v0.4.11

What you can do now

A variant file with no index is read. Every reader of a genome file used to
need an index beside it, and the tools that build one are not on a physician's
machine. Such a file is now read once from beginning to end — the catalogue's
positions in both builds, the counts that tell what kind of file it is, and the
header — and no index is written, because one written subtly wrong would be
trusted by every other tool. What that reading cannot answer is refused by
name: a question about a whole region says it needs an index and names the two
commands that make one, rather than answering with an empty list that reads as
«this gene carries no variants».

The screen for what is worth acting on runs from an installed package. The
secondary-findings screen over the 84 ACMG genes does not compute when asked: it
reads a table, and the pass that writes that table lived in the data-preparation
directory, which does not travel with pip install. scholion acmg-scan runs it
now, with no external tools and no index, from the person's variant file and the
published ClinVar file; when that file is missing the command prints the one
download it needs, for the build the person's file is in. Each file's build is
established from the file itself, and a crossed pair — a GRCh37 genome against a
GRCh38 ClinVar — is refused before a single position is compared, because a
crossed pair does not fail: it finds nothing, or matches a position that belongs
to a different base, and both look like an answer.

An exome is told apart from a panel. Breadth used to be probed in windows
that are gene-poor by construction, where an exome is empty, so an exome was
classed as a sparse panel — and that class shuts the ClinVar and ACMG paths, on
the one input where a screen for known pathogenic variants is most obviously
worth running. A second set of probes in gene-dense windows tells the two apart
by contrast. The two paths open on an exome and say what an exome can and cannot
answer; polygenic scores stay shut, because a score summed over the coding two
per cent of the genome has no distribution behind it.

The status says which questions this input can carry, before any finding.
Six paths — catalogue loci, pharmacogenetics, a whole region, ClinVar, the ACMG
panel, polygenic scores — each marked open or shut for this file, with the
reason; «this input cannot carry the answer» is told apart from «the annotation
this path reads has not been produced», which used to be invisible because the
narrower gate fired first and blamed the file for a missing table.

A gene is asked of every shelf that holds anything about one. What this build
knows about a gene sits in four places, each keyed differently — the curated
catalogue by rsID, the ClinVar scan by coordinate, the shipped ACMG secondary
findings panel by symbol, coverage by gene — and nothing joined them. Asking about
a gene read the catalogue alone and answered «not in the coordinate reference»,
which is a statement about one shelf and reads as a statement about the genome. A
clinician asked about the bile-acid transporters and was told there was nothing to
say «even in general terms from your genome», while the ClinVar table on that
machine held 386 findings.

scholion genome --gene X now prints a frame before the findings: what each layer holds,
that it holds nothing, or that it could not be asked and what would let it be. A
gene in the ACMG panel is recognised with no network and no annotation file,
because those 84 symbols travel inside the build — so a question about BRCA1 on a
machine that cannot reach Ensembl gets an answer rather than a shrug.

ClinVar can be asked by gene. scholion clinvar --gene X matches findings to a gene by
COORDINATE — the scan table carries no gene column, and this needs no re-scan of
the genome. A gene whose coordinates cannot be obtained is reported as unresolved,
with what would resolve it, rather than as a gene with no findings.

What is fixed

A row at the position was taken for the locus. The reader took the first
variant row at a catalogue position and built the genotype from that row's own
alleles. A coordinate is not an identity: an insertion, a neighbouring
substitution or a multi-allelic row can stand on the same base, and the genotype
printed then belonged to somebody else's variant while carrying the locus's name
and the label «called». On three clinical files the alleles at the Factor V
Leiden position disagreed with the catalogue in every one. The row is now
chosen, not taken — its alleles must be the catalogue's — and the two ways of
failing to find one are named: another variant on this base, and a reference
base that is not ours at all, which is a statement about the file's build, never
about the person.

A genome file with no index that had been cut short was read up to the cut
and answered «reference» at every position past it. A copy or a download that
did not finish leaves such a file; a heterozygous APOE ε4 carrier could be
printed as a non-carrier under a status line saying the genome was connected.
Such a file is now refused by name — the status says the file ends before its
end — and a reading that dies part-way is answered as a failure rather than as
an empty result.

Two shapes of a gVCF row printed the strongest label the layer has over
stretches that were never read. A reference block whose genotype is a no-call
(./., depth 0 — what a caller writes over an unread region) answered
«confirmed reference»; and a row whose only alternative is a spanning deletion
(*), left behind when a multi-allelic row is split and one half filtered,
answered «confirmed reference» at a base that lies inside a deletion on one
chromosome. The first is now a no-call; the second a refusal naming the allele
found.

