PCR Fold Amplification Calculator

PCR Fold Amplification Calculator

Theoretical yield as (1 + E) raised to the number of cycles — and what the exponent does to a small efficiency deficit, which is why qPCR efficiency is measured rather than assumed.

PCR Fold Amplification

Efficiency, cycles → fold
Efficiency as a percentage, where 100% means every template molecule is copied every cycle. Take it from a standard curve rather than assuming it; values above 100% are usually an artefact rather than a triumph.
Cycles of amplification. Beyond about 35 to 40 cycles a real reaction has reached plateau, so the theoretical figure increasingly overstates what is actually in the tube.
1,073,741,824× amplificationExample

30 cycles at 100% amplification efficiency

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Formula

fold amplification = (1 + E)^n
E = efficiency as a fraction, so 1.0 is 100%
at E = 1, fold = 2^n
E
amplification efficiency as a fraction. E = 1 means every template molecule present at the start of a cycle is copied during it, so the quantity doubles; E = 0.8 means only 80% are copied and the quantity multiplies by 1.8. The page takes it as a percentage and divides by 100
n
the number of cycles. Because it is the exponent, it multiplies the effect of any efficiency difference — which is the point of the page
(1 + E)
the per-cycle multiplier. The whole behaviour of the formula is in the fact that this number is raised to a power: a 10% shortfall in the multiplier becomes a 20-fold shortfall in yield over thirty cycles, and a 40-fold shortfall over thirty-five
why efficiency is measured
because it cannot be inferred from a successful reaction. An assay at 80% efficiency still produces abundant product and a clean curve; it simply produces 24 times less of it than a 100% assay over 30 cycles, and quantification that assumes doubling gets the wrong answer
what the formula ignores
plateau. Exponential growth is a good description of the early and middle cycles only. Once reagents