĚĞůŝǀĞƌLJ;ŝ͘Ğ͘ŐĞƐƚĂƟŽŶĂůĚŝĂďĞƚĞƐ͕ŐĞƐƚĂƟŽŶĂů ŚLJƉĞƌƚĞŶƐŝŽŶ͕ƐŵŽŬŝŶŐŽĨƚŚĞŵŽƚŚĞƌ͕ŵĂƚĞƌŶĂůĂŐĞĂƚĚĞůŝǀĞƌLJͿǁĞƌĞƌĞĐŽƌĚĞĚ͘dŚĞƐƚƵĚLJ ĚĞƐŝŐŶŝŶĐůƵĚĞĚĂŶƚŚƌŽƉŽŵĞƚƌŝĐŵĞĂƐƵƌĞŵĞŶƚƐ;ŝŶĐůƵĚŝŶŐǁĞŝŐŚƚ͕ŚĞŝŐŚƚ͕ŚĞĂĚ͕ǁĂŝƐƚĂŶĚ ŚŝƉĐŝƌĐƵŵĨĞƌĞŶĐĞͿƉĞƌĨŽƌŵĞĚďLJƐƉĞĐŝĮĐĂůůLJƚƌĂŝŶĞĚŶƵƌƐĞƐĂƚŵƵŶŝĐŝƉĂůŚĞĂůƚŚƐĞƌǀŝĐĞƐ ĂƚƚŚĞĂŐĞŽĨϬ͘ϱ͕ϭ͕Ϯ͕ϯ͕ϰ͕ϱ͕ϲ͕ϳ͕ϵ͕ϭϭ͕ϭϰ͕ϭϴ͕Ϯϰ͕ϯϲ͕ϰϱĂŶĚϲϬŵŽŶƚŚƐ͘YƵĞƐƟŽŶŶĂŝƌĞƐ ĂďŽƵƚůŝĨĞƐƚLJůĞĂŶĚĞŶǀŝƌŽŶŵĞŶƚ;ŝŶĐůƵĚŝŶŐŵĂƚĞƌŶĂůĞĚƵĐĂƟŽŶůĞǀĞůͿǁĞƌĞĮůůĞĚŝŶďLJ ƉĂƌĞŶƚƐŝŶƚŚĞůĂƐƚƚƌŝŵĞƐƚĞƌŽĨƉƌĞŐŶĂŶĐLJĂŶĚĂƚĞĂĐŚŚĞĂůƚŚĐŽŶƚƌŽůǀŝƐŝƚ͘ dŚĞϮϰͲŵŽŶƚŚǀŝƐŝƚǁĂƐĐŽŵƉůĞŵĞŶƚĞĚďLJĂŵĞĂƐƵƌĞŵĞŶƚŽĨĂƌƚĞƌŝĂůďůŽŽĚƉƌĞƐƐƵƌĞ ĂŶĚĂƵƌŝŶĞĐŽůůĞĐƟŽŶ͘&ŽƌƚŚĞƉƌĞƐĞŶƚĂŶĂůLJƐĞƐ͕ĞdžĐůƵƐŝŽŶǁĂƐďĂƐĞĚŽŶĂǀĂŝůĂďŝůŝƚLJŽĨ ƵƌŝŶĞƐĂŵƉůĞǁŝƚŚĂůďƵŵŝŶŵĞĂƐƵƌĞŵĞŶƚ͘ƵƌŝŶĂƌLJĂůďƵŵŝŶŵĞĂƐƵƌĞŵĞŶƚǁĂƐŽďƚĂŝŶĞĚ ŝŶϭϯϱϮĐŚŝůĚƌĞŶ͘