A deletion or multi-base change standing on a catalogue base was reported as
«the file is in another build» — a claim about the file made from a row that
merely carried a different variant; it is now «another variant at this
position». A multi-allelic row written with a shared trailing base rendered a
heterozygote as a four-letter string labelled «called»; it now prints the
locus's own allele pair, and a genotype naming an allele of another length
beside ours is refused by name instead of concatenated.

An owner of a genotyping chip saw a status that said the array was connected
and, six lines later, «no genome is connected» on every question — closing
the locus catalogue and the pharmacogenetics a chip answers as designed. The
frame now belongs to the input that answered: the catalogue and
pharmacogenetics are open, a gene region is closed because a chip reads chosen
positions and a gene is a stretch nobody chose, and the screens are closed as
too narrow; a gene query on a chip refuses with the same reason instead of
proceeding without a file.

The secondary-findings screen could report a variant a person does not carry,
and miss one they do. A row whose genotype was not called at all — the
ordinary shape of a family file or a gVCF — was written as a finding, because
«not a reference» was the only test. A row with two alternate alleles was
matched on the pathogenic one and judged from the other, so a person homozygous
for a benign second allele was reported homozygous for the pathogenic first. And
in a file holding several samples the first column was read as the person's: a
mother's BRCA1 heterozygote, screened as her child's. Each is now a named step —
the column is chosen, the allele index is required in the genotype, a no-call is
counted and said with the result — and a call the caller itself flagged as not
PASS is written as filtered rather than decided.

The refusal against matching two builds could be switched off by the one
variable meant to arm it. Declaring the build of a headerless personal file
also declared it for the ClinVar file, so a declared GRCh37 against the
downloaded GRCh38 ClinVar read as «GRCh37 against GRCh37» and ran. The ClinVar
build is now read from the ClinVar file alone. And a personal file whose build
could not be told at all went into the scan with a clean «ok»; it now refuses
and names what closes it, the same way the ClinVar side already did.

The table was written beside the variant file while the screen read it from
the genome folder, so with the file anywhere else the command said «written»
and the screen said «not run». It now lands where the screen looks, and carries
a sidecar saying which builds it was matched in, which ClinVar release, when,
and how many positions were unread — so a stale or crossed table can be told
from a current one.

The advice about external tools described a product that needed them. The
first command a new person types offered four binaries and explained that
without them «the genome layer does not work at all». True when written, false
since a file without an index became readable and the ACMG screen became
runnable. It now says what the four buy — seeking a region or a whole gene, and
the wide ClinVar annotation — and what answers without them.

The gene frame said the wrong thing about a scan that had not run. Asking
about a gene prints, above its findings, which shelves of the build hold
anything about it. When the ClinVar scan had simply never been run, that frame
said the gene's coordinates could not be obtained — sending a person to fetch an
annotation file they did not need — and clinvar --gene blamed a missing or
broken index. Worse, the ACMG line printed «in it, 0 findings» for a panel
nobody had scanned: a false «clean» on a hereditary-cancer gene. Each layer now
says which of three things is true — what it holds, that the scan has not been
run, or that it could not be asked and why — and a warning that only part of the
findings table was read now reaches the frame instead of dying on the way.

The web page still showed a genotype for a position with no row. A position
absent from the variant file means either «reference» or «never read», and the
command line had already stopped rendering that state as an answer. The page
had not: the card printed the reference bases in large type with the caveat in
small type beside it, and a gene listing did the same for every such locus. The
page now prints a dash there, on both views.

A prescription's status could not be set, was erased on re-entry, and stopped
drugs looked current. No writer — command, page or API — could record whether
a drug was current, so for anyone not editing the file by hand every entry was
«no status recorded» while the wording claimed those entries predated the field.
Re-adding a name to change its dose replaced the whole entry, so a stopped drug
came back current with its start date and monitoring gone, silently. And every
listing of the regimen drew a stopped drug like one taken this morning, while the
interaction check had already excluded it. A status can now be written
(add-med --status, a field on the page, status in the API); re-adding merges
and says what it kept; and every listing — command, page, and the context handed
to a model — marks entries that are not current. A pulse course counts as
current everywhere, by one rule.

A gene filter over a truncated scan said the gene was clear. The ClinVar
scan is read a page at a time, and the gene filter took the page: on a profile
with more findings than one read, «0 in this gene» would have been printed
where the finding sat past the cut. The filter now compares what it read with
what exists and says when it could not see everything. In the same pass: a gene
frame that failed to build vanished without a trace and now reports itself
unavailable with the reason; a single letter of a supplement's name matched a
drug and earned it a pharmacogenetic tag, and a match now needs a whole name; a
folded provenance note could still run to three hundred characters and now has
a ceiling.

