biochemistry 101

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Biochemistry for Software Developers

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Page 1: Biochemistry 101

Biochemistry for Software Developers

Page 2: Biochemistry 101

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.

Page 3: Biochemistry 101

Objectives

Introduction to biochemistry Biochemistry techniques Prenatal diagnosis Common genetic abnormalities

Page 4: Biochemistry 101

Key Biochem Personnel Senior 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

Page 5: Biochemistry 101

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 Accessioning = Hemanth Kumar (TCS),

Robert Bradford (on security team now) Reporting = Jose George

Page 6: Biochemistry 101

Santa Fe Development Staff Biochem 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

TCS personnel onsite do customer service Srini Srikiram, Triven Mukkala

Analysts (Focused on GeDI) Juan Blea, Tracy Archuleta, Regina Garrick, Jim

Walters, Jeannie Bilbo

Page 7: Biochemistry 101

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

Page 8: Biochemistry 101

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

Page 9: Biochemistry 101

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 partner’s families) have a history of genetic disorders

Twins (or more) Women who have had miscarriages

Page 10: Biochemistry 101

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

Page 11: Biochemistry 101

Robert and His Family

Page 12: Biochemistry 101

Trisomy 21 Karyotype

Page 13: Biochemistry 101

Trisomy 21 = Down’s Syndrome

Results in Down syndrome 1 in 800 liveborn infants ~75% spontaneously abort Phenotypic features

“Dysmorphic” features Mental retardation Low muscle tone Congenital heart disease Gastrointestinal anomalies

Page 14: Biochemistry 101

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

Page 15: Biochemistry 101

Trisomy 18

Page 16: Biochemistry 101

Trisomy 18

Page 17: Biochemistry 101

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.

Page 18: Biochemistry 101

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

General Process 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

Genetic Counseling is the last stage

Page 19: Biochemistry 101

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

Page 20: Biochemistry 101

Analytes hCG: Human Chorionic Gonadotropin PAPP-A: Pregnancy-associated plasma protein A

Low level indicates Down’s AFP: Alpha-fetoprotein

Produced by the fetus and mainly goes away a year after birth

High level indicates NTD, low level indicates Down’s UE3: Unconjugated Estriol

One of three main estrogens Low level is indicative of Down’s, T18

DIA: Dimeric Inhibin A High level is indicative of Down’s

Page 21: Biochemistry 101

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

Page 22: Biochemistry 101

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

Amnio: One-shot amniotic fluid tests AFAFP = Amniotic Fluid AFP

Integrated and Sequential INT-1/INT-2 SEQ-1/SEQ-2

Tay Sachs LSD

Page 23: Biochemistry 101

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

Page 24: Biochemistry 101

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”

Page 25: Biochemistry 101

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

Page 26: Biochemistry 101

Tests and Analytes

Test AFP HCG UE3 DIA PAPP-A

FIRSTSCREEN

X X

SEQ-1 X X

INT-1 X X

Test AFP HCG UE3 DIA PAPP-A

AFAFP X

AFP3 X X X

AFP4 X X X X

MSAFP X

SEQ-2 X X X X X

INT-2 X X X X

Page 27: Biochemistry 101

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

Page 28: Biochemistry 101

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

Page 29: Biochemistry 101

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)

Page 30: Biochemistry 101

Risks and the Math Behind Them It’s 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)

Page 31: Biochemistry 101

Risk Adjustments Anti-Convulsant meds (for epilepsy

patients) Egg Donors

Page 32: Biochemistry 101

Amniocentesis

Amniotic 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

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

Page 33: Biochemistry 101

Amniocentesis Advantages

Testing fetus directly rather than indirectly through expectant mother

Can test for neural tube defects – increased alpha-fetoprotein 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)

Page 34: Biochemistry 101

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

Page 35: Biochemistry 101

Amniocentesis

Page 36: Biochemistry 101

Processing Amniotic Fluid

Page 37: Biochemistry 101

Genetic Disorder Risk Factors Family History Maternal Weight Maternal Age

Age of an egg donor also applies

Mother’s age 

Risk for having a child with Down syndrome

20 1 in 1,60025 1 in 1,30030 1 in 1,00035 1 in 365 40 1 in 90 45 1 in 30

Page 38: Biochemistry 101

Fetal Measurements The role of sonographers

There are differences among them Nuchal Translucency (NT)

At 11-13 weeks, measure the amount of fluid behind the baby’s neck

Crown-to-Rump Length (CRL) How big is the baby from top of head to

buttocks? This measurement drives calculation of

gestational age

Page 39: Biochemistry 101

Tay Sachs A 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 biochemistry

Different codebase Enzyme test and DNA test

Page 40: Biochemistry 101

Tay Sachs New Directions Robots, Robots, Robots

Working with the R&D Lab Dr. Deirdre Thomas is the expert New Assay Under Development

