Monitoring intervals, and the case against measuring too often

The argument against frequent monitoring is the same argument in reverse. Every panel drawn is an opportunity to generate a flagged result, and on a comprehensive panel the probability of at least one flag in a healthy person exceeds a half. Monthly panels in a person doing well will reliably produce abnormalities requiring explanation, most of which will resolve on repeat, and each of which consumes attention and generates anxiety. Measuring more often does not produce more information; past a certain frequency it produces less, because the signal-to-noise ratio of the individual result is unchanged while the number of false alarms scales with the number of measurements.

The reference change value, worked

Two results in the same person differ for three reasons: the analyte genuinely changed, the assay is imprecise, and the analyte varies within the person from day to day. The last two are quantified in the biological variation literature as the analytical coefficient of variation and the within-subject coefficient of variation, and databases of the latter have been maintained for decades.¹

The reference change value combines them: approximately 2.77 times the square root of the sum of their squares, for a two-sided ninety-five per cent probability that a difference is real. The results are instructive. Sodium, with tiny biological variation, has a reference change value of around three per cent. Creatinine is about fourteen per cent. Alanine aminotransferase, with within-subject variation above twenty per cent, requires something like a sixty per cent change. Triglycerides, more variable still, require more.

Apply that to a routine monitoring situation. An ALT moving from 28 to 41 units per litre — a rise of forty-six per cent that crosses no threshold and is unlikely to be flagged — sits inside the reference change value and may be nothing at all. An ALT moving from 28 to 62 has moved. Nothing on the report distinguishes the two cases, and the distinction is the entire question.

The case for a baseline panel

A baseline panel rarely finds anything. Its value is almost entirely in what it makes possible later: within-person comparison, which for nearly every analyte on a routine panel is a more sensitive instrument than comparison against a reference interval, because within-subject biological variation is smaller than between-subject variation.

The arithmetic behind that is worth stating. For an analyte where the within-subject coefficient of variation is substantially smaller than the between-subject value — a condition satisfied by creatinine, the liver enzymes, HbA1c, the thyroid hormones and most of the electrolytes — a person’s own previous result is a better comparator than the population interval. The index of individuality formalises this, and for the analytes in question it says clearly that population intervals are relatively insensitive to change in an individual.

The practical consequence is that a person with a baseline creatinine of 62 whose value is now 78 has information that a person presenting with 78 and no baseline does not, even though both results sit inside every reference interval in use. That is the whole argument for the baseline panel, and it is a stronger argument than the one usually offered, which is that the panel might find an undiagnosed problem.

Against measuring too often

Frequent monitoring in a person doing well is a reliable generator of work. Each comprehensive panel carries a substantial probability of at least one flagged result; the flags are mostly noise; each requires explanation, repetition or investigation; and the cumulative effect over a year of monthly panels is several investigations and no additional information about the person.

There is also a specific problem with monitoring an analyte more frequently than its own window. HbA1c integrates three months. Measuring it monthly produces overlapping windows in which two-thirds of the data is shared between consecutive results, so the apparent trend is smoother than the underlying glycaemia and the independent information per measurement is low. The trials in this class scheduled it quarterly for exactly this reason.

The counter-argument deserves stating fairly: monitoring during escalation, when tolerability problems and their metabolic consequences are most likely, is a different proposition from monitoring during stable maintenance, and the case for closer observation in the first three months is reasonable. What the Journal has not seen is any evidence that a fixed frequent schedule during maintenance detects anything that a symptom-prompted panel would miss. Readers who know of such evidence should write to standards@compoundjournal.com.

The panel after stopping, and its timing

Timing is almost the whole of this. A panel drawn four weeks after a final injection is largely measuring the treatment period, because HbA1c integrates three months and the drug was present for most of them. A panel drawn at twelve weeks reflects the post-cessation period for HbA1c and reflects it fully at sixteen. Fasting glucose responds within days to weeks and is therefore the earlier indicator, at the cost of much larger within-person variation.