What the person is taking NOW is asked instead of assumed. Every comparison —
interactions, drug classes, the laboratory monitoring rules, the limitations —
ran against every name in the prescriptions file, so a drug the physician stopped
carried exactly as much weight as one taken this morning. A statin that left the
scheme on the day an azole course was replaced still produced «↑ statin
concentration, risk of myopathy», and beside it a warning about a probiotic
paused six weeks earlier.

A status decides now, and it decides by a WHITE list, so a value nobody taught the
code about is not silently treated as current. An entry with no status at all
stays current: those predate the field, and reading them as stopped would delete
real prescriptions from every check at once — silence where a warning belongs is
the worse mistake. And what was left out is named in the answer, because a red
line that is absent for a reason and a red line nobody computed look identical on
the page.

How well a gene was read comes with the answer about it. Coverage was a
footnote at the bottom of a report, and the question it qualifies is asked one
gene at a time. It now travels beside the answer — and only when it is worth
saying: a gene read in line with the rest of the file is left in silence, a gene
far below it says so and says by how much.

The ruler is the file's own middle, and it was measured before it was chosen. At
20× on a 30× whole genome the callable fraction runs to a median of 79.8 %, with
the best gene of ninety-three at 92 % and none at 95 %: any clinical-looking
threshold therefore fires on 89 of 93 and is measuring the shape of a depth curve
rather than anything about a gene. Against the file's own median, eight fire —
and they are the genes that are hard to sequence for known reasons, X-linked or
carrying a pseudogene. The rule travels with the sequencing depth, so it says
something useful at 30× and at 100×.

Four states, one of them silent. «In line with the rest of this file» is never
reported as «adequate»: what is adequate depends on the question, which the
product does not know. A gene the coverage table does not cover, and a profile
where coverage was never computed, both say so — a silence that means «nobody
measured» is read as reassurance, which is the same mistake as a missing row
printing as «reference».

A position with no row in the file was printed as a confirmed reference. A VCF
of variants has no line where the genome matches the reference, and none where
nothing was read either; the layer calls that state «assumed», and every decision
in the engine already excluded it. The last mile did not. It rendered the state in
the shape of an ANSWER — «genotype TT (reference)» — with the honest note beneath.
On a single locus a reader got both, a reassuring label and a warning contradicting
it on the next line. In a GENE LISTING they got only the first, because a listing
keeps one line per locus and the note is the second.

A physician running this over DPYD — fluoropyrimidines, where the genotype is
required before the first dose — met eight positions labelled reference, six of
which have no row in the file at all. The state is now rendered as the refusal it
is, in one line, so it survives being cut to one line.

A genotype with no curated reading behind it says so. A variant outside the
curated set reached the reader as a bare genotype, and the silence where a reading
should be was filled by whoever was talking: asked about COMT, the product
correctly said the variant is outside its set, and the conversation supplied «the
low-activity variant» from general knowledge with no source inside the product.
The sentence is a statement about this build's catalogue, not about medicine.

A refusal about a drug names which silence it is. «We could not look», «we
looked and there is no such drug» and «we looked, found it, and no guideline for it
is in our copy» wore one sentence. The third now carries the date of the guideline
copy it is a statement about — which is what tells «the literature has nothing»
from «this build is behind».

The regimen says which entries the model can speak about at all. A list of
supplements produced «no interactions found», which is true and uninformative:
most of them are outside pharmacogenetics and always were. Entries with a
gene-drug pair are marked; the rest are named as outside the model rather than
left to look unexamined. Long provenance notes fold to their first sentence — a
list of forty-five entries carrying a paragraph each is not a list anybody reads.

The build says when it is old. It reported a stale reference database and said
nothing about its own age. It now reads its own release date out of the journal it
ships and says so on the first screen once that date is old enough to matter.
Nobody is contacted to find this out: a product whose claim is that the profile
never leaves the disk does not acquire an outbound host to deliver a convenience.

What is retracted

Answers that labelled a position «reference» where the file has no row at it. No
stored value changes — the engine never counted those positions — but a printed
page or an exported summary made before this version may carry the old label, and
for DPYD and CYP2D6 that label reads as permission to prescribe.

A genotype printed at a catalogue locus whose row carried other alleles than the
catalogue's. It was somebody else's variant under our locus's name; it is now
withheld with the reason, so a report made before this version may carry a call
that will not be repeated — the Factor V Leiden conclusion among them.

An exome classed as a sparse panel, with ClinVar and the ACMG screen reported
shut. The same file now opens both paths; the earlier statement about what that
input could answer no longer stands.

What needs recomputing

An ACMG table written by an earlier version was matched without checking that
the personal file and the ClinVar file share a build. If the two were crossed,
the table is a silent zero or a match on a different base. scholion acmg-scan
rebuilds it from the files, refusing a crossed pair; a table whose files were
of one build is unchanged by this.