New software, new equipment “Tay Sachs Automation” is biggest Santa

Fe development project at the moment Tied to AJ Panel Not a whole lot shared from an

architecture pipeline perspective

Page 41: Biochemistry 101

Lysosomal Storage Diseases Due to lacking enzymes that break down

bad things; “fatty build up” Gauchers, Niemann-Pick, 40 others… Biochem team wants to integrate into

LMS, but we have a separate application for now

Smallest line, no concrete plans for now Jim Walters is the IT SME

Page 42: Biochemistry 101

Biochem Lab Process

Page 43: Biochemistry 101

A Quick Taste of Biochem IT Systems Biochem Core Pipeline Architecture Biochem LMS Integration Biochem Peripheral Applications Modeling Reporting

Page 44: Biochemistry 101

Biochem Core Pipeline Architecture

DSX (INHIBIN)

DXI (T2 AFP, hCG, UE3)

DPC (T1 hCG, PAPP-A)

Run Creation

Result Tables

B_ASSAY_RESULTSB_AF_RESULT

B_SERUM_RESULTSB_INTEGRATED_RESULT

Analyzer/Verify(VB6)

Supervisor Review(WPF

Application)

Check Run Creation Results

Senior Tech Pulls Data; Check for

Problems and Trends

Analyze Run Data

Review Specimens

Auto-Recalc(WCF

Service)

Case Calculations and Risk

Interpretations

Upload

Upload (WPF

Application)

Modeling(gzuBIO –

VB 6)

Auto-Approval

Manual Approval

Auto-Approval(WCF Service)

gzRep32 (VB6) and REP.EXE

(VB3)

Director Review

REPORTED

Accessioning Tables

AC_SPECIMENAC_SPECIMEN_PROCEDURE

AC_FILEAC_CASE

AC_GEST_AGEAC_PATIENT

AC_RACEAC_RELATIONSHIP

Reporting Tables

Get Sample Data

REP_AFACHEREP_FIRSTSCREEN

REP_INTSCREENREP_AFP3REP_AFP4

REP_MSAFP

Page 45: Biochemistry 101

Biochem LMS Integration

Samples

Amniotic Fluids

Blood

Dried Bloodspot

Report Distribution

Remote Station (VB 6)

Faxing

Autofax

Rightfax

Accessioning

ACC (VB6) Accessioning Tables

AC_SPECIMENAC_SPECIMEN_PROCEDURE

AC_FILEAC_CASE

AC_GEST_AGEAC_PATIENT

AC_RACEAC_RELATIONSHIP

OTHER

Event Recording

Audit Systems

Problem Track

Common Systems

Data Portal

Exception Handling

Entities

Common Components

Security

Notification

Biochemistry Core System

ECI Systems

Accessioning Processes

Page 46: Biochemistry 101

Biochem Peripheral Applications PTRF, PTRF Reminder, gzLink, gzMedians Cancel/Convert, ICIS, gzuDeUnite Call Tracker, gzuMaintain, gzuMRPro Nontech, LSD, Bluesheets, Requeue gzuBIODSX_SF and instrument interface

apps

Page 47: Biochemistry 101

Modeling Part of gzuBIO If you want to understand biochemistry, start

here If you are a biochem developer and do not use

modeling, you aren’t really a biochem developer yet

If you do something new and do not match modeling, your stuff is probably broken

Nonetheless, modeling is complex enough that we find some new issue every week or two

Jim Walters is the SME

Page 48: Biochemistry 101

Modeling

Page 49: Biochemistry 101

Reporting IMPORTANT to distinguish between

reporting a result through a biochem director and physically sending the reports through large reporting support team

Three types of reports: Positive, Negative, Inconclusive Positive is bad, negative is good, Inconclusive

usually because missing some data HOLD-ACC with Client Services Followup

Page 50: Biochemistry 101

Reporting Interpretations based on fragments Most of our reports go out automatically

This includes positives and negatives, but not inconclusives

Getting “director review” to zero is a lucrative goal

Manual Reporting split across REP.EXE and gzRep32

Page 51: Biochemistry 101

Report Curve

Page 52: Biochemistry 101

Reporting: Director Review Data Flow

Upload

Recalc

Modeling Auto-Approval

Reported

DIRREV

Page 53: Biochemistry 101

Cyto and FISH

Diagnose genetic disorders rather than just predict them

Cyto = inspection of karyotypes

FISH = Fluorescence in situ hybridization

FISH uses DNA technology applied to chromosomes

FISH provides higher resolution answers than standard cyto FISH is like like a zoom lens

LOTS of cyto directors

Page 54: Biochemistry 101

1321

18XY

Down’s Syndrome (Male)

Page 55: Biochemistry 101

1321

18XY

Trisomy 18 (Male)

Page 56: Biochemistry 101

Molecular Genetics: FISH

rRNA15cen