status and trends in in-vitro diagnostics and … irmm... · · 2016-06-03• contribute up to 94...

Protection notice / © 2010 Siemens Healthcare Diagnostics Products GmbH. All rights reserved.

Status and Trends in In-Vitro Diagnostics and Considerations for Reference Materials

The Future of Reference Materials

– Science and Innovation –

Conference in the frame of the 50th anniversary of the JRC’sInstitute for Reference Materials and Measurements

Geel, Belgium, 23-25 November 2010

Frank Vitzthum, Siemens Healthcare Diagnostics Products GmbH

23.-25.11.2010 Protection notice / © 2010 Siemens Healthcare Diagnostics Products GmbH

Overview

Status of laboratory diagnostics in healthcare

Global trends and trends in in-vitro diagnostics

Proteomics research

Considerations for reference materials


In-vitro diagnostics is hardly ‚visible‘ any more...

In-Vitro Diagnostics – Status Quo

IVD / laboratory spacePatient care space


IVD: the hidden treasure in healthcare

Minimal IVD expenditures save lives and money.

Impact of IVDs

• contribute up to 94 % of the objective data in clinical records

• influence 60 - 70 % of critical decisionmaking

• reduce mortality and morbidity• improve quality of life and patient care• reduce health care costs

Health ExpendituresWorld-Wide

~ 1-2 % IVD

2,780 BIO US $

Still, IVD expenditures are deemed too high, and their value is underestimated.

Protection notice / © 2010 Siemens Healthcare Diagnostics Products GmbH. All rights reserved.

Trends


Megatrends shape our future

Globalization

From 1950 to 2004, the volume of global trade has increased 27.5-fold.

The number of global players has grown from 17,000 in 1980 to over 70,000 today.

Ocean freight has increased over the past four decades from less than 6,000 billion ton-miles to over 27,500 billion ton-miles a year.

Urbanization

2007: for the first time in history, more people live in cities than in rural areas. Today 280 million people live in megacities (> 10 million residents)2030: 60 % of the world’s population will live in citiesUrban conglomerations contribute a high share of a nation’s economic output: Tokyo provides 40 % of Japan’s GDP, Paris generates 30 % of France’s GDP.


Megatrends shape our future

Climate Change

The average global surface temperature has increased by 0.76 °C compared to the 18th century.11 of the 12 years between 1994 and 2005 rank among the 12 warmest since weather observations began.Greenhouse gas emissions haven risen dramatically since industrialization. Today we face the highest CO2 concentration in the atmosphere for the past 350,000 years.

Demographic Change

Average life expectancy worldwide will increase to 72 years in 2025 from 46.6 years in 1950.World population will grow from more than 6 billion now to 8 billion by 2025.95 % of the global population growth is taking place in developing countries.The 65+ generation will nearly double worldwide by 2030 (from 7 % to 12 %),


Key impacts of Megatrends on In-Vitro Diagnostics

Infectious Disease Diagnostics

Disease of aging or lifestyle, e.g.

Neurological diseases

Cardiovascular diseases

Diabetes

Cancer

Disease prevention

Globalization of healthcare: standardization & harmonization


Major trends in In-Vitro Diagnostics

• Further economization also in healthcare → cost pressure to persist

• Demand for increased efficiency & efficacy

• Consolidation (laboratories, IVD manufacturers, instruments, automation,

miniaturization, etc.)

• Process & workflow optimization

• Information management (IT solutions)

• Near patient testing and POC when needed

• Nucleic acid diagnostics

• Improved treatment through IVDs (personalized/stratifying medicine)

• New technologies

• New biomarkers

• Standardization & Harmonization


Reference materials: the hidden treasure in IVD

No matter what trends will materialize or not…

IVD results should be the same

in Geel and in Marburg and all over the world

yesterday, today and tomorrow

Reference materials are essential for reliable reference intervals and decision points to diagnose, monitor and treat patients appropriately.


IVD Biomarkers

Gases

Electrolytes / Trace Elements

Metabolites

Amino acids (derivatives)

Lipids

Nucleic Acids

Carbohydrates

Peptides/Proteins

Com

plexityof

analyte


Protein testingis usually close

Proteins will continue to dominatethe emerging IVD biomarker arena

to the phenotype


ProteomicsNew Horizons in Protein Diagnostics?


Despite great expectations and investments for proteomicsendeavour, the success in

delivering new in-vitro diagnosticshas been limited so far!


Major challenges

• Reproducibility & comparability

• Preanalytics including the clinical question & study design

• Transferability to installed base and/or clinical workflow

• Verification challenges by proteomics technologies• Accuracy versus throughput & multiplexing• Challenge to discover & measure low abundance protein

biomarkers in complex samples such as blood specimens

• Verification challenges by immunoassays• Resources & time for assay development (of multiple tests)

(definition of the measurand, antibody development, etc.)


Can we leverage thestrengths of different fields to get clinicalrelevant and standardizedimmunoassays faster to the market for the benefitof healthcare and thepatients?