Blood pressure measurement

ůŽŽĚƉƌĞƐƐƵƌĞŵĞĂƐƵƌĞŵĞŶƚǁĂƐƉĞƌĨŽƌŵĞĚĂƚƚŚĞůĞŌĂƌŵŝŶƐŝƫŶŐƉŽƐŝƟŽŶ͕ǁŝƚŚĂŶ ĂƵƚŽŵĂƟĐĚĞǀŝĐĞ;ŝŶĂŵĂƉ͕:ŽŚŶƐŽŶͲ:ŽŚŶƐŽŶŵĞĚŝĐĂůͿ͘ůŽŽĚƉƌĞƐƐƵƌĞŵĞĂƐƵƌĞŵĞŶƚ ǁĂƐƌĞƉĞĂƚĞĚŝĨƚŚĞĐŚŝůĚǁŽƵůĚƌĞŵĂŝŶĐŽŵĨŽƌƚĂďůĞĚƵƌŝŶŐƉƌŽĐĞĚƵƌĞŽƌŝĨƚŚĞĮƌƐƚ ŵĞĂƐƵƌĞŵĞŶƚǁĂƐƵŶƐƵĐĐĞƐƐĨƵů͘ hƌŝŶĞĐŽůůĞĐƟŽŶĂŶĚŵĞĂƐƵƌĞŵĞŶƚƐ hƌŝŶĞĐŽůůĞĐƟŽŶŝŶƚŽĚĚůĞƌƐŝƐŬŶŽǁŶƚŽďĞĐƵŵďĞƌƐŽŵĞĂŶĚƵƌŝŶĞĐĂŶŶŽƚďĞĞdžƚƌĂĐƚĞĚ ĨƌŽŵĚŝƐƉŽƐĂďůĞĚŝĂƉĞƌƐ͘dŚĞĐƵƌƌĞŶƚůLJĂǀĂŝůĂďůĞƉůĂƐƟĐďĂŐƐĨŽƌƵƌŝŶĞĐŽůůĞĐƟŽŶƚĞŶĚ ƚŽĚĞƚĂĐŚĞĂƐŝůLJĨƌŽŵĐŚŝůĚƌĞŶ͛ƐƐŬŝŶ͘tĞƚŚĞƌĞĨŽƌĞĚĞƐŝŐŶĞĚĂŶĚǀĂůŝĚĂƚĞĚĂƐƉĞĐŝĮĐ ƉƌŽƚŽĐŽůĨŽƌƵƌŝŶĞĐŽůůĞĐƟŽŶĂƚƚŚĞůŝŶŝĐĂůWŚĂƌŵĂĐŽůŽŐLJĞƉĂƌƚŵĞŶƚŽĨƚŚĞhŶŝǀĞƌƐŝƚLJ DĞĚŝĐĂůĞŶƚĞƌ'ƌŽŶŝŶŐĞŶ;hD'ͿƵƐŝŶŐƉĂŶƚLJůŝŶĞƌƐ͘tĞĐŚŽƐĞĂƉĂŶƚLJůŝŶĞƌǁŝƚŚĂƐŝŵƉůĞ ĐŽƩŽŶǁŽŽůĮůůŝŶŐ͕ďĞĐĂƵƐĞƉŝůŽƚƐƐŚŽǁĞĚƚŚĂƚĞdžƚƌĂĐƟŶŐƚŚĞƵƌŝŶĞĨƌŽŵƚŚĞƐĞƉĂŶƚLJůŝŶĞƌƐ ǁĂƐĞĂƐLJĂŶĚĐŽŶǀĞŶŝĞŶƚĨŽƌƉĂƌĞŶƚƐĂŶĚĐŚŝůĚƌĞŶ͘WĂƌĞŶƚƐƌĞĐĞŝǀĞĚĚƵƌŝŶŐƚŚĞϮϰͲŵŽŶƚŚ ŚĞĂůƚŚĐŽŶƚƌŽůǀŝƐŝƚĂŬŝƚǁŝƚŚĂƉĂŶƚLJůŝŶĞƌ;<ƌƵŝĚǀĂƚ&ĞŵŵĞĂƌĞŵŝŶŝΠ͕<ƌƵŝĚǀĂƚ͕dŚĞ EĞƚŚĞƌůĂŶĚƐͿ͕ĂƉůĂƐƟĐǀŝĂůĂŶĚƐĂĨĞƚLJďĂŐ;ďŽƚŚĨƌŽŵDŝŶŝŐƌŝƉ͕dŚĞEĞƚŚĞƌůĂŶĚƐͿ͕Ă ĐŽůůĞĐƟŽŶĨŽƌŵĂŶĚĂƉŽƐƚĂůƉůĂƐƟĐĞŶǀĞůŽƉĞĨŽƌďŝŽůŽŐŝĐĂůŵĂƚĞƌŝĂůƐ͘WĂƌĞŶƚƐǁĞƌĞĂƐŬĞĚ ƚŽƉůĂĐĞƚŚĞƉĂŶƚLJůŝŶĞƌŝŶƚŚĞĐŚŝůĚ͛ƐĚŝĂƉĞƌĂŶĚƌĞŵŽǀĞŝƚŽŶĐĞƚŚĞĐŚŝůĚŚĂĚǀŽŝĚĞĚ͘ dŚĞLJǁĞƌĞĂůƐŽĂƐŬĞĚƚŽǁƌŝƚĞĚŽǁŶƟŵĞŽĨƉůĂĐĞŵĞŶƚĂŶĚƌĞŵŽǀĂůŽĨƚŚĞƉĂŶƚLJůŝŶĞƌ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 27PDF page: 27PDF page: 27PDF page: 27 27 WĂƌĞŶƚƐǁĞƌĞŝŶƐƚƌƵĐƚĞĚƚŽĚŝƐĐĂƌĚƉĂŶƚLJůŝŶĞƌƐŝŶĐĂƐĞŽĨĨĂĞĐĂůĐŽŶƚĂŵŝŶĂƟŽŶĂŶĚƚŽ ƌĞƉĞĂƚƚŚĞŽƉĞƌĂƟŽŶůĂƚĞƌŝŶƟŵĞ͘WĂŶƚLJůŝŶĞƌƐǁŝƚŚƉƌŽƉĞƌůLJĐŽůůĞĐƚĞĚƵƌŝŶĞǁĞƌĞƉůĂĐĞĚ ďLJƉĂƌĞŶƚƐŝŶƚŚĞƉůĂƐƟĐǀŝĂůĂŶĚƐĞŶƚĂƐƐŽŽŶĂƐƉŽƐƐŝďůĞǁŝƚŚƌĞŐƵůĂƌŵĂŝůƚŽƚŚĞŚŽƐƉŝƚĂů ƵƐŝŶŐĂĚĞĚŝĐĂƚĞĚĞŶǀĞůŽƉĞĨŽƌďŝŽůŽŐŝĐĂůŵĂƚĞƌŝĂůƐ͘WĂƌĞŶƚƐǁĞƌĞĂůƐŽĂƐŬĞĚƚŽŝŶĐůƵĚĞ ĂĐŽůůĞĐƟŽŶĨŽƌŵƐƚĂƟŶŐĐŽůůĞĐƟŽŶĚĂƚĞ͕ĐŚŝůĚ͛ƐƐƚƵĚLJŶƵŵďĞƌĂŶĚƉŽƐƐŝďůĞĐŽŶĐƵƌƌĞŶƚ ĚŝƐĞĂƐĞƐ͘ŝƌĞĐƚůLJƵƉŽŶĂƌƌŝǀĂůĂƚƚŚĞůĂďŽƌĂƚŽƌLJ͕ƚŚĞĐŽƩŽŶĮůůŝŶŐŽĨƚŚĞƉĂŶƚLJůŝŶĞƌƐǁĂƐ ĞdžƚƌĂĐƚĞĚĂŶĚĐĞŶƚƌŝĨƵŐĞĚĂƚϯϲϬϬƌƉŵĨŽƌϭϬŵŝŶ;DŝƐƚƌĂůϯϬϬϬ͕D^Ϳ͘h_ǁĂƐŵĞĂƐƵƌĞĚ ŝŶƚŚĞĐĞŶƚƌŝĨƵŐĞĚƵƌŝŶĞďLJŶĞƉŚĞůŽŵĞƚƌLJ;ĞŚƌŝŶŐEĞƉŚĞůŽŵĞƚĞƌŶĂůLJnjĞƌ//͕^ŝĞŵĞŶƐ DĞĚŝĐĂů^ŽůƵƟŽŶƐͿ͕ǁŝƚŚĂƚŚƌĞƐŚŽůĚŽĨϮ͘ϭŵŐͬ>͘sĂůƵĞƐŽĨh_ďĞůŽǁƚŚĞĚĞƚĞĐƟŽŶůŝŵŝƚ ǁĞƌĞĂƐƐŝŐŶĞĚƚŚĞǀĂůƵĞŽĨϮ͘ϭŵŐͬ>͘hƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶ;h_ͿǁĂƐŵĞĂƐƵƌĞĚ ďLJĞŶnjLJŵĂƟĐŵĞƚŚŽĚ;ZŽĐŚĞDŽĚƵůĂƌͿ͕ǁŝƚŚĂƚŚƌĞƐŚŽůĚŽĨϬ͘ϭŵŵŽůͬ>͘ WĞƌĨŽƌŵĂŶĐĞ ŽĨ ƚŚĞ ŵĞƚŚŽĚ ĂŐĂŝŶƐƚ ƐƚĂŶĚĂƌĚ ƵƌŝŶĞ ĐŽůůĞĐƚŝŽŶ ĨŽƌ ĂůďƵŵŝŶ ŵĞĂƐƵƌĞŵĞŶƚǁĂƐĂŶĂůLJƐĞĚĂƐƉƌŽƉŽƐĞĚďLJ^ƚĞǀĞŶƐƉƌĞƐĞŶƟŶŐďŝĂƐ͕ƉƌĞĐŝƐŝŽŶĂŶĚ ĂĐĐƵƌĂĐLJ͘ŝĂƐǁĂƐĚĞĮŶĞĚĂƐƚŚĞŵĞĚŝĂŶĚŝīĞƌĞŶĐĞďĞƚǁĞĞŶƐƚĂŶĚĂƌĚƵƌŝŶĞĐŽůůĞĐƟŽŶ ĂŶĚƉĂŶƚLJůŝŶĞƌŵĞƚŚŽĚ͕ƉƌĞĐŝƐŝŽŶĂƐƚŚĞŝŶƚĞƌƋƵĂƌƟůĞƌĂŶŐĞŽĨƚŚĞĚŝīĞƌĞŶĐĞďĞƚǁĞĞŶ ƐƚĂŶĚĂƌĚŵĞƚŚŽĚĂŶĚƉĂŶƚLJůŝŶĞƌŵĞƚŚŽĚĂŶĚĂĐĐƵƌĂĐLJĂƐƉĞƌĐĞŶƚĂŐĞŽĨĞƐƟŵĂƚĞƐŽĨ ƉĂŶƚLJůŝŶĞƌŵĞƚŚŽĚǁŝƚŚŝŶϯϬйŽĨƚŚĞǀĂůƵĞŽĨƚŚĞƐƚĂŶĚĂƌĚŵĞƚŚŽĚ͘15_{ŝĂƐŽĨƚŚĞŵĞƚŚŽĚ} ǁĂƐͲϭϰ͘ϬŵŐͬ>͕ƉƌĞĐŝƐŝŽŶϯϭ͘ϯŵŐͬ>ĂŶĚĂĐĐƵƌĂĐLJϰϴ͘ϭй͘ Adult cohort dŚĞWZsEƐƚƵĚLJƉƌŽƚŽĐŽůŚĂƐďĞĞŶĞdžƚĞŶƐŝǀĞůLJĚĞƐĐƌŝďĞĚĞůƐĞǁŚĞƌĞĂŶĚĐĂŶďĞĨŽƵŶĚ at ǁǁǁ͘ƉƌĞǀĞŶĚ͘ŽƌŐ͘5_{/ŶƐŚŽƌƚ͕ŝŶƚŚĞƉĞƌŝŽĚďĞƚǁĞĞŶϭϵϵϳĂŶĚϭϵϵϴ͕ĂůůŝŶŚĂďŝƚĂŶƚƐŽĨ} ƚŚĞĐŝƚLJŽĨ'ƌŽŶŝŶŐĞŶ;ŝŶƚŚĞŶŽƌƚŚĞƌŶƉĂƌƚŽĨdŚĞEĞƚŚĞƌůĂŶĚƐͿ͕ĂŐĞĚϮϴͲϳϱLJĞĂƌƐ;Ŷс ϴϱϰϮϭͿ͕ǁĞƌĞŝŶǀŝƚĞĚƚŽĂŶƐǁĞƌĂƐŚŽƌƚƋƵĞƐƟŽŶŶĂŝƌĞƌĞŐĂƌĚŝŶŐĚĞŵŽŐƌĂƉŚŝĐƐĂŶĚƌŝƐŬ ĨĂĐƚŽƌƐĨŽƌƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐĂŶĚƚŽĐŽůůĞĐƚĂĮƌƐƚŵŽƌŶŝŶŐǀŽŝĚƵƌŝŶĞ ƐĂŵƉůĞĨŽƌĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶŵĞĂƐƵƌĞŵĞŶƚ͘ƚŽƚĂůŽĨϰϬϴϱϰŝŶĚŝǀŝĚƵĂůƐ;ϰϴйͿŐĂǀĞ ǁƌŝƩĞŶŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚĂŶĚǁĞƌĞŝŶĐůƵĚĞĚŝŶƚŚĞWZsEĐŽŚŽƌƚ͘dŚĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ŽĨƚŚĞϰϬϴϱϰWZsEƐƚƵĚLJƉĂƌƟĐŝƉĂŶƚƐĂƌĞƐŚŽǁŶŝŶ^ƵƉƉůĞŵĞŶƚĂƌLJĚĂƚĂ͕dĂďůĞ^ϭ͘ ^ƚĂƟƐƟĐĂůĂŶĂůLJƐŝƐ ĞƐĐƌŝƉƟǀĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶǁĞƌĞƌĞƉŽƌƚĞĚĂƐŵĞĂŶцƐƚĂŶĚĂƌĚ ĚĞǀŝĂƟŽŶŽƌŵĞĚŝĂŶ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞͿ͕ĂƐƌĞƋƵŝƌĞĚ͘dŚĞĚŝƐƚƌŝďƵƟŽŶƐŽĨh} ďĞƚǁĞĞŶ ƚŚĞƚŽĚĚůĞƌĂŶĚĂĚƵůƚƉŽƉƵůĂƟŽŶǁĞƌĞĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞƌŽǁŶĂŶĚ&ŽƌƐLJƚŚĞŵŽĚŝĮĞĚ >ĞǀĞŶĞ͛ƐƌŽďƵƐƚƐƚĂƟƐƟĐƐƚĞƐƚ͘^ŝŶĐĞƵƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞǁĂƐŶŽƚŵĞĂƐƵƌĞĚŝŶƚŚĞWZsE ĐŽŚŽƌƚ͕ŽŶůLJĐŽŵƉĂƌŝƐŽŶŽĨh_ǁĂƐƉŽƐƐŝďůĞďĞƚǁĞĞŶƚŚĞƚǁŽĐŽŚŽƌƚƐ͘ŝīĞƌĞŶĐĞŝŶ ƉƌĞǀĂůĞŶĐĞŽĨŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂ;h_шϮϬŵŐͬ>ͿďĞƚǁĞĞŶ'<KĂŶĚWZsEǁĂƐ ƚĞƐƚĞĚǁŝƚŚĂʖ2_{ƚĞƐƚ͘WŽƐƐŝďůĞĂƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂů} ĨĂĐƚŽƌƐĂŶĚƚŚĞůŽŐĂƌŝƚŚŵŽĨh_ǁĞƌĞĂŶĂůLJƐĞĚǁŝƚŚƵŶŝǀĂƌŝĂƚĞůŝŶĞĂƌƌĞŐƌĞƐƐŝŽŶĂŶĂůLJƐŝƐ͘ h_ǁĂƐůŽŐͲƚƌĂŶƐĨŽƌŵĞĚƚŽĂĐĐŽƵŶƚĨŽƌŝƚƐƐŬĞǁĞĚĚŝƐƚƌŝďƵƟŽŶ͘WͲǀĂůƵĞŽĨфϬ͘ϬϱǁĂƐ

2

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 28PDF page: 28PDF page: 28PDF page: 28 28 ĐŽŶƐŝĚĞƌĞĚƚŽďĞƐƚĂƟƐƟĐĂůůLJƐŝŐŶŝĮĐĂŶƚ͘ĂƚĂǁĞƌĞĂŶĂůLJƐĞĚƵƐŝŶŐ^ddǀĞƌƐŝŽŶϭϯ͘ϭ ĂŶĚ^W^^^ƚĂƟƐƟĐƐǀĞƌƐŝŽŶϮϮ͘

Results

KĨƚŚĞϭϯϱϮĐŚŝůĚƌĞŶŝŶĐůƵĚĞĚŝŶƚŚŝƐƐƚƵĚLJ;&ŝŐƵƌĞϭͿ͕ŵĞĂƐƵƌĞŵĞŶƚƐŽĨh_ǁĞƌĞĂǀĂŝůĂďůĞ ŝŶ ϭϮϴϴ ĐŚŝůĚƌĞŶ͘ ĂƚĂ ĨŽƌ ďŽĚLJ ŵĂƐƐ ŝŶĚĞdž ;D/Ϳ ǁĞƌĞ ĂǀĂŝůĂďůĞ ŝŶ ϭϬϭϳ ĐŚŝůĚƌĞŶ͕ ďůŽŽĚƉƌĞƐƐƵƌĞŵĞĂƐƵƌĞŵĞŶƚŝŶϴϭϳĐŚŝůĚƌĞŶĂŶĚƉůĂĐĞŶƚĂǁĞŝŐŚƚŝŶϵϰϬĐŚŝůĚƌĞŶ͘dŚĞ ĐŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨƚŚĞƐƚƵĚLJƉŽƉƵůĂƟŽŶĂƌĞƐŚŽǁŶŝŶdĂďůĞϭ͘ dŚĞĚŝƐƚƌŝďƵƟŽŶŽĨh_ŝŶƚŚĞ'<KĐŽŚŽƌƚŝƐƐŚŽǁŶŝŶ&ŝŐƵƌĞϮ͘dŚĞŵĞĚŝĂŶh_ ǁĂƐϮ͘ϯŵŐͬ>;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞŝŶƚĞƌǀĂůϮ͘ϭͲϳ͘ϭŵŐͬ>Ϳ͘dŚĞϱ}th _{and 95}th_{ƉĞƌĐĞŶƟůĞƐǁĞƌĞ͕} ƌĞƐƉĞĐƟǀĞůLJ͕Ϯ͘ϭĂŶĚϮϱ͘ϱŵŐͬ>͘dŚĞŵĞĚŝĂŶh_ZǁĂƐϭϰ͘ϬŵŐͬŐ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞ} ŝŶƚĞƌǀĂůϴ͘ϬͲϮϱ͘ϲŵŐͬŐͿ͘dŚĞϱth _{and 95}th_{ƉĞƌĐĞŶƟůĞƐǁĞƌĞ͕ƌĞƐƉĞĐƟǀĞůLJ͕ϰ͘ϯĂŶĚϴϵ͘ϯŵŐͬŐ͘} dŚĞƉƌĞǀĂůĞŶĐĞŽĨĞůĞǀĂƚĞĚĂůďƵŵŝŶƵƌŝĂďĂƐĞĚŽŶh_;шϮϬŵŐͬ>ͿĂŶĚh_Z;шϯϬŵŐͬŐͿ ǁĂƐ͕ƌĞƐƉĞĐƟǀĞůLJ͕ϲ͘ϵйĂŶĚϮϯ͘ϰй͘ dŚĞĚŝƐƚƌŝďƵƟŽŶŽĨh_ŝŶƚŚĞWZsEƉŽƉƵůĂƟŽŶ;ŶсϰϬϴϱϰͿŝƐƐŚŽǁŶŝŶ&ŝŐƵƌĞϮ͘ dŚĞŵĞĚŝĂŶh_ǁĂƐϲ͘ϬŵŐͬ>;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞŝŶƚĞƌǀĂůϯ͘ϳͲϵ͘ϴŵŐͬ>΁͘dŚĞϱ}th _{and 95}th ƉĞƌĐĞŶƟůĞƐǁĞƌĞ͕ƌĞƐƉĞĐƟǀĞůLJ͕Ϯ͘ϯŵŐͬ>ĂŶĚϮϴ͘ϲŵŐͬ>͘dŚĞƉƌĞǀĂůĞŶĐĞŽĨĞůĞǀĂƚĞĚh_ ǁĂƐϳ͘ϴй͘dŚĞĚŝƐƚƌŝďƵƟŽŶŽĨh_ŝŶƚŚĞ'<KĂŶĚWZsEƉŽƉƵůĂƟŽŶĚŝĚŶŽƚĚŝīĞƌ ƐŝŐŶŝĮĐĂŶƚůLJ;&ŝŐƵƌĞϮ͖WсϬ͘ϬϱϯͿ͕ĂƐĚŝĚƚŚĞƉƌĞǀĂůĞŶĐĞŽĨĞůĞǀĂƚĞĚĂůďƵŵŝŶƵƌŝĂ;&ŝŐƵƌĞ ϯ͖WсϬ͘ϭϵϱͿ͘ Figure 1.)ORZFKDUWRILQFOXVLRQVWXG\SRSXODWLRQ

