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Biochemistry 101

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Text of Biochemistry 101

Biochemistry for Software Developers

Important Disclaimer This

presentation is intended for IT use only and is intended as background information only. It is not a substitute for speaking with a qualified clinician, which you should do if you have a question on biochemistry fundamentals.

Objectives Introduction

to biochemistry Biochemistry techniques Prenatal diagnosis Common genetic abnormalities

Key Biochem Personnel Director = Dr. Phil Wyatt, M.D. Directors = Faye Myrick, Stan Marenberg, Deirdre Thomas Lab Manager = Nancy Maner Senior Techs = Doris Langley, Kim Pritchard Arielle Mills Senior

Santa Fe Development SMEs Biochemistry

= Jim Walters, Joe Francis

Jim specializes in legacy, especially gzuBIO and Modeling. Jim is on the BSA team now, but is still an SME Joe specializes in new apps, especially AutoApp, Review, and Upload Biochemistry requires a team effort

= Hemanth Kumar (TCS), Robert Bradford (on security team now) Reporting = Jose George Accessioning

Santa Fe Development StaffBiochem is 75% of our business Development staff = Joe Francis and Gary Topp Biochem Project Manager = Mary Sorvig Three QA staff know biochem well

Carlos Guevara, Vickie Sievers, Ram Turaga Training Indira Varanasi and Vanita Patel Srini Srikiram, Triven Mukkala Juan Blea, Tracy Archuleta, Regina Garrick, Jim Walters, Jeannie Bilbo

TCS personnel onsite do customer service

Analysts (Focused on GeDI)

Prenatal Genetic Concerns 46

chromosomes in 23 pairs

Some people have an extra chromosome, a trisomy

Downs

Syndrome (T21) T18 (Edwards Syndrome) Neural Tube Defects (Spina Bifida mainly) T13 is common, but is a FISH test

Genetic Disorder Screening Only Healthy

pregnant women typically get four sets of labs

Test happen only when indicated

First

prenatal visit

Pregnancy test, Pap smear, Blood type and Rh type, Antibody screen, HCT/HGB (CBC), Rubella, VDRL, Urine, HBsAg, HIV

GG

handles the second set of labs Unrelated set of labs in eight month Unrelated set of labs in ninth month

Who Should be Screened? Women

over 35 Women with a history of problem pregnancies Women with medical problems like high blood pressure, diabetes, asthma, or epilepsy Women whose families (or partners families) have a history of genetic disorders Twins (or more) Women who have had miscarriages

When Does Screening Take Place? Late

in first trimester at 10.4 weeks to 13.9 week gestational age

Optimally 10-12 weeks

Second

trimester at 14.0 weeks to 21.9 weeks gestational age

Optimally 16-18 weeks

Robert and His Family

Trisomy 21 Karyotype

Trisomy 21 = Downs Syndrome Results

in Down syndrome 1 in 800 liveborn infants ~75% spontaneously abort Phenotypic featuresDysmorphic features Mental retardation Low muscle tone Congenital heart disease Gastrointestinal anomalies

Trisomy 18

1 in 10,000 liveborn infants ~95% spontaneously abort Characteristic features

Small for gestational age Characteristic hand posturing with overlapping fingers Small face and chin Rocker-bottom feet

Trisomy 18

Trisomy 18

Neural Tube Defects Open

spina bifida (OSB)

Latin for split spine Is the spinal cord closed?Other

NTD conditions involve non-fusion of brain and are worse.

Screening vs. Diagnosis

Our biochemistry tests cannot diagnose a genetic condition

That is where cyto comes in if needed

Biochemistry tests do suggest the likelihood of a genetic condition

There will be some false positives and false negatives Physician orders a non-invasive test If non-invasive test suggests risk, Amniocentesis is typically ordered along with chromosome analysis, which will diagnose a problem Other tests are 80-90% accurate; amnios are 99% accurate

General Process

Genetic Counseling is the last stage

Genetic Counseling We

have counselors that travel the country, often with bad news Must be board certified in genetic counseling Also serve as SMEs internally Work closely with Client Services

AnalyteshCG: Human Chorionic Gonadotropin PAPP-A: Pregnancy-associated plasma protein A

Low level indicates Downs Produced by the fetus and mainly goes away a year after birth High level indicates NTD, low level indicates Downs One of three main estrogens Low level is indicative of Downs, T18 High level is indicative of Downs

