University

of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Previous Milestone Lectures

1B (NE 102) Module 1: Nanomaterials Health Risk Assessment Hazard Iden*ca*on, Risk Assessment, Exposure Assessment; External and Internal Dose; Reference Dose; Hazard Index; Life*me Cancer Risk; 2A (Ne 201) Module 2: Nanotoxicology ADME; Inhala*on Eects and Transloca*on; Dermal Eects; Oxida*ve Stress; Cytotoxicity; Neurotoxicity; Genotoxicity, Mutagenicity and Cancer;

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Previous Milestone Lectures

2B (NE 202) Module 3:

Nanomaterials Exposure Assessment and Ecotoxicology

How to protect yourself: Occupa*onal Exposure Assessment; Sampling; Nanometrics; masks/gloves

How to protect the environment: Environmental Fate and Transport Processes, Ecotoxicology; Aqua*c Toxicology; Biopersistence; Biomagnica*on;

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Current / Future Milestone Lectures

3A Module 4: Nanomaterials Consumer Products

What do we know about the nanostu out there? Sensors and Screening; Sensi*vity and Specicity; Posi*ve/Nega*ve Predic*ve Values; Consumer Products (TiO2, Ag, CNT); Consumer Exposure and disease risks; Cosme*cs; Product Life Cycle analysis

3B Module 5: Nanomaterials Risks and Benets How would you know if it aec;ng humans? Epidemiology; How to compare dierent human groups; Rela*ve risks and Odds ra*os; Confounding; Eng. and non-engineered Ultranes; Diesel Exhaust;

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Using Nanoparticles: Making and Understanding Sensors and Medical Screening Devices

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

BETTER SENSORS: CNT and Diabetes

Nanodevices are being proposed as better alternative to current sensors: Based on redox active CNT/metal/metal oxide electrode: enzymatic redox conversion of glucose Current sensors suffer from limited lifetime immune response to sensor.
Cash 2010 Trends Molec. Med. 16:584

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

NEW SENSORS: Gold and Cancer

Bind volatile organic compounds that are known markers for cancer; based on chemoresistance

Mazzone 2009 Nature Nanotech 4:621

Au particles show different patters from healthy and lung cancer patients
Dr Haick Chem Eng. Nanotech Inst, Ben-Gurion Univ., Israel

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

NEW SENSORS: Gold and Cancer

HS-CH2-CH2-R

Thiol-capped 5 nm Au particles ~ 75% effectiveness at catching those with lung tumors ~ 25% false negative rate what is impact of false negative? Healthy Lung Cancer Analysis by GCMS
Peng 2009 Nature Nanotech 4:669

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Comparing your test to the real answer

When you compare your test (or device) to another (say industry standard) or to the actual state of patients, there are two important test results; Sensitivity and Specificity Disease State or standard test + # your sensor + true + false false + true -

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Comparing your test to the real answer

Sensitivity : is the probability that a test result is positive when administered to someone who has the disease. SEN = Disease State or standard test + # your sensor + true + false false + true -

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Comparing your test to the real answer

Specificity: is the probability that a test result is negative when administered to someone who does not have the disease. SPEC = Disease State or standard test + # your sensor + true + false false + true -

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Comparing your test to the real answer

Disease State or standard test + # your sensor + true + false false + true Which is more important, sensitivity or specificity?

Low sensitivity could mean that: _______________________________________ Low specificity would mean that: _______________________________________

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

Comparing your test to the real answer

You make a device to test for a disease and compare your test to the currently used standard. 10 samples compare the tests. What is the sensitivity and specificity for your device? Standard 1. 2. + 3. 4. + 5. 6. + 7. 8. 9. 10. + Yours + + + + + -

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

What if they told you your test was positive?

# Disease State + # your sensor + true + false false + true -

When you are handed a positive test, what you want to know is whether it is real Positive Predictive Value PPV : the probability that a person with a positive result actually has the disease. PPV = _______________

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

What if they told you your test was negative?

# Disease State + # your sensor + true + false false + true -

When you are handed a negative test, what you want to know is whether it is real Negative Predictive Value NPV: the probability that a person with a negative result actually has no disease. NPV = ___________

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

About Sensors: Specific Example HIV

Youve made a sensor for HIV It is used on 100,000 people. Of the 500 HIVpositive people, 475 tested positive, and of the HIV-negative group, 94,525 tested negative. Determine the sensitivity, specificity, positivepredictive and negative-predictive values. Whats going on with the +ve pred. value?

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

About Sensors: Specific Example HIV

Generally, if prevalence is low, PPV is also low. Low PPV means lots of False Positives: False positives: Type I errors: - you rejected the null hypothesis when the null hypothesis was true. You accused the wrong guy False negatives: Type II errors: - failure to reject the null hypothesis when the null hypothesis is true. You let the bad guy go

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

About Sensors: ELISA HIV

HIV test measuring fluorescence from HIV antibody in enzyme-linked immunosorbent assay (ELISA). HIV antigen protein on a surface reacts with antibodies in blood from someone infected with HIV. Antibodies are enzyme linked for detection. High sensitivity: even low levels of antibody detected. Some people without HIV will still have non-specific binding (other antibodies) that leads to some fluorescence: what is cutoff? Lower specificity.

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

About Sensors: ELISA HIV

A,B,C: cutoffs in optical density to separate positive (high density) from negative (low density) result. A: large number of false-positives, no FN B: lower FP but now also FN C: no FP, but high FN
# people HIV-free with HIV A B C

For infec*ous diseases, choose no FN; then retest all posi*ves

Op*cal density ra*o (uorescence intensity)

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

About Sensors: Western Blot

1 .Gel electropheresis separates out by electropheretic mobility blood proteins and looks for HIV proteins. 2. Proteins are moved from gel into separate membrane by blotting, by capillary action. 3. Expensive human antibodies are used to bind to the HIV proteins. 4. Antibody is linked to fluorescent enzyme that is activated upon binding. Antibodies are very structure specific, wrong binding does not occur; No false positives: High spec.

University of Waterloo; Nanomaterial Health Risk Milestone; Dr. L. Deakin

HIV: Run the Cheap Sensor First

ELISA + TP + FP WESTERN BLOT + TP (no FP) TN (+ FN) TN (no FN) HIGH SEN: strong binding HIGH SPEC: specic binding