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 29PDF page: 29PDF page: 29PDF page: 29 29 dŚĞƉƌĞǀĂůĞŶĐĞŽĨĞůĞǀĂƚĞĚĂůďƵŵŝŶƵƌŝĂŝŶWZsEǁĂƐĚĞƉĞŶĚŝŶŐŽŶĂŐĞ;ƚŚĞ ŽůĚĞƌ͕ƚŚĞŵŽƌĞŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂͿ͘dŚĞƌĞĨŽƌĞǁĞƉůŽƩĞĚƚŚĞƉĞƌĐĞŶƚĂŐĞŽĨŝŶĐƌĞĂƐĞĚ ĂůďƵŵŝŶƵƌŝĂŽĨƚŚĞ'<KƐƚƵĚLJĐŽŵďŝŶĞĚǁŝƚŚƚŚĞWZsEƐƚƵĚLJĂĐĐŽƌĚŝŶŐƚŽĂŐĞ ;&ŝŐƵƌĞϰͿ͘ůƚŚŽƵŐŚƚŚĞƌĞŝƐĂůĂƌŐĞĂŐĞŐĂƉďĞƚǁĞĞŶƚŚĞƚǁŽĐŽŚŽƌƚƐ͕ŝƚƐĞĞŵƐƚŚĂƚ ƚŚĞ'<KĚĂƚĂĂƌĞƐŝŵŝůĂƌƚŽƚŚŽƐĞŽĨƚŚĞLJŽƵŶŐĂĚƵůƚƉŽƉƵůĂƟŽŶŽĨWZsE͘dŚĞ ƉƌĞǀĂůĞŶĐĞŽĨŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂŝŶƚŚĞWZsEƉŽƉƵůĂƟŽŶďĞůŽǁϱϬLJĞĂƌƐŽĨĂŐĞ ǁĂƐϱ͘ϴǀĞƌƐƵƐϲ͘ϵйŝŶ'<K;WсϬ͘ϬϵͿ͘ tĞƚĞƐƚĞĚƚŚĞŚLJƉŽƚŚĞƐŝƐŽĨƉŽƐƐŝďůĞĂƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶh_Žƌh_ZŝŶƚŚĞ'<K ĐŽŚŽƌƚĂŶĚĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůĂŶĚŵĂƚĞƌŶĂůĨĂĐƚŽƌƐ͘h_ĂŶĚh_ZǁĞƌĞŶĞŐĂƟǀĞůLJ ĂƐƐŽĐŝĂƚĞĚǁŝƚŚŵĂůĞŐĞŶĚĞƌ;ƉфϬ͘ϬϬϭͿ͘EŽĂƐƐŽĐŝĂƟŽŶǁĂƐĨŽƵŶĚďĞƚǁĞĞŶh_ and other ĂŶƚĞŶĂƚĂů͕ƉŽƐƚŶĂƚĂůŽƌŵĂƚĞƌŶĂůĨĂĐƚŽƌƐ͘h_ZǁĂƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŐĞĂŶĚŐĞƐƚĂƟŽŶĂů ĚŝĂďĞƚĞƐ;dĂďůĞϮͿ͘ Table 1. &KDUDFWHULVWLFVRIWKHVWXG\SRSXODWLRQ KǀĞƌĂůůƉŽƉƵůĂƟŽŶ (n = 1352) U(n = 1288)ACRƉŽƉƵůĂƟŽŶ dŽĚĚůĞƌĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ŐĞ͕ŵŽŶƚŚƐ;Ϯϱth_-75th_{ƉĞƌĐĞŶƟůĞͿ Ϯϱ͘ϴ;Ϯϰ͘ϴͲϮϳ͘ϭͿ Ϯϱ͘ϴ;Ϯϰ͘ϴͲϮϳ͘ϭͿ} DĂůĞ͕Ŷ;йͿ ϲϴϯ;ϱϬ͘ϱͿ ϲϱϱ;ϱϬ͘ϵͿ h_͕ŵŐͬ>;Ϯϱth_{- 75}th_{ƉĞƌĐĞŶƟůĞͿ Ϯ͘ϯ;Ϯ͘ϭͲϳ͘ϭͿ Ϯ͘ϰ;Ϯ͘ϭͲϳ͘ϭͿ} ŽĚLJǁĞŝŐŚƚ͕ŬŐ;^Ϳ ϭϯ͘Ϯ;ϭ͘ϱͿ ϭϯ͘Ϯ;ϭ͘ϱͿ D/͕ŬŐͬŵϮ;^Ϳ ϭϲ͘ϯ;ϭ͘ϯͿ ϭϲ͘ϯ;ϭ͘ϯͿ ^LJƐƚŽůŝĐW͕ŵŵ,Ő;^Ϳ ϭϬϭ͘ϭ;ϭϮ͘ϱͿ ϭϬϭ͘Ϯ;ϭϮ͘ϲͿ ŝĂƐƚŽůŝĐW͕ŵŵ,Ő;^Ϳ ϲϬ͘ϱ;ϭϭ͘ϱͿ ϲϬ͘ϱ;ϭϭ͘ϲͿ WƌĞŐŶĂŶĐLJ͕ďŝƌƚŚĂŶĚŵĂƚĞƌŶĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐ 'ĞƐƚĂƟŽŶĂůĂŐĞĂƚďŝƌƚŚ͕ǁĞĞŬƐ;^Ϳ ϯϵ͘ϴ;ϭ͘ϲͿ ϯϵ͘ϴ;ϭ͘ϲͿ ŝƌƚŚǁĞŝŐŚƚ͕Ő;^Ϳ ϯϱϱϬ͘ϴ;ϱϲϱ͘ϵͿ ϯϱϱϯ;ϱϲϯͿ WůĂĐĞŶƚĂǁĞŝŐŚƚ͕Ő;^Ϳ ϲϱϰ͘ϰ;ϭϱϯ͘ϴͿ ϲϱϬ;ϭϰϵͿ DĂƚĞƌŶĂůĂŐĞĂƚĚĞůŝǀĞƌLJ͕LJĞĂƌƐ;^Ϳ ϯϬ͘ϵ;ϰ͘ϯͿ ϯϬ͘ϵ;ϰ͘ϮϱͿ 'ĞƐƚĂƟŽŶĂůĚŝĂďĞƚĞƐ͕Ŷ;йͿ ϰϳ;ϯ͘ϱͿ ϰϯ;ϯ͘ϯϲͿ 'ĞƐƚĂƟŽŶĂůŚLJƉĞƌƚĞŶƐŝŽŶ͕Ŷ;йͿ ϭϰϲ;ϭϬ͘ϵͿ ϭϰϬ;ϭϬ͘ϵϮͿ ^ŵŽŬŝŶŐĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJ͕Ŷ;йͿ ϭϲϰ;ϭϮ͘ϯͿ ϭϱϱ;ϭϮ͘ϮϬͿ DĂƚĞƌŶĂůĞĚƵĐĂƟŽŶůĞǀĞů;ƵŶŝǀĞƌƐŝƚLJͿ͕Ŷ;йͿ ϰϵϳ;ϯϴ͘ϬͿ ϰϳϴ;ϯϴ͘ϮϰͿ

Values for continuous variables are described as mean ± standard deviation or median (25th_-75th_{SHUFHQWLOHDVUHTXLUHGYDOXHVIRUFDWHJRULFDOYDULDEOHVDVQXPEHUSHUFHQWDJH}

UACXULQDU\DOEXPLQFRQFHQWUDWLRQ8ACRXULQDU\DOEXPLQFUHDWLQLQHUDWLR%3EORRG

SUHVVXUH%0,ERG\PDVVLQGH[

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 30PDF page: 30PDF page: 30PDF page: 30 30

Table 2. Association of urinary albumin concentration (UACDQGXULQDU\DOEXPLQFUHDWLQLQH