How can we leverage different strengths

Communication & collaboration

Leverage methodologies and know-how used in different fields

Align & harmonize search for new biomarkers

More rigorous examination of existing biomarkers

Defining the clinically relevant measurand(s)

Leverage existing and develop new reference materials


Reference materials and mass spectrometryfor protein & peptide testing in R&D & IVD

AQUA MassSpectrometry

Reference Materials

ReferenceMeasurement

System

Immunoassaydevelopmentfor a definedmeasurand

Initiate Support

Standardized

Immunoassay

Research &

Developm

ent

In-vitroD

iagnostics

Mass Spectrometry

(Proteomics)Research

ProteomicsResearchStandard

3

45

6

1

2


ID-LC-MS² under consideration as reference measurement procedure

1

C-Reactive Protein

Myoglobin

Cystatin C

Insulin

Etc.


Assessment of manufacturer’s control for Proteomics research purposes

2

Aprotinin

m/z

Vitzthum F, Siest G, Bunk DM, Preckel T, Wenz C, Hoerth P, Schulz-Knappe P, Tammen H, Adamkiewicz J, Merlini G, Anderson NL (2007) Proteomics Clin. Appl. 1, 1016-1035.

Overlay of Mean Differential Peptide Display of Human Plasma (red) and a Manufacturer’s Control (N/T Protein Control SL Level L (blue))

Liqu

id c

hrom

atog

raph

yfra

ctio

n#


„Orientation measurements“

3

Albu

min

IgG

IgG

1Tr

ansf

errin

Fibr

inog

enIg

G 2

a2-m

acro

glob

ulin

Apol

ipop

rote

in A

-Ia1

-ant

itryp

sin

C3c IgA

Apol

ipop

rote

in B

Oro

som

ucoi

dH

emop

exin

IgM

Hap

togl

obin

Apol

ipop

rote

in A

-IIFi

bron

ectin

IgG

3C

erul

opla

smin

Prea

lbum

inAn

tithr

ombi

n III C4

IgG

4Pl

asm

inog

enR

bPAp

olip

opro

tein

EC

RP

sTfR

ß2-M

icro

glob

ulin

Myo

glob

inM

yogl

obin

IgE

Ferri

tinFe

rritin

TPSA

FPSA

MM

BH

CG

TSH

CTN

I --

1E-9

1E-8

1E-7

1E-6

1E-5

1E-4

1E-3

0,01

0,1

1

10

100

Con

cent

ratio

n (g

/L)

Serum Heparin plasma EDTA plasma Citrate plasma Reference intervals

Human ProteomeOrganization

Plasma Protein Project

Pilot Phase

Referencespecimensevaluation withtraceable tests


Assessment of performance of Proteomics methods

4

1E7 1E8 1E9 1E10 1E111E-3

0.01

0.1

1

10

100

Tota

l pro

tein

spec

tral i

nten

sity

[a

rbitr

ary

units

]

Assigned values of N/T Protein Control SL/M [g/L]

Albumin

IgG1

TransferrinIg к chain

C3 Haptoglobin

Ceruloplasmin

Retinol-bindingprotein

Ig α1 chainα2-Macroglobulin

Ig ג chainOrosomucoidTransthyretin

C4

β2-Microglobulin

α1-Antitrypsin

R=0.97

OFFGEL electrophoresis (Agilent Application Note 5989-5814EN) into 24 pI-fractions (pH 4 – 7). Individual fractions were desalted, trypsinatedand analysed by C18-RP-MS/MS.


Clinical research on Factor VII-activating Protease (FSAP)

5

FSAP(HABP2)

F VII & F VIII

TGFs / PAR 1/3, RhoA,Rho kinase

Interactions with cells

NF-kappaB

Coagulation Fibrinolysis

Atherosclerosis

Prourokinase

Cardiac

Cell deathPDGF-BB

Inflammation Matrix Remodeling

Thrombosis


Detection of Marburg I Polymorphism (MRI) of FSAP

6

WT FSAP

LC-MS/MS (Standard Addition Calibration)

MRI FSAP

Calibration line parameters:R2 of 0.9906, 0.9972 (WT and MRI)All points within ± 20% (±25 at LLOQ) precisionAll points within ± 20% (±25 at LLOQ) accuracy

Richard Kay et al.


6

Proteotypic peptide peaks of MR I FSAP

1 µg/mL STD MRI peptide No MRI peptide in plasma

MRI peptide in plama

Richard Kay et al.


6

Plotted peak areas of both MRI peptide transitions

Richard Kay et al.


Conclusions

Reference materials are the hidden treasure in IVD

• Standardization is important to generate high quality results

• Global comparability of test results is key for effective and safeclinical decision making

• International standardization and availability of respective reference materials directly impacts healthcare independent of trends

• Current trends will support reference material development and application

• There may be potential opportunities for standardization & harmonization for biomarker research & development

• Is it time to lift the reference material treasure for R&D?


Thank you for your attention!

status and trends in in-vitro diagnostics and … irmm... · · 2016-06-03• contribute up to 94...

Documents