
What is the difference between Signal/Cut off and the usual EIA index o Pushed by CDC, who pointed out one can avoid confirmatory tests for Hepatitis C diagnosis if reports the EIA index and that value is above a given threshold. One that varies by instrument. o So some labs report these tests as ordinals, using the test specific threshold – which when pos is a really a positive.- and report three grads, neg, intermediate, positive o Two questions
 Is a sig/cutoff any different than a EIA index (standard EIA tests)
 Do labs actually report quan sig/cut off and if so how do they indicate the pos vs. confirmed

What we need in submissions (and are not always getting o Need submitter’s order, and test, name ( would be nice to get the submitter’s local codes for these as well)
 Needed to find inconsistencies in what is really being reported versus the way it was conceptualized in LOINC by the submitter (and/or by LOINC home)
 Need them to help pick the best of alternatives when many exist.
 Need the order name (code) so that we can identify what the submitter defines as a panel- to make sense of “test codes” that are not tests per se and only make sense when associated with real test codes, and to grist for defining formal panels in LOINC o For most new tests we absolutely need kit vender and package insert .
 Get them very reliably from some high volume submitters
 If send out then provide the reference lab name and test number o Have to get answer lists for any test that is reported off a menu (Ords and Noms) we have to get your answer list. So we really know what is intended and so we have a real life example answer list for any ordinal or nominal code. (These are not normative). o Units of measure that you use in the test –that we mostly get now

Clean up or ancient use of ACNC as place holder for property among ORD tests o Historically have used ACNC as a “filler” for the property in the case of ordinal laboratory tests. This was never right and we have long intended to change it o Internally, most automated laboratory test that have ordinal scales, are based on a numerical reading and when that reading is above a threshold specified in the package insert its reported as a positive and below a negative. Sometimes the package insert provides more than one threshold, below the first its neg, between the first and second, indeterminate, and above the third positive.
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 o When we can tell the ordinal test is based on an internal (but not reported) numeric value, and thresholds (or cut off) we are defining the property as
“threshold” because that is a the name used in IUPAC’s silver book. . When don’t that there is an underlying number we will call them “presence”. There is no fundamental difference between these two semantics—and we should never have two terms one with property of presence and one with property of threshold- but with all of the other parts the same. We have begun this process and will try to eliminate “ACNC” as a property for ordinal terms entirely in the next year.
Clean up of enzyme (and other measures within blood cells) o Find them reported with three different properties (But trending toward one) will illustrate with enzyme measures such as G6PD on red cells-same applies to WBCs and platelets
 EntCCnc Amount per cell (or per billion cells
 CCnt amount of enzyme per gram of hemoglobin (this is probably the best and most accurate- and is becoming dominant way to report
 CCnc amount of enzyme in red spun or packed red cells o Think there is a better way to represent the component for two of these
 EntCnc <enzyme>/Red blood cells EntCcNC Bld
 CCNT <enzyme>/Hemoglobin CcNT
 Not sure how to represent the last one
 <enzyme> CCnc Bld.Spun

We have other terms with specimen. Somehow they are measuring the volume of red cells to adjust compute the concentration- but do they really spin the bld then measure the enzymes or do the figure the total volume of RBCs from the
MCV and RBC count. If so how to describe it.

Reporting Allele results o Variant 1. Two terms one for allele 1 and one for allele 2
 40833-6 SOD1 gene allele 1 [Identifier] in Blood or Tissue by Molecular genetics method Nominal
 51951-2 UGT1A1 gene allele 1 [Identifier] in Blood or Tissue by Molecular genetics method
Nominal

42940-7 GALT gene allele 1 [Presence] in Blood by Molecular genetics method
 42938-1 CFTR gene allele 1 [Presence] in Blood or Tissue by Molecular genetics method
 40461-6 GJB1 gene allele 1 [Identifier] in Blood or Tissue by Molecular genetics method Nominal
 First four are problematic – because no answer lists and no hint of which of many possible mutations may be reported (except last one—but that one has no answer list
2

o Variant 2 – allele 1, allele 2
 49631-5 ATN1 gene allele 1.CAG repeats [Entitic number] in Blood or
Tissue by Molecular genetics method
 This one is OK because it reports the number of repeats for the genes for which the repeats predict seriousness , but many labs just report the normal, high or very high ( ordinal based on some cut off o Variant 3a
 34731-0 APOE gene allele 1 [Identifier] in Blood or Tissue by Molecular genetics method Nominal
 34732-8 APOE gene allele 2 [Identifier] in Blood or Tissue by Molecular genetics method Nominal
 34733-6 APOE gene allele 3 [Identifier] in Blood or Tissue by Molecular genetics method Nominal