ratio (UACRZLWKSUHQDWDOSRVWQDWDODQGPDWHUQDOIDFWRUV

UAC UACR ŽĞĸĐŝĞŶƚ;ϵϱй/Ϳ WͲǀĂůƵĞ ŽĞĸĐŝĞŶƚ;ϵϱй/Ϳ WͲǀĂůƵĞ dŽĚĚůĞƌĐŚĂƌĂĐƚĞƌŝƐƟĐƐ ŐĞ͕ŵŽŶƚŚƐ ͲϬ͘ϬϮ;ͲϬ͘ϬϰʹϬ͘ϬϭͿ Ϭ͘ϭϭϵ ͲϬ͘Ϭϰ;ͲϬ͘ϬϳʹϬ͘ϬϭͿ Ϭ͘ϬϬϯ DĂůĞŐĞŶĚĞƌ ͲϬ͘ϮϬ;Ϭ͘ϭϭʹϬ͘ϯϬͿ фϬ͘ϬϬϭ ͲϬ͘ϭϯ;Ϭ͘ϬϯʹϬ͘ϮϰͿ Ϭ͘ϬϭϬ D/͕ŬŐͬŵϮ Ϭ͘Ϭϯ;ͲϬ͘ϬϭʹϬ͘ϬϳͿ Ϭ͘ϭϱϴ Ϭ͘Ϭϰ;ͲϬ͘ϬϬʹϬ͘ϬϭͿ Ϭ͘Ϭϲϯ ^LJƐƚŽůŝĐW͕ŵŵ,Ő Ϭ͘ϬϬ;Ϭ͘ϬϬʹϬ͘ϬϭͿ Ϭ͘ϲϴϳ Ϭ͘ϬϬ;ͲϬ͘ϬϭʹϬ͘ϬϭͿ Ϭ͘ϵϭϰ ŝĂƐƚŽůŝĐW͕ŵŵ,Ő Ϭ͘ϬϬ;ͲϬ͘ϬϭʹϬ͘ϬϭͿ Ϭ͘ϵϮϲ ͲϬ͘ϬϬ;Ϭ͘ϬϭʹϬ͘ϬϬͿ Ϭ͘ϱϴϱ WƌĞŐŶĂŶĐLJ͕ďŝƌƚŚĂŶĚŵĂƚĞƌŶĂůĐŚĂƌĂĐƚĞƌŝƐƟĐƐ 'ĞƐƚĂƟŽŶĂůĂŐĞĂƚďŝƌƚŚ͕ǁĞĞŬƐ ͲϬ͘ϬϬ;ͲϬ͘ϬϯʹϬ͘ϬϯͿ Ϭ͘ϵϬϯ ͲϬ͘Ϭϭ;ͲϬ͘ϬϰʹϬ͘ϬϮͿ Ϭ͘ϱϴϲ ŝƌƚŚǁĞŝŐŚƚ͕Ő Ϭ͘ϬϬ;ͲϬ͘ϬϬʹϬ͘ϬϬͿ Ϭ͘ϵϵϰ Ϭ͘ϬϬ;ͲϬ͘ϬϬʹϬ͘ϬϬͿ Ϭ͘ϮϬϯ WůĂĐĞŶƚĂǁĞŝŐŚƚ͕Ő ͲϬ͘ϬϬ;ͲϬ͘ϬϬʹϬ͘ϬϬͿ Ϭ͘ϰϴϴ Ϭ͘ϬϬ;ͲϬ͘ϬϬʹϬ͘ϬϬͿ Ϭ͘ϵϰϴ DĂƚĞƌŶĂůĂŐĞĂƚĚĞůŝǀĞƌLJ͕LJĞĂƌƐ ͲϬ͘ϬϬ;ͲϬ͘ϬϭʹϬ͘ϬϭͿ Ϭ͘ϲϭϱ ͲϬ͘ϬϬ;ͲϬ͘ϬϭʹϬ͘ϬϬͿ Ϭ͘ϴϵϵ 'ĞƐƚĂƟŽŶĂůĚŝĂďĞƚĞƐ Ϭ͘ϭϴ;ͲϬ͘ϬϴʹϬ͘ϰϰͿ Ϭ͘ϭϲϱ Ϭ͘ϯϰ;Ϭ͘ϬϲʹϬ͘ϲϯͿ Ϭ͘Ϭϭϵ 'ĞƐƚĂƟŽŶĂůŚLJƉĞƌƚĞŶƐŝŽŶ ͲϬ͘Ϭϱ;ͲϬ͘ϮϬʹϬ͘ϭϬͿ Ϭ͘ϱϯϮ ͲϬ͘ϭϭ;ͲϬ͘ϮϳʹϬ͘ϬϲͿ Ϭ͘ϮϬϮ ^ŵŽŬŝŶŐĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJ ;LJĞƐǀĞƌƐƵƐŶŽͿ ͲϬ͘ϭϭ;ͲϬ͘ϮϲʹϬ͘ϬϯͿ Ϭ͘ϭϮϯ Ϭ͘ϬϮ;ͲϬ͘ϭϰʹϬ͘ϭϴͿ Ϭ͘ϴϮϭ DĂƚĞƌŶĂůƵŶŝǀĞƌƐŝƚLJ ;LJĞƐǀĞƌƐƵƐŶŽͿ ͲϬ͘ϬϮ;ͲϬ͘ϭϮʹϬ͘ϬϴͿ Ϭ͘ϳϮϳ ͲϬ͘Ϭϯ;ͲϬ͘ϭϰʹϬ͘ϬϴͿ Ϭ͘ϲϭϮ

Univariate linear regression on LogUACDQG/RJ8ACR

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&,FRQÀGHQFHLQWHUYDO%3EORRGSUHVVXUH%0,ERG\PDVVLQGH[

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Processed on: 17-4-2018 PDF page: 31PDF page: 31PDF page: 31PDF page: 31 31

Figure 3. Prevalence of different levels of urinary albumin concentration (UACLQWKHJHQHUDO

WRGGOHUSRSXODWLRQ*(&.2ZKHQFRPSDUHGZLWKWKHJHQHUDODGXOWSRSXODWLRQ35(9(1' LQWKHQRUWKHUQ'XWFKSURYLQFHV

Figure 4. Prevalence of increased albuminuria (UAC>PJ/LQGLIIHUHQWDJHUDQJHVLQ

WKHJHQHUDOSRSXODWLRQRIWKH'XWFKQRUWKHUQSURYLQFHVGDWDIURPWKH*(&.2DQGWKH 35(9(1'FRKRUW

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 32PDF page: 32PDF page: 32PDF page: 32

32

Figure 5. Individual variation of urinary albumin concentration is relatively constant with

DJHLQJ0HGLDQDQGth_{SHUFHQWLOHRIWKH8}

AC distribution according to different age

FDWHJRULHVLQWZRDGXOWJHQHUDOSRSXODWLRQFRKRUWV35(9(1'DQG1+$1(6DFKLOGUHQ FRKRUW/HKUQEHFKHUDQGDWRGGOHUFRKRUW*(&.2 th_{SHUFHQWLOHRI8} ACLQ1+$1(6ZDVSORWWHG

Discussion

dŚŝƐƐƚƵĚLJƉƌŽǀŝĚĞƐƵŶŝƋƵĞŝŶĨŽƌŵĂƟŽŶĂďŽƵƚƚŚĞŶĂƚƵƌĂůĚŝƐƚƌŝďƵƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂ ŝŶƚŚĞŐĞŶĞƌĂůƚŽĚĚůĞƌƉŽƉƵůĂƟŽŶ͘dŚĞŵŽƐƚŝŶƚĞƌĞƐƟŶŐĮŶĚŝŶŐŝƐƚŚĞǁŝĚĞƌĂŶŐĞŽĨ ĂůďƵŵŝŶƵƌŝĂŝŶLJŽƵŶŐĐŚŝůĚƌĞŶ͘dŚŝƐƐŚŽǁƐŚŽǁŝŶƚŽĚĚůĞƌƐ͕ũƵƐƚĂƐŝŶƚŚĞŐĞŶĞƌĂůĂĚƵůƚ ƉŽƉƵůĂƟŽŶŽĨƚŚĞƐĂŵĞŐĞŽŐƌĂƉŚŝĐƌĞŐŝŽŶ͕ƚŚĞƌĞŝƐĂŶŝŵƉŽƌƚĂŶƚǀĂƌŝĂďŝůŝƚLJŝŶĂůďƵŵŝŶ ĞdžĐƌĞƟŽŶ͘DŽƌĞŽǀĞƌ͕ǁŚĞŶĐŽŵƉĂƌŝŶŐƚŚĞƉƌĞǀĂůĞŶĐĞŽĨh_шϮϬŵŐͬ>ŝŶƚŚĞLJŽƵŶŐ ĂĚƵůƚĂŶĚƚŽĚĚůĞƌĐŽŚŽƌƚƐ͕ƚŚĞƐĞĂƌĞƐƚƌŝŬŝŶŐůLJƐŝŵŝůĂƌ͕ƌŝƐŝŶŐƚŚĞŶŝŶƟŵĞĂƐŝŶĚŝǀŝĚƵĂůƐ ŐĞƚŽůĚĞƌ͘dŽŽƵƌŬŶŽǁůĞĚŐĞ͕ƚŚŝƐŝƐƚŚĞĮƌƐƚƟŵĞƚŚĂƚƵƌŝŶĞĂůďƵŵŝŶůĞǀĞůƐŚĂǀĞďĞĞŶ ƐƚƵĚŝĞĚŽŶĂŶĞƉŝĚĞŵŝŽůŽŐŝĐĂůƐĐĂůĞŝŶƚŽĚĚůĞƌƐ͘ tŚĂƚŝƐƚŚĞŵĞĂŶŝŶŐŽĨƚŚĞƐĞŝŶĐƌĞĂƐĞĚůĞǀĞůƐŽĨƵƌŝŶĂƌLJĂůďƵŵŝŶĂůƌĞĂĚLJŝŶƐƵĐŚ LJŽƵŶŐŝŶĚŝǀŝĚƵĂůƐ͍ŶĚǁŚĂƚŝƐƚŚĞŵĞĂŶŝŶŐŽĨƚŚĞƐƚƌŝŬŝŶŐƐŝŵŝůĂƌŝƚLJŽĨƚŚĞƉƌĞǀĂůĞŶĐĞŽĨ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶƚŚĞƚŽĚĚůĞƌĂŶĚƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶ͍/ĨŝŶĐƌĞĂƐĞĚůĞǀĞůƐŽĨĂůďƵŵŝŶ ŝŶƚŚĞƵƌŝŶĞĂƌĞĂĐŽŶƐĞƋƵĞŶĐĞŽĨƌĞŶĂůĚĂŵĂŐĞ͕ƚŚĞƐĞĐŚŝůĚƌĞŶŵƵƐƚŚĂǀĞďĞĞŶĚĂŵĂŐĞĚ ũƵƐƚĂŌĞƌďŝƌƚŚŽƌŝŶƵƚĞƌŽ͘dŚŝƐĐŽƵůĚĮƚǁŝƚŚƚŚĞƐŽͲĐĂůůĞĚĂƌŬĞƌŚLJƉŽƚŚĞƐŝƐŝŶǁŚŝĐŚ ͚ĞdžƚĞƌŶĂů͛ŝŶŇƵĞŶĐĞƐĚĞƚĞƌŵŝŶĞƚŚĞŝŶƚƌĂͲƵƚĞƌŝŶĞĚĞǀĞůŽƉŵĞŶƚŽĨƚŚĞĨŽĞƚƵƐ͕ĐĂƵƐŝŶŐ ĚŝƐĞĂƐĞƐůĂƚĞƌŝŶůŝĨĞ͘16_{tĞŚĂĚƐĞůĞĐƚĞĚĂŶƵŵďĞƌŽĨǀĂƌŝĂďůĞƐƚŚĂƚ͕ĂĐĐŽƌĚŝŶŐƚŽƚŚĞĂƌŬĞƌ}