AFP: Alpha-fetoprotein

UE3: Unconjugated Estriol

DIA: Dimeric Inhibin A

Specimen Types Serum

(Blood) Amniotic Fluid Dried Bloodspot Occasional Outliers like cystic hygroma

Five Lab Flows

One-shot serum (blood) tests

FIRSTSCREEN: Uses NT as well MSAFP = Maternal serum AFP AFP3 = Three marker test AFP4 = Four marker test AFAFP = Amniotic Fluid AFP INT-1/INT-2 SEQ-1/SEQ-2

Amnio: One-shot amniotic fluid tests

Integrated and Sequential

Tay Sachs LSD

Tests Ordered in 2008 as of 10/5/08 817247

total 75378 Sequentials 71885 AFP4 55232 FIRSTSCREEN 44521 AFAFP 32309 Integrateds 15216 MSAFP 3689 AFP3

Integrated and Sequential Tests Test

late in first trimester and early in second trimester Integrated reports only after result of second serum Sequential reports on 1st trimester results, then again in 2nd trimester Full Integrated adds non-chemistry markers

Not separated at database level

302 issue

IT Issues Around INT and SEQ Linking

What if two different patients are used for these procedures

PTRF/PTRF

Reminder

Need to remind clients to call patients to come in for the second part of the test

Tests and AnalytesTest FIRSTSCREEN SEQ-1 INT-1 AFP HCG X X X UE3 DIA PAPP-A X X X

Test AFAFP AFP3 AFP4 MSAFP SEQ-2 INT-2

AFP X X X X X X

HCG

UE3

DIA

PAPP-A

X X

X X X

X X

X X

X X

X

Multiple of the Median (MoM) How

far does an individual test result deviate from the median? Need results from several hundred women at each GA to establish a set of medians Used for a variety of medical screening tests where the medians are highly variable Medians are sometimes updated

Multiple of the Median (MoM) Experienced

personnel can simply look at the MoMs and visualize the risks Simple math: Divide the chemistry test result by the median for that population; it will ideally come out to 1.0 and should not deviate much from 1.0 Weight correction factors

We truncate the weight at high and low weights (90 and 280 lbs?) for calculation purposes, but not for reporting purposes

MoM Adjustments Twins

Hard limits on triplets and no risk assessment available at all for higher parity

Ethnic

Origin

Native Japanese African-American Other distinctions could be made Insulin-dependent

diabetes (IDDM)

Risks and the Math Behind ThemIts all about statistics and accumulated experience Calculate the MoM from the raw chemistry values Use the MoMs to calculate the risk Moderately complex mathematics

Logarithmic equations Calculator project to refine/redefine what we are doing

Gestational Age: How many days/weeks since conception?

Weeks GA used to drive the calculation coefficient GA Methods include Ultrasound, CRL measurement, and Last Menstrual Period (LMP)

Risk Adjustments Anti-Convulsant Egg

meds (for epilepsy patients)

Donors

Amniocentesis fluid provides a sterile environment and cushion for unborn baby 14 21 Weeks Gestation (most at ~16 weeks with ~30cc fluid) Early amnios done at 12 weeks (little fluid) Fluid contains skin cells/gut cells from baby Chorionic Villus Sampling Amniotic

Takes a piece of the placenta Can be done in first trimester, but is more risky

Amniocentesis Advantages

Testing fetus directly rather than indirectly through expectant mother Can test for neural tube defects increased alphafetoprotein in amniotic fluid indicates a 90% chance of a neural tube defect

Disadvantages

Later in pregnancy 1/2% chance of pregnancy loss due to the procedure (miscarriage, bleeding, infection)

Amniocentesis Ultrasound

always done before the Amnio CHROM test (cyto analysis) almost always ordered with Amnio Separated cells must be cultured in cyto lab to have enough for analysis

No culturing necessary for biochemistry screening tests

AChE

(Acetylcholinesterase) test often added

Depends on how Amnio results are looking

HGB

Amniocentesis

Processing Amniotic Fluid

Genetic Disorder Risk FactorsFamily History Maternal Weight Maternal Age

Mothers age

Risk for having a child with Down syndrome

Age of an egg donor also applies

20 25 30 35 40 45

1 in 1,600 1 in 1,300 1 in 1,000 1 in 365 1 in 90 1 in 30

Fetal Measurements The

role of sonographers Translucency (NT)

There are differences among them At 11-13 weeks, measure the amount of fluid behind the babys neck

Nuchal

Crown-to-Rump

Length (CRL)

How big is the baby from top of head to buttocks? This measurement drives calculation of gestational age

Tay Sachs lysosomal storage disease Children develop normally, but slowly deterioriate and die by the age of five Cherry red spot in each eye Not a part of mainstream biochemistryA

Different codebase

Enzyme

test and DNA test

Tay Sachs New

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