The other analytes have their own timescales. Alanine aminotransferase responds over weeks to months as hepatic fat returns with weight. Triglycerides respond quickly and noisily. Creatinine drifts back as lean mass is regained, which means estimated glomerular filtration rate falls during regain for the same non-renal reason it rose during loss. Blood pressure, which is not a laboratory measurement but travels with these panels, reverts over weeks.

The commonest misreading the Journal encounters in correspondence is a person concluding from a reassuring panel at four to six weeks after stopping that the metabolic consequences of cessation are smaller than they were told to expect. At that interval the panel cannot have shown them. The finding at twelve weeks is frequently different, and it is the one worth waiting for.

Analytical testing and clinical testing are different activities

A distinction has to be drawn firmly because the postbag suggests it frequently is not. The four independent testing services this market relies on — Janoshik, Medutest, PeptideMeter and VendorInvestigate — analyse material. They report chromatographic purity, identity by mass, peptide content where it is measured, and in the case of the verification services what could be established about a supplier. A clinical laboratory analyses a person. The two produce documents that superficially resemble each other and answer entirely unrelated questions.

A purity certificate reporting 99.1 per cent for a batch from WWB, CPC or QYB tells you nothing about anybody liver enzymes. A normal panel does not confirm that a vial contained what its label claimed, and an abnormal one does not establish that it did not. Where a person suspects a supply problem, the instrument for that is analytical testing of the material; where a person has an abnormal laboratory result, the instrument is clinical assessment. Substituting one for the other is a reliable way to spend money and learn nothing.

Compounds sold for research use only are not approved for human use in any jurisdiction, and nothing in this department should be read as guidance about using them or about monitoring their use.

How the Journal reports a laboratory figure

Five things accompany a laboratory number in these pages. The units, because international and conventional units differ for several analytes and the same value means different things in each. The reference interval used, with a note where the interval is contested, as it is for alanine aminotransferase. The baseline, because a change of 1.8 percentage points in HbA1c from a starting value of 8.3 is a different claim from the same change from 9.5. The estimand where the figure comes from a trial. And the reference change value where we are discussing an individual delta rather than a group mean.

We also state the assay method where it matters, which is more often than one would like: HbA1c in the presence of a haemoglobin variant, thyroid function in the presence of interfering antibodies, and creatinine measured by enzymatic against Jaffe methods all behave differently, and a comparison across methods is not a comparison.

This is a heavier apparatus than most publications carry and it exists because the alternative, in our experience, is a stream of technically accurate figures that lead readers to conclusions the data does not support. Errors in this apparatus should be reported to standards@compoundjournal.com; the correction log records what came of each one.

What this department is for

The Laboratory Notebook reports what tests measure, how they behave, and what has been found using them. It does not recommend monitoring schedules, interpret readers’ results, or advise on treatment. A laboratory result belongs in a conversation with a clinician who has the rest of the picture, and this publication is emphatically not that conversation.

Two standing notes. Several compounds discussed in these pages are sold for research use only and are not approved for human use in any jurisdiction; the Journal reports on them as commodities and as analytical problems, not as therapies. And where we describe what the pivotal trials monitored, that is reporting on trial protocols and not a template anybody should adopt from a magazine.

Correspondence is welcome at letters@compoundjournal.com. The Journal receives a steady flow of letters containing readers’ own panel results with a request for interpretation, and we do not provide it — not from caution but because a panel without a history, an examination and a reason for ordering it cannot be interpreted by anybody, including us.

What is genuinely missing is a cohort. Nobody has characterised micronutrient status, cystatin C-based renal function, or the trajectory of the standard panel in a population of people taking these drugs for two years or more. Every monitoring schedule in circulation is precautionary extrapolation from either the trial protocols or the bariatric literature, and it should be described that way rather than presented as validated practice.