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 33PDF page: 33PDF page: 33PDF page: 33 33 ŚLJƉŽƚŚĞƐŝƐ͕ĐŽƵůĚŚĂǀĞŚĂĚĂƌĞůĂƟŽŶƐŚŝƉǁŝƚŚŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘^ŽŵĞĂƐƐŽĐŝĂƟŽŶƐŚĂǀĞ ďĞĞŶƉƌĞǀŝŽƵƐůLJƌĞƉŽƌƚĞĚ͘17,18 _{/ŶŽƵƌƐƚƵĚLJǁĞĐŽƵůĚŶŽƚĮŶĚĂŶĂƐƐŽĐŝĂƟŽŶǁŝƚŚĨĂĐƚŽƌƐ} ƐƵĐŚĂƐďŝƌƚŚǁĞŝŐŚƚŽƌƉůĂĐĞŶƚĂǁĞŝŐŚƚ͕ĂƐǁĞǁŽƵůĚŚĂǀĞĞdžƉĞĐƚĞĚŽŶƚŚĞďĂƐŝƐŽĨƚŚĞ ĂƌŬĞƌŚLJƉŽƚŚĞƐŝƐ͘dŚĞŽŶůLJĂƐƐŽĐŝĂƟŽŶĨŽƵŶĚǁĂƐďĞƚǁĞĞŶh_ZĂŶĚŐĞƐƚĂƟŽŶĂůĚŝĂďĞƚĞƐ ĂŶĚďĞƚǁĞĞŶh_ZĂŶĚĂŐĞ͘/ƚĐŽƵůĚďĞƚŚĂƚĂůďƵŵŝŶƵƌŝĂĂƚƚŚĞƉĂĞĚŝĂƚƌŝĐĂŐĞŝƐŵŽƐƚůLJ ĂīĞĐƚĞĚďLJŐĞŶĞƟĐĨĂĐƚŽƌƐĂŶĚƉƌĞĚŝƐƉŽƐŝƟŽŶĂŶĚŶŽƚďLJ;ŽƌůĞƐƐďLJͿĞŶǀŝƌŽŶŵĞŶƚĂů ŽƌƉƌĞŐŶĂŶĐLJĨĂĐƚŽƌƐ͘dŚŝƐĚŽĞƐŶŽƚĞdžĐůƵĚĞƚŚĂƚƚŚĞƐĞĨĂĐƚŽƌƐĐŽƵůĚŚĂǀĞĂƐƚƌŽŶŐĞƌ ŝŶŇƵĞŶĐĞŽŶƌĞŶĂůŽƵƚĐŽŵĞůĂƚĞƌŝŶůŝĨĞ͘EĞǀĞƌƚŚĞůĞƐƐ͕ƚŚĞůĂĐŬŽĨĂƐƐŽĐŝĂƟŽŶƐďĞƚǁĞĞŶ ĂůďƵŵŝŶƵƌŝĂĂŶĚďŝƌƚŚǁĞŝŐŚƚ͕ŐĞƐƚĂƟŽŶĂůĂŐĞ͕ŝŵƉĂŝƌĞĚƉůĂĐĞŶƚĂůŐƌŽǁƚŚ͕ŐĞƐƚĂƟŽŶĂů ŚLJƉĞƌƚĞŶƐŝŽŶĂŶĚƐŵŽŬŝŶŐĚƵƌŝŶŐƉƌĞŐŶĂŶĐLJĚŽĞƐŶŽƚƐƵƉƉŽƌƚƚŚĞĂƌŬĞƌŚLJƉŽƚŚĞƐŝƐĂƐ ŵĞĐŚĂŶŝƐŵĨŽƌƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐ͘ ŶĂůƚĞƌŶĂƟǀĞŚLJƉŽƚŚĞƐŝƐǁŽƵůĚďĞƚŚĂƚĐŚŝůĚƌĞŶĂƌĞďŽƌŶǁŝƚŚĂĐŽŶƐƟƚƵƟǀĞĚŝīĞƌĞŶƚ ĂůďƵŵŝŶƵƌŝĂĞdžĐƌĞƟŽŶ;ŶĂƚƵƌĂůǀĂƌŝĂƟŽŶͿ͘/ƚŝƐǁĞůůƉŽƐƐŝďůĞƚŚĂƚĐŚŝůĚƌĞŶĂƌĞďŽƌŶǁŝƚŚĂ ǀĂƌŝĞƚLJŽĨǀĂƐĐƵůĂƌĨƵŶĐƟŽŶ;ĞŶĚŽƚŚĞůŝĂůĨƵŶĐƟŽŶͿĂŶĚƚŚĂƚƚŚŝƐŝƐƌĞŇĞĐƚĞĚďLJĂǀĂƌLJŝŶŐ ĚĞŐƌĞĞŽĨĂůďƵŵŝŶůĞĂŬĂŐĞŝŶĂůůǀĞƐƐĞůƐŝŶĐůƵĚŝŶŐƚŚĞŬŝĚŶĞLJ͘13_{tŚĞŶƵƌŝŶĂƌLJĂůďƵŵŝŶ} ĐŽŶĐĞŶƚƌĂƟŽŶŝƐƉůŽƩĞĚĂŐĂŝŶƐƚĂŐĞŝŶƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶŝƚďĞĐŽŵĞƐĐůĞĂƌƚŚĂƚƵƌŝŶĂƌLJ ĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶǀĂƌŝĞƐďĞƚǁĞĞŶŝŶĚŝǀŝĚƵĂůƐĂƚĂůůĂŐĞƐ;&ŝŐƵƌĞϱͿ͘5,19_{/ŶƚƌŝŐƵŝŶŐůLJ͕} ǁŚĞŶƚŚĞŝŶĚŝǀŝĚƵĂůǀĂƌŝĂƟŽŶŽĨĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐĂŶĚĐŚŝůĚƌĞŶŝƐĐŽŵƉĂƌĞĚǁŝƚŚƚŚĞ ĂĚƵůƚƉŽƉƵůĂƟŽŶ͕ĂƐƚƌŝŬŝŶŐůLJƐŝŵŝůĂƌƉĂƩĞƌŶŝƐŽďƐĞƌǀĞĚǁŝƚŚŶĞĂƌůLJƐŝŵŝůĂƌŵĞĚŝĂŶĂŶĚ ϵϱƚŚƉĞƌĐĞŶƟůĞƐŽĨƚŚĞƵƌŝŶĂƌLJĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶĨƌŽŵLJŽƵŶŐĂŐĞƚŽĂĚŽůĞƐĐĞŶĐĞ͘11 dŚĞƐĞĮŶĚŝŶŐƐƐƵŐŐĞƐƚƚŚĂƚĂŶŝŶĚŝǀŝĚƵĂůŝƐďŽƌŶǁŝƚŚĂĐĞƌƚĂŝŶĂůďƵŵŝŶƵƌŝĂůĞǀĞůƚŚĂƚ ƌĞŵĂŝŶƐ;ƌĞůĂƟǀĞůLJͿĐŽŶƐƚĂŶƚĨŽƌƚŚĂƚŝŶĚŝǀŝĚƵĂůŽǀĞƌƟŵĞĂŶĚŵĂLJƌĞƉƌĞƐĞŶƚĂǀĂƐĐƵůĂƌ ƐƚĂƚĞƚŚĂƚŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂƌŝƐŬĨŽƌŽƌŐĂŶĚĂŵĂŐĞ͘dŚĞƐĞĮŶĚŝŶŐƐŵĂŬĞƚŚĞĂůƚĞƌŶĂƟǀĞ ŚLJƉŽƚŚĞƐŝƐƚŚĂƚŚŝŐŚƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶŝŶƚŽĚĚůĞƌƐŝƐĂŶĞdžƉƌĞƐƐŝŽŶŽĨǀĂƐĐƵůĂƚƵƌĞ ĚĞǀĞůŽƉŵĞŶƚĞĂƌůLJŝŶůŝĨĞĂŶĚŝŶĐƌĞĂƐĞĚĂůďƵŵŝŶƵƌŝĂĚŝŵŝŶŝƐŚĞƐĚƵƌŝŶŐĚĞǀĞůŽƉŵĞŶƚ ůĞƐƐůŝŬĞůLJ͘>ŽŶŐŝƚƵĚŝŶĂůƐƚƵĚŝĞƐǁŝƚŚŵƵůƟƉůĞĂůďƵŵŝŶƵƌŝĂŵĞĂƐƵƌĞŵĞŶƚƐĚƵƌŝŶŐůŝĨĞĂƌĞ ŽďǀŝŽƵƐůLJŶĞĐĞƐƐĂƌLJƚŽĐŽŶĮƌŵŽƌƌĞĨƵƚĞƚŚŝƐŚLJƉŽƚŚĞƐŝƐ͘ DŽƐƚĂĚƵůƚƐƚƵĚŝĞƐƵƐĞĂĐƌĞĂƟŶŝŶĞͲĐŽƌƌĞĐƚĞĚƵƌŝŶĂƌLJĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶĂƐƚŚĞ ŽƉƟŵĂůƌĞƉƌĞƐĞŶƚĂƟŽŶĨŽƌĚĞƐĐƌŝďŝŶŐƚŚĞĂŵŽƵŶƚŽĨĂůďƵŵŝŶůĞĂŬĂŐĞ͘7,20 _{The use of} ĐƌĞĂƟŶŝŶĞŝƐŵĞĂŶƚƚŽĐŽƌƌĞĐƚĂůďƵŵŝŶĨŽƌƵƌŝŶĞĐŽŶĐĞŶƚƌĂƟŽŶĂŶĚĚŝůƵƟŽŶĚŝīĞƌĞŶĐĞƐ͕ ĂŶĚŝŶĚĞĞĚǁŽƌŬƐǁĞůůŝŶĂĚƵůƚƐ͘21_{ƐƚƌŝŬŝŶŐĮŶĚŝŶŐŽĨŽƵƌƐƚƵĚLJŝƐƚŚĂƚ͕ĂĐĐŽƌĚŝŶŐƚŽ} ƚŚĞh_ZĐƵƚͲŽīƉŽŝŶƚƐƵƐĞĚŝŶƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶ;ŝĞh_ZшϯϬŵŐͬŐͿ͕Ϯϯ͘ϰйŽĨƚŚĞ ƚŽĚĚůĞƌƐǁĞƌĞĨŽƵŶĚƚŽŚĂǀĞĂŚŝŐŚƵƌŝŶĂƌLJĂůďƵŵŝŶ͘dŚŝƐĞdžƚƌĞŵĞůLJŚŝŐŚƉƌĞǀĂůĞŶĐĞ ŵŝŐŚƚďĞĚƌŝǀĞŶďLJƚŚĞůŽǁƵƌŝŶĂƌLJĐƌĞĂƟŶŝŶĞǀĂůƵĞƐŝŶƚŽĚĚůĞƌƐ͕ǁŚŝĐŚƌĞŇĞĐƚƐƚŚĞůŽǁĞƌ ŵƵƐĐůĞŵĂƐƐǁŚĞŶĐŽŵƉĂƌĞĚǁŝƚŚŽůĚĞƌĐŚŝůĚƌĞŶĂŶĚĂĚƵůƚƐ͘ůƚŚŽƵŐŚh_Z is a useful ŵĞĂƐƵƌĞŵĞŶƚĂůƐŽŝŶƚŽĚĚůĞƌƐ͕ǁĞďĞůŝĞǀĞƚŚĂƚƚŚĞĐƵƚͲŽīƉŽŝŶƚƐƵƐĞĚĨŽƌĂĚƵůƚƐĂƌĞŶŽƚ ĂƉƉƌŽƉƌŝĂƚĞĨŽƌLJŽƵŶŐĐŚŝůĚƌĞŶĂŶĚǁĞƐƵŐŐĞƐƚƚŚĂƚƚŚĞϵϱƚŚƉĞƌĐĞŶƟůĞƐŚŽƵůĚďĞƵƐĞĚ͘ /ŶƚŚĞƐƚƵĚLJďLJ^ĂŶĐŚĞnjͲĂLJůĞ͕ĂƐŝŵŝůĂƌŵĞĚŝĂŶh_Zhad been found in children under ƚŚĞĂŐĞŽĨϲLJĞĂƌƐ͕ďƵƚŽƵƌĐŽŚŽƌƚƐŚŽǁƐǁŝĚĞƌĚŝƐƚƌŝďƵƟŽŶ͘22 _{We speculate that this}