34735-1 APOE gene allele 4 [Identifier] in Blood or Tissue by Molecular genetics method
 There are three isoforms of APOE, first detected by isoelectric focusing. These se might correspond to the APOE allele 2 through 4. But not at all clear what these terms really expect as answers
 These are described as star (*) alleles o Variant 3b
Pharmaco genomic terms that are have * notation o Variant 4
 Apo lipoprotein E phenotyping [Identifier] in Blood
 Has answer list for picking one of the four alleles
 Or mutation analysis that lists just the explicit alleles found

Bring up to emphasize the importance of complete submissions. If we had demanded answer lists and sample reports for all of these we would not have these ambiguous terms

Two kinds of things we have to deal with o Reporting can be at the allele level which may represent complex mappings between combinations of specific mutations to some important summary attribute expressed by the allele notation and might map to increase or decrease in drug activity as is the case in pharmaco genomics o Reporting can also include the individual mutations that lead up to the allelic state o In many cases have to identify the state in each chromosome. What convention to use
 Two tess one for Alelle1 the other for Allele 2?
 One test with syntax for reporting the states of both alleles in one value

E.g. “*4/*9” where the first string in front of the “/” represents the allelic state of one chromosome and one after the “/” represent the state of the other.

Like the 2 nd option, and see it a lot, but need to have a reference
(authority) to the reporting syntax to include in the test description.

Want to avoid nar scales for anything that is typically is or could be reported as structured results. Huge complicated things might still be reported as narrative globs might be exception but even these can usually report the core results in structured way using HGVS syntax for mutations. Standard naming rules for alleles and ISCN for cytogenetics.
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
Who/how to pull together labs and instrument venders to come up with common reporting styles

Homocysteine versus Homocystine
Best we can tell these two chemicals can not be distinguished by analytic methods because they interconvert so quickly.
We have about 19 terms with homocysteine in the component and about 21 with Homocystine in the component. (Believe the equilibrium shifts to one of them in most analytic processes
We have four terms of the form:
72501-0 Homocyst(e)ine [Moles/volume] in Serum or Plasma --6 hours post dose methionine
Where the homcyst(e)ine is meant to convey the idea that the two are interchangeable
However the usual LOINC way to say that you are measuring both regardless of which is there is
Homocystine+homocysteine
We are assuming they are not distinguishable and should either be represented as a sum or
(maybe-but a different convention) with the parentheses, and would have to pick one representation and retire some of the many terms we have with both forms.
But we have at least two past (Old) submissions for both terms at the same time, and wonder if these can be distinguished with some kind of mass spec or nuclear magnetic resonance.
One example of a pair of terms requested for each term spe
13758-8 Homocysteine/Creatinine [Mass Ratio] in Urine
13759-6 Homocystine/Creatinine [Mass Ratio] in Urine
Pubchem reports homocysteine as follows below
Quesiton. Are they reall not distinguishable
(CID 49791978 )
Also known as: 2-ammonio-4-sulfanylbutanoate, 2-azaniumyl-4-sulfanylbutanoate,
CHEBI:58065
Molecular Formula: C
4
H
9
NO
2
S Molecular Weight: 135.18476 InChIKey :
4

A thiol-co of METHIONINE. ntaining amino acid formed by a demethylation
(CID
69382 )
Also known as: Homocystine, L-, 626-72-2,
AC1L2BQQ, AC1Q5S8T, HMDB00676, EINECS
210-962-5, 4,4'-dithiobis-2-amino-L-Butyrate, AR-
1J2004, SBB067836
Molecular Formula: C
8
H
16
N
2
O
4
S
2
Molecular
Weight: 268.35364
APOE gene
Three common APOE alleles have been identified: APOE*2, APOE*3, and
APOE*4. The corresponding three major
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isoforms, E2, E3, and E4, are recognized according to their relative position after isoelectric focusing. Different mutations causing the same migration pattern after isoelectric focusing define different isoform subtypes. The most common isoform is E3 and is present in 40-90% of the population. Common APOE variants influence lipoprotein metabolism in healthy individuals.
Defects in APOE are a cause of hyperlipoproteinemia type 3 (HLPP3)
[MIM: 107741 ]; also known as familial dysbetalipoproteinemia. Individuals with HLPP3 are clinically characterized by xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause.
The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease
(CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD. Ref.16
Ref.26
Ref.27
Ref.29
Involvement in disease
Genetic variations in APOE are associated with
Alzheimer disease type 2 (AD2) [MIM: 104310 ]. It is a late-onset neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. Note=The APOE*4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease.
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Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known. Ref.16
Defects in APOE are a cause of sea-blue histiocyte disease (SBHD) [MIM: 269600 ]; also known as seablue histiocytosis. This disorder is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses. Ref.16
Ref.33
Ref.36
Defects in APOE are a cause of lipoprotein glomerulopathy (LPG) [MIM: 611771 ]. LPG is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries. It mainly affects people of Japanese and
Chinese origin. The disorder has rarely been described in Caucasians. Ref.16
Ref.3
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