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 34PDF page: 34PDF page: 34PDF page: 34 34 ŵŝŐŚƚďĞƌĞůĂƚĞĚƚŽĂĚŝīĞƌĞŶƚŐĞŶĞƟĐďĂĐŬŐƌŽƵŶĚŽĨƚŚĞƉŽƉƵůĂƟŽŶƐŽƌƚŽĚŝīĞƌĞŶĐĞƐ ŝŶĞŶǀŝƌŽŶŵĞŶƚĂůĨĂĐƚŽƌƐ͘ ĐĞƌƚĂŝŶůLJŝŶƚĞƌĞƐƟŶŐĮŶĚŝŶŐŝŶŽƵƌĐŽŚŽƌƚŝƐƚŚĞŐĞŶĚĞƌĚŝīĞƌĞŶĐĞŝŶĂůďƵŵŝŶƵƌŝĂ͕ ďŽƚŚŝĨĞdžƉƌĞƐƐĞĚĂƐh_ŽƌĂƐh_Z͘DĂůĞŐĞŶĚĞƌŚĂĚĂƐƚĂƟƐƟĐĂůůLJƐŝŐŶŝĮĐĂŶƚŶĞŐĂƟǀĞ ĂƐƐŽĐŝĂƟŽŶǁŝƚŚĂůďƵŵŝŶƵƌŝĂ͕ŵĞĂŶŝŶŐƚŚĂƚĨĞŵĂůĞƚŽĚĚůĞƌƐŚĂǀĞĂŚŝŐŚĞƌƵƌŝŶĂƌLJĂůďƵŵŝŶ ĐŽŶĐĞŶƚƌĂƟŽŶǁŚĞŶĐŽŵƉĂƌĞĚǁŝƚŚŵĂůĞƐ͘/ŶƐƚƵĚŝĞƐŽŶŐĞŶĞƌĂůĂĚƵůƚƉŽƉƵůĂƟŽŶƐ͕Ă ŚŝŐŚĞƌŵĂůĞƉƌĞǀĂůĞŶĐĞŽĨĂůďƵŵŝŶƵƌŝĂŚĂƐŵŽƐƚůLJďĞĞŶĨŽƵŶĚ͘/ŶƉĂĞĚŝĂƚƌŝĐƐƚƵĚŝĞƐĚĂƚĂ ĂƌĞŶŽŶͲĐŽŶƐŝƐƚĞŶƚ͘22,23_{EĞǀĞƌƚŚĞůĞƐƐ͕ĂŚŝŐŚĞƌƉƌĞǀĂůĞŶĐĞŽĨŚŝŐŚƵƌŝŶĂƌLJĂůďƵŵŝŶƵƌŝĂŚĂƐ} ďĞĞŶĨŽƵŶĚĂůƐŽŝŶƚŚĞEĂƟŽŶĂů,ĞĂůƚŚĂŶĚEƵƚƌŝƟŽŶdžĂŵŝŶĂƟŽŶ^ƵƌǀĞLJ;E,E^Ϳ͘19 ůďƵŵŝŶƵƌŝĂŝŶƚŚŝƐƐƵƌǀĞLJǁĂƐĞdžƉƌĞƐƐĞĚĂƐh_ZĂŶĚƚŚĞĐŚŝůĚƌĞŶŽĨƚŚŝƐƐƵƌǀĞLJǁĞƌĞ ŽůĚĞƌ;ϲͲϭϵLJĞĂƌƐͿ͕ƐŽƚŚĞĚŝīĞƌĞŶĐĞƐǁĞƌĞŝŶƚĞƌƉƌĞƚĞĚĂƐĚŝīĞƌĞŶĐĞƐŝŶŵƵƐĐůĞŵĂƐƐ͘dŚŝƐ ĞdžƉůĂŶĂƟŽŶĐĂŶŶŽƚďĞĂƉƉůŝĞĚƚŽŽƵƌĐŽŚŽƌƚ͕ĂƐh_ĚŝĚŶŽƚĚŝīĞƌƉĞƌŐĞŶĚĞƌ͘tĞĐĂŶŶŽƚ ĞdžĐůƵĚĞƚŚĂƚƚŚŝƐĮŶĚŝŶŐŝŶŽƵƌĐŽŚŽƌƚŝƐŽŶůLJĚƵĞƚŽĐŚĂŶĐĞĂŶĚŚĂƐƚŽďĞĐŽŶĮƌŵĞĚŽƌ ƌĞĨƵƚĞĚŝŶƌĞƉĞĂƚĞĚƐƚƵĚŝĞƐ͘ WƌŽďĂďůLJďĞĐĂƵƐĞŽĨĚŝĸĐƵůƟĞƐŝŶƵƌŝŶĞĐŽůůĞĐƟŽŶŝŶƚŽĚĚůĞƌƐĂŶĚLJŽƵŶŐĐŚŝůĚƌĞŶ͕ ŵŽƐƚƉƌĞǀŝŽƵƐƉĂĞĚŝĂƚƌŝĐƐƚƵĚŝĞƐŚĂǀĞŝŶǀĞƐƟŐĂƚĞĚƵƌŝŶĂƌLJĂůďƵŵŝŶŝŶƐĐŚŽŽůͲĂŐĞĚ ĐŚŝůĚƌĞŶŽƌĂĚŽůĞƐĐĞŶƚƐ͘22-25_{ĂƚĂĐŽŶĐĞƌŶŝŶŐĂůďƵŵŝŶƵƌŝĂŝŶƚŽĚĚůĞƌƐĂƌĞůŝŵŝƚĞĚƚŽ} ƐŵĂůůŶƵŵďĞƌƐŽĨŝŶĚŝǀŝĚƵĂůƐ͘11_{dŽŽƵƌŬŶŽǁůĞĚŐĞ͕ƚŚŝƐŝƐƚŚĞĮƌƐƚƐƚƵĚLJŝŶǀĞƐƟŐĂƟŶŐ} ĂůďƵŵŝŶƵƌŝĂŝŶĂůĂƌŐĞƚŽĚĚůĞƌĐŽŚŽƌƚ͘DĂŶLJŽĨƚŚĞƉƌĞǀŝŽƵƐƐƚƵĚŝĞƐŽŶĂůďƵŵŝŶƵƌŝĂ ŝŶĐŚŝůĚƌĞŶƌĞƉŽƌƚĚĂŝůLJƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ͕h_ZŽƌh_in spot urine, but not ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂƉƌĞǀĂůĞŶĐĞ͘hŶĨŽƌƚƵŶĂƚĞůLJ͕ƚŚŝƐŚĂŵƉĞƌƐĚŝƌĞĐƚĐŽŵƉĂƌŝƐŽŶǁŝƚŚŽƵƌ ĚĂƚĂ͘/ŶĂĚĚŝƟŽŶ͕ƚŽŽƵƌŬŶŽǁůĞĚŐĞƚŚŝƐŝƐƚŚĞĮƌƐƚƐƚƵĚLJƚŚĂƚĚŝƌĞĐƚůLJĐŽŵƉĂƌĞĚƚŚĞ ƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶĂƚŽĚĚůĞƌƉŽƉƵůĂƟŽŶǁŝƚŚƚŚĞĂĚƵůƚƉŽƉƵůĂƟŽŶŽĨƚŚĞ ƐĂŵĞŐĞŽŐƌĂƉŚŝĐĂůƌĞŐŝŽŶ͘ KƵƌƐƚƵĚLJŚĂƐƐĞǀĞƌĂůůŝŵŝƚĂƟŽŶƐ͘dŚĞh_ŵĞĂƐƵƌĞŵĞŶƚǁĂƐĚŽŶĞŽŶĂƐŝŶŐůĞƐĂŵƉůĞ͘ tĞŚĂǀĞƚŚƵƐŶŽŝŶĨŽƌŵĂƟŽŶŽŶǁŚĞƚŚĞƌƚŚĞĂůďƵŵŝŶƵƌŝĂǀĂůƵĞƐŝŶƚŚĞƐĞĐŚŝůĚƌĞŶĂƌĞ ĐŽŶƐƚĂŶƚŝŶƟŵĞŽƌĐŽƵůĚďĞŝŶŇƵĞŶĐĞĚďLJĐŽŶĐƵƌƌĞŶƚƉƌŽďůĞŵƐƐƵĐŚĂƐǀŝƌĂůŝŶĨĞĐƟŽŶƐ ŽƌƟŵŝŶŐŽĨƚŚĞƐĂŵƉůŝŶŐ;ŵŽƌŶŝŶŐǀĞƌƐƵƐĂŌĞƌŶŽŽŶͿ͕ĂŶĚǁĞĚŽŶŽƚŬŶŽǁŝĨƚŚĞƐĞ ǀĂůƵĞƐĂƌĞƌĞƉƌĞƐĞŶƚĂƟǀĞŽĨƚŚĞĚĂŝůLJƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ͘,ŽǁĞǀĞƌ͕ǁĞŵĂĚĞ ƚŚĞĐŽŵƉĂƌŝƐŽŶǁŝƚŚĂŶĂĚƵůƚƉŽƉƵůĂƟŽŶĂůƐŽƵƐŝŶŐƐŝŶŐůĞƵƌŝŶĞƐĂŵƉůĞƐƚŽĚĞƚĞƌŵŝŶĞ ƚŚĞƉƌĞǀĂůĞŶĐĞŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘^ĞĐŽŶĚůLJ͕ƚŚĞƵƌŝŶĞĐŽůůĞĐƟŽŶŵĞƚŚŽĚƵƐĞĚŚĂƐĂ ƌĂƚŚĞƌƉŽŽƌƌĞĐŽǀĞƌLJ͘/ƚŝƐƉŽƐƐŝďůĞƚŚĂƚƚŚĞĂůďƵŵŝŶŝƐƌĞƚĂŝŶĞĚŝŶƚŚĞĐŽƩŽŶǁŽŽůŽĨƚŚĞ ƉĂŶƚLJůŝŶĞƌƐŝŶƐŽŵĞŝŶĚŝǀŝĚƵĂůƐůĞĂĚŝŶŐƚŽĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶƐďĞůŽǁƚŚĞĚĞƚĞĐƟŽŶ ůŝŵŝƚ͘dŚŝƐďŝĂƐ͕ŚŽǁĞǀĞƌ͕ĚŽĞƐŶŽƚŚĂǀĞĂďŝŐŝŵƉĂĐƚŽŶŽƵƌĐŽŶĐůƵƐŝŽŶƐŝŶĐĞŝƚŽŶůLJůĞĂĚƐ ƚŽĂŶƵŶĚĞƌĞƐƟŵĂƟŽŶŽĨƚŚĞh_ŵĞĂƐƵƌĞŵĞŶƚƐŝŶƚŚĞƚŽĚĚůĞƌƐ͘ /ŶĐŽŶĐůƵƐŝŽŶ͕ƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶŝŶƚŽĚĚůĞƌƐŝƐǀĞƌLJƐŝŵŝůĂƌƚŽƚŚĂƚŝŶLJŽƵŶŐ ĂĚƵůƚƐ͕ ŝŶĐůƵĚŝŶŐ ƚŚĞ ƉƌĞǀĂůĞŶĐĞ ŽĨ ŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ dŚŝƐ ĮŶĚŝŶŐ ŚĂƐ ŝŵƉŽƌƚĂŶƚ ŝŵƉůŝĐĂƟŽŶƐ ĨŽƌ ƚŚĞ ĐƵƌƌĞŶƚ ƉĂƚŚŽƉŚLJƐŝŽůŽŐŝĐĂů ǀŝĞǁ ŽŶ ĂůďƵŵŝŶƵƌŝĂ ĂƐ Ă ĐĂƵƐĞ Žƌ ĐŽŶƐĞƋƵĞŶĐĞŽĨƌĞŶĂůĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘KƵƌĚĂƚĂƐƵŐŐĞƐƚƚŚĂƚĂůďƵŵŝŶĞdžĐƌĞƟŽŶ

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 35PDF page: 35PDF page: 35PDF page: 35 35 ŵĂLJƌĞƉƌĞƐĞŶƚĂŶŝŶďŽƌŶĐŽŶƐƟƚƵƟǀĞĐŚĂƌĂĐƚĞƌŝƐƟĐ͕ĚĞƚĞƌŵŝŶŝŶŐĨĂƚĞŽĨƚŚĞŝŶĚŝǀŝĚƵĂů ŝŶůĂƚĞƌůŝĨĞ͘

Funding statement

dŚĞ'<KƌĞŶƚŚĞďŝƌƚŚĐŽŚŽƌƚǁĂƐĨƵŶĚĞĚďLJĂŶƵŶƌĞƐƚƌŝĐƚĞĚŐƌĂŶƚŽĨ,ƵƚĐŚŝƐŽŶ tŚĂŵƉŽĂ>ƚĚ͕,ŽŶŐ<ŽŶŐĂŶĚƌĞĐĞŝǀĞĚƐƵƉƉŽƌƚĨƌŽŵƚŚĞhD'͘

Acknowledgment

tĞƚŚĂŶŬĂůůƉĂƌĞŶƚƐĂŶĚĐŚŝůĚƌĞŶĨŽƌƉĂƌƟĐŝƉĂƟŽŶŝŶƚŚĞ'<KƌĞŶƚŚĞĐŽŚŽƌƚ͕WƌŽĨ͘ ^͘:͘>͘ĂŬŬĞƌĨŽƌŚŝƐƐƵƉƉŽƌƚŝŶĚĞƐŝŐŶŝŶŐƵƌŝŶĞĐŽůůĞĐƟŽŶƐĂŶĚƌ<ƌƂƉĞůŝŶĨŽƌƐƚĂƟƐƟĐĂů ĂĚǀŝĐĞĂŶĚƐƵƉƉŽƌƚ͘

&RQÁLFWRI,QWHUHVW

ĚŝƐĂĐŽŶƐƵůƚĂŶƚĨŽƌĂŶĚƌĞĐĞŝǀĞƐŚŽŶŽƌĂƌŝĂ;ƚŽĞŵƉůŽLJĞƌͿĨƌŽŵďďsŝĞ͕ƐƚĞůůĂƐ͕ ŚĞŵŽĞŶƚƌLJdž͕ ůŝ >ŝůůLJ͕ :ĂŶƐƐĞŶ͕ &ƌĞƐĞŶŝƵƐ ĂŶĚ DĞƌĐŬ ĂƌŵƐƚĂĚƚ͘ ,:>, ƌĞĐĞŝǀĞĚ Ă ƌĞƐĞĂƌĐŚŐƌĂŶƚĨƌŽŵƐƚƌĂĞŶĞĐĂ;ƉĂLJŵĞŶƚƚŽĞŵƉůŽLJĞƌͿĂŶĚŝƐĂĐŽŶƐƵůƚĂŶƚĨŽƌĂŶĚ ƌĞĐĞŝǀĞƐŚŽŶŽƌĂƌŝĂ;ƚŽĞŵƉůŽLJĞƌͿĨƌŽŵďďsŝĞ͕ƐƚĞůůĂƐ͕:ĂŶƐƐĞŶ͕ZĞĂƚĂWŚĂƌŵĂĐĞƵƟĐĂůƐ͕ sŝƚĂĞĂŶĚ^ͲWŚĂƌŵĂ͘

6XSSOHPHQWDU\ÀJXUHV

Supplementary table 1. &KDUDFWHULVWLFVRI35(9(1'VWXG\SRSXODWLRQ

dŽƚĂůƐƚƵĚLJƉŽƉƵůĂƟŽŶ (n=40854) ŐĞ͕LJĞĂƌƐ;^Ϳ ϰϵ͘ϱ;ϭϮ͘ϴͿ DĂůĞ͕E;йͿ ϭϴϲϮϱ;ϰϱ͘ϲͿ DĞĚŝĂŶh_͕ŵŐͬ>;Ϯϱth_{- 75}th_{ƉĞƌĐĞŶƟůĞͿ ϲ͘Ϭ;ϯ͘ϳͲϵ͘ϵͿ} ŝĂďĞƚĞƐ͕E;йͿ ϭϬϱϭ;Ϯ͘ϲͿ ,LJƉĞƌƚĞŶƐŝŽŶ͕E;йͿ ϰϰϭϵ;ϭϭ͘ϮͿ ^ŵŽŬŝŶŐ͕E;йͿ ϭϳϭϰϴ;ϰϮ͘ϮͿ ^ƚƌŽŬĞ͕E;йͿ ϯϯϯ;Ϭ͘ϴͿ $EEUHYLDWLRQV8ACXULQDU\DOEXPLQFRQFHQWUDWLRQ

2

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 36PDF page: 36PDF page: 36PDF page: 36 36

References

ϭ͘ <ĞĞŶ,͕ŚůŽƵǀĞƌĂŬŝƐ͕&ƵůůĞƌ:͕:ĂƌƌĞƩZ:͘ dŚĞ ĐŽŶĐŽŵŝƚĂŶƚƐ ŽĨ ƌĂŝƐĞĚ ďůŽŽĚ ƐƵŐĂƌ͗ ^ƚƵĚŝĞƐŝŶŶĞǁůLJͲĚĞƚĞĐƚĞĚŚLJƉĞƌŐůLJĐĂĞŵŝĐƐ͗ //͘ƵƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ͕ďůŽŽĚƉƌĞƐƐƵƌĞ ĂŶĚƚŚĞŝƌƌĞůĂƟŽŶƚŽďůŽŽĚƐƵŐĂƌůĞǀĞůƐ͘/Ŷƚ: ƉŝĚĞŵŝŽů͘ϮϬϭϰ͖ϰϯ;ϭͿ͗ϭϭͲϭϱ͘ Ϯ͘ tĂĐŚƚĞůů <͕ WĂůŵŝĞƌŝ s͕ KůƐĞŶ D,͕ Ğƚ Ăů͘ hƌŝŶĞ ĂůďƵŵŝŶͬĐƌĞĂƚŝŶŝŶĞ ƌĂƚŝŽ ĂŶĚ ĞĐŚŽĐĂƌĚŝŽŐƌĂƉŚŝĐůĞŌǀĞŶƚƌŝĐƵůĂƌƐƚƌƵĐƚƵƌĞ ĂŶĚ ĨƵŶĐƚŝŽŶ ŝŶ ŚLJƉĞƌƚĞŶƐŝǀĞ ƉĂƚŝĞŶƚƐ ǁŝƚŚĞůĞĐƚƌŽĐĂƌĚŝŽŐƌĂƉŚŝĐůĞŌǀĞŶƚƌŝĐƵůĂƌ ŚLJƉĞƌƚƌŽƉŚLJ͗ dŚĞ >/& ƐƚƵĚLJ͘ ůŽƐĂƌƚĂŶ ŝŶƚĞƌǀĞŶƟŽŶ ĨŽƌ ĞŶĚƉŽŝŶƚ ƌĞĚƵĐƟŽŶ͘ ŵ ,ĞĂƌƚ:͘ϮϬϬϮ͖ϭϰϯ;ϮͿ͗ϯϭϵͲϯϮϲ͘ ϯ͘ EŝŶŽŵŝLJĂ d͕ WĞƌŬŽǀŝĐ s͕ ĚĞ 'ĂůĂŶ ͕ Ğƚ Ăů͘ ůďƵŵŝŶƵƌŝĂ ĂŶĚ ŬŝĚŶĞLJ ĨƵŶĐƚŝŽŶ ŝŶĚĞƉĞŶĚĞŶƚůLJ ƉƌĞĚŝĐƚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĂŶĚƌĞŶĂůŽƵƚĐŽŵĞƐŝŶĚŝĂďĞƚĞƐ͘:ŵ^ŽĐ EĞƉŚƌŽů͘ϮϬϬϵ͖ϮϬ;ϴͿ͗ϭϴϭϯͲϭϴϮϭ͘ ϰ͘ ǀĂŶĚĞƌsĞůĚĞD͕,ĂůďĞƐŵĂE͕ĚĞŚĂƌƌŽ&d͕ ĞƚĂů͘^ĐƌĞĞŶŝŶŐĨŽƌĂůďƵŵŝŶƵƌŝĂŝĚĞŶƟĮĞƐ ŝŶĚŝǀŝĚƵĂůƐĂƚŝŶĐƌĞĂƐĞĚƌĞŶĂůƌŝƐŬ͘:ŵ^ŽĐ EĞƉŚƌŽů͘ϮϬϬϵ͖ϮϬ;ϰͿ͗ϴϱϮͲϴϲϮ͘ ϱ͘ ,ŝůůĞŐĞ ,>͕ :ĂŶƐƐĞŶ tD͕ ĂŬ ͕ Ğƚ Ăů͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝƐ ĐŽŵŵŽŶ͕ ĂůƐŽ ŝŶ Ă ŶŽŶĚŝĂďĞƚŝĐ͕ ŶŽŶŚLJƉĞƌƚĞŶƐŝǀĞ ƉŽƉƵůĂƟŽŶ͕ĂŶĚĂŶŝŶĚĞƉĞŶĚĞŶƚŝŶĚŝĐĂƚŽƌ of cardiovascular risk factors and ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŵŽƌďŝĚŝƚLJ͘ : /ŶƚĞƌŶ DĞĚ͘ ϮϬϬϭ͖Ϯϰϵ;ϲͿ͗ϱϭϵͲϱϮϲ͘ ϲ͘ ,ŝůůĞŐĞ,>͕&ŝĚůĞƌs͕ŝĞƌĐŬƐ'&͕ĞƚĂů͘hƌŝŶĂƌLJ ĂůďƵŵŝŶĞdžĐƌĞƟŽŶƉƌĞĚŝĐƚƐĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĂŶĚŶŽŶĐĂƌĚŝŽǀĂƐĐƵůĂƌŵŽƌƚĂůŝƚLJŝŶŐĞŶĞƌĂů ƉŽƉƵůĂƟŽŶ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϮ͖ϭϬϲ;ϭϰͿ͗ϭϳϳϳͲ ϭϳϴϮ͘ ϳ͘ ZŽŵƵŶĚƐƚĂĚ^͕,ŽůŵĞŶ:͕<ǀĞŶŝůĚ<͕,ĂůůĂŶ ,͕ ůůĞŬũĂĞƌ ,͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂŶĚ ĂůůͲ ĐĂƵƐĞŵŽƌƚĂůŝƚLJŝŶϮ͕ϬϴϵĂƉƉĂƌĞŶƚůLJŚĞĂůƚŚLJ ŝŶĚŝǀŝĚƵĂůƐ͗  ϰ͘ϰͲLJĞĂƌ ĨŽůůŽǁͲƵƉ ƐƚƵĚLJ͘ ƚŚĞ ŶŽƌĚͲƚƌŽŶĚĞůĂŐ ŚĞĂůƚŚ ƐƚƵĚLJ ;,hEdͿ͕ ŶŽƌǁĂLJ͘ŵ:<ŝĚŶĞLJŝƐ͘ϮϬϬϯ͖ϰϮ;ϯͿ͗ϰϲϲͲ ϰϳϯ͘ ϴ͘ ƌŶůŽǀ:͕ǀĂŶƐ:͕DĞŝŐƐ:͕ĞƚĂů͘>ŽǁͲŐƌĂĚĞ albuminuria and incidence of cardiovascular ĚŝƐĞĂƐĞ ĞǀĞŶƚƐ ŝŶ ŶŽŶŚLJƉĞƌƚĞŶƐŝǀĞ ĂŶĚ ŶŽŶĚŝĂďĞƟĐ ŝŶĚŝǀŝĚƵĂůƐ͗ dŚĞ ĨƌĂŵŝŶŐŚĂŵ ŚĞĂƌƚƐƚƵĚLJ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϱ͖ϭϭϮ;ϳͿ͗ϵϲϵͲ ϵϳϱ͘ ϵ͘ ^ĂůŵŽŶ,͕&ĞƌŐƵƐŽŶ:<͕ƵƌĨŽƌĚ:>͕ĞƚĂů͘ >ŽƐƐ ŽĨ ƚŚĞ ĞŶĚŽƚŚĞůŝĂů ŐůLJĐŽĐĂůLJdž ůŝŶŬƐ ĂůďƵŵŝŶƵƌŝĂĂŶĚǀĂƐĐƵůĂƌĚLJƐĨƵŶĐƟŽŶ͘:ŵ ^ŽĐEĞƉŚƌŽů͘ϮϬϭϮ͖Ϯϯ;ϴͿ͗ϭϯϯϵͲϭϯϱϬ͘ ϭϬ͘ ^ĂůŵŽŶ ,͕ ^ĂƚĐŚĞůů ^͘ ŶĚŽƚŚĞůŝĂů ŐůLJĐŽĐĂůLJdž ĚLJƐĨƵŶĐƚŝŽŶ ŝŶ ĚŝƐĞĂƐĞ͗ Albuminuria and increased microvascular ƉĞƌŵĞĂďŝůŝƚLJ͘:WĂƚŚŽů͘ϮϬϭϮ͖ϮϮϲ;ϰͿ͗ϱϲϮͲϱϳϰ͘ ϭϭ͘ >ĞŚƌŶďĞĐŚĞƌ d͕ 'ƌĞŝƐƐŝŶŐĞƌ ^͕ EĂǀŝĚ &͕ WĨƵůůĞƌ,͕:ĞƐĐŚŬĞZ͘ůďƵŵŝŶ͕/Ő'͕ƌĞƟŶŽůͲ ďŝŶĚŝŶŐƉƌŽƚĞŝŶ͕ĂŶĚĂůƉŚĂϭͲŵŝĐƌŽŐůŽďƵůŝŶ ĞdžĐƌĞƟŽŶ ŝŶ ĐŚŝůĚŚŽŽĚ͘ WĞĚŝĂƚƌ EĞƉŚƌŽů͘ ϭϵϵϴ͖ϭϮ;ϰͿ͗ϮϵϬͲϮϵϮ͘ ϭϮ͘ 'ƐĐŚǁĞŶĚ^͕ƵŝŬĞŵĂ,͕EĂǀŝƐ'͕,ĞŶŶŝŶŐ Z,͕ĚĞĞĞƵǁ͕ǀĂŶŽŬŬƵŵZW͘ŶĚŽƚŚĞůŝĂů ĚŝůĂƚŽƌLJ ĨƵŶĐƚŝŽŶ ƉƌĞĚŝĐƚƐ ŝŶĚŝǀŝĚƵĂů ƐƵƐĐĞƉƟďŝůŝƚLJƚŽƌĞŶĂůĚĂŵĂŐĞŝŶƚŚĞϱͬϲ ŶĞƉŚƌĞĐƚŽŵŝnjĞĚ ƌĂƚ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϮ͖ϭϯ;ϭϮͿ͗ϮϵϬϵͲϮϵϭϱ͘ ϭϯ͘ ĚĞ ĞĞƵǁ ͕ WĂƌǀŝŶŐ ,,͕ ,ĞŶŶŝŶŐ Z,͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ĂƐ ĂŶ ĞĂƌůLJ ŵĂƌŬĞƌ ĨŽƌ ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘:ŵ^ŽĐEĞƉŚƌŽů͘ ϮϬϬϲ͖ϭϳ;ϴͿ͗ϮϭϬϬͲϮϭϬϱ͘ ϭϰ͘ >͛ďĞĞ͕^ĂƵĞƌW:͕ĂŵĞŶD͕ZĂŬĞ:W͕ĂƚƐ ,͕ ^ƚŽůŬ ZW͘ ŽŚŽƌƚ ƉƌŽĨŝůĞ͗ dŚĞ '<K ĚƌĞŶƚŚĞ ƐƚƵĚLJ͕ ŽǀĞƌǁĞŝŐŚƚ ƉƌŽŐƌĂŵŵŝŶŐ ĚƵƌŝŶŐ ĞĂƌůLJ ĐŚŝůĚŚŽŽĚ͘ /Ŷƚ : ƉŝĚĞŵŝŽů͘ ϮϬϬϴ͖ϯϳ;ϯͿ͗ϰϴϲͲϰϴϵ͘ ϭϱ͘ ^ƚĞǀĞŶƐ>͕ŚĂŶŐz͕^ĐŚŵŝĚ,͘ǀĂůƵĂƟŶŐ ƚŚĞƉĞƌĨŽƌŵĂŶĐĞŽĨĞƋƵĂƟŽŶƐĨŽƌĞƐƟŵĂƟŶŐ ŐůŽŵĞƌƵůĂƌ ĨŝůƚƌĂƚŝŽŶ ƌĂƚĞ͘ : EĞƉŚƌŽů͘ ϮϬϬϴ͖Ϯϭ;ϲͿ͗ϳϵϳͲϴϬϳ͘ ϭϲ͘ ĂƌŬĞƌ:͘dŚĞĨĞƚĂůĂŶĚŝŶĨĂŶƚŽƌŝŐŝŶƐŽĨ ĂĚƵůƚĚŝƐĞĂƐĞ͘D:͘ϭϵϵϬ͖ϯϬϭ;ϲϳϲϭͿ͗ϭϭϭϭ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018

Processed on: 17-4-2018 PDF page: 37PDF page: 37PDF page: 37PDF page: 37 37 ϭϳ͘ <ĞŝũnjĞƌͲsĞĞŶD'͕^ĐŚƌĞǀĞůD͕&ŝŶŬĞŶD:͕Ğƚ Ăů͘DŝĐƌŽĂůďƵŵŝŶƵƌŝĂĂŶĚůŽǁĞƌŐůŽŵĞƌƵůĂƌ ĮůƚƌĂƟŽŶƌĂƚĞĂƚLJŽƵŶŐĂĚƵůƚĂŐĞŝŶƐƵďũĞĐƚƐ ďŽƌŶǀĞƌLJƉƌĞŵĂƚƵƌĞĂŶĚĂŌĞƌŝŶƚƌĂƵƚĞƌŝŶĞ ŐƌŽǁƚŚ ƌĞƚĂƌĚĂƚŝŽŶ͘ : ŵ ^ŽĐ EĞƉŚƌŽů͘ ϮϬϬϱ͖ϭϲ;ϵͿ͗ϮϳϲϮͲϮϳϲϴ͘ ϭϴ͘ <ĞŝũnjĞƌͲsĞĞŶD'͕<ůĞŝŶǀĞůĚ,͕>ĞƋƵŝŶD,͕ ĞƚĂů͘ZĞŶĂůĨƵŶĐƟŽŶĂŶĚƐŝnjĞĂƚLJŽƵŶŐĂĚƵůƚ ĂŐĞ ĂŌĞƌ ŝŶƚƌĂƵƚĞƌŝŶĞ ŐƌŽǁƚŚ ƌĞƐƚƌŝĐƟŽŶ ĂŶĚǀĞƌLJƉƌĞŵĂƚƵƌĞďŝƌƚŚ͘ŵ:<ŝĚŶĞLJŝƐ͘ ϮϬϬϳ͖ϱϬ;ϰͿ͗ϱϰϮͲϱϱϭ͘ ϭϵ͘ :ŽŶĞƐ͕&ƌĂŶĐŝƐD͕ďĞƌŚĂƌĚƚD^͕ĞƚĂů͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝŶ ƚŚĞ h^ ƉŽƉƵůĂƟŽŶ͗ Third national health and nutrition ĞdžĂŵŝŶĂƚŝŽŶ ƐƵƌǀĞLJ͘ ŵ : <ŝĚŶĞLJ ŝƐ͘ ϮϬϬϮ͖ϯϵ;ϯͿ͗ϰϰϱͲϰϱϵ͘

ϮϬ͘ zƵLJƵŶ D&͕ <ŚĂǁ <d͕ >ƵďĞŶ Z͕ Ğƚ Ăů͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂŝŶĚĞƉĞŶĚĞŶƚůLJƉƌĞĚŝĐƚƐ ĂůůͲĐĂƵƐĞ ĂŶĚ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŵŽƌƚĂůŝƚLJ in a british population: The european ƉƌŽƐƉĞĐƚŝǀĞ ŝŶǀĞƐƚŝŐĂƚŝŽŶ ŝŶƚŽ ĐĂŶĐĞƌ ŝŶ ŶŽƌĨŽůŬ;W/ͲŶŽƌĨŽůŬͿƉŽƉƵůĂƟŽŶƐƚƵĚLJ͘/Ŷƚ :ƉŝĚĞŵŝŽů͘ϮϬϬϰ͖ϯϯ;ϭͿ͗ϭϴϵͲϭϵϴ͘ Ϯϭ͘ ĂŬŬĞƌ:͘ĞƚĞĐƟŽŶŽĨŵŝĐƌŽĂůďƵŵŝŶƵƌŝĂ͘ ƌĞĐĞŝǀĞƌ ŽƉĞƌĂƚŝŶŐ ĐŚĂƌĂĐƚĞƌŝƐƚŝĐ ĐƵƌǀĞ ĂŶĂůLJƐŝƐĨĂǀŽƌƐĂůďƵŵŝŶͲƚŽͲĐƌĞĂƟŶŝŶĞƌĂƟŽ ŽǀĞƌĂůďƵŵŝŶĐŽŶĐĞŶƚƌĂƟŽŶ͘ŝĂďĞƚĞƐĂƌĞ͘ ϭϵϵϵ͖ϮϮ;ϮͿ͗ϯϬϳͲϯϭϯ͘ ϮϮ͘ ^ĂŶĐŚĞnjͲĂLJůĞD͕ZŽĚƌŝŐƵĞnjͲŝŵĂĚĞǀŝůůĂ͕ ƐĞŶƐŝŽ͕ĞƚĂů͘hƌŝŶĂƌLJĂůďƵŵŝŶĞdžĐƌĞƟŽŶ ŝŶƐƉĂŶŝƐŚĐŚŝůĚƌĞŶ͘ŶŝŶŽũĞƐƵƐŐƌŽƵƉ͘WĞĚŝĂƚƌ EĞƉŚƌŽů͘ϭϵϵϱ͖ϵ;ϰͿ͗ϰϮϴͲϰϯϬ͘ Ϯϯ͘ dƐŝŽƵĨŝƐ ͕ DĂnjĂƌĂŬŝ ͕ ŝŵŝƚƌŝĂĚŝƐ <͕ ^ƚĞĨĂŶŝĚŝƐ :͕ ^ƚĞĨĂŶĂĚŝƐ ͘ DŝĐƌŽĂůďƵŵŝŶƵƌŝĂ ŝŶ ƚŚĞ ƉĂĞĚŝĂƚƌŝĐ ĂŐĞ͗ ƵƌƌĞŶƚŬŶŽǁůĞĚŐĞĂŶĚĞŵĞƌŐŝŶŐƋƵĞƐƟŽŶƐ͘ ĐƚĂWĂĞĚŝĂƚƌ͘ϮϬϭϭ͖ϭϬϬ;ϵͿ͗ϭϭϴϬͲϭϭϴϰ͘ Ϯϰ͘ ZĂĚĞŵĂĐŚĞƌZ͕^ŝŶĂŝŬŽZ͘ůďƵŵŝŶƵƌŝĂ ŝŶĐŚŝůĚƌĞŶ͘ƵƌƌKƉŝŶEĞƉŚƌŽů,LJƉĞƌƚĞŶƐ͘ ϮϬϬϵ͖ϭϴ;ϯͿ͗ϮϰϲͲϮϱϭ͘ Ϯϱ͘ ZĂĚĞŵĂĐŚĞƌ ͕ DĂƵĞƌ D͕ :ĂĐŽďƐ Z͕ :ƌ͕ ŚĂǀĞƌƐ ͕ ^ƚĞŝŶŬĞ :͕ ^ŝŶĂŝŬŽ ͘ ůďƵŵŝŶ ĞdžĐƌĞƚŝŽŶ ƌĂƚĞ ŝŶ ŶŽƌŵĂů ĂĚŽůĞƐĐĞŶƚƐ͗ Relation to insulin resistance and cardiovascular risk factors and comparisons ƚŽƚLJƉĞϭĚŝĂďĞƚĞƐŵĞůůŝƚƵƐƉĂƟĞŶƚƐ͘ůŝŶ: ŵ^ŽĐEĞƉŚƌŽů͘ϮϬϬϴ͖ϯ;ϰͿ͗ϵϵϴͲϭϬϬϱ͘

518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt 518800-L-sub01-bw-vdBelt Processed on: 17-4-2018 Processed on: 17-4-2018 Processed on: 17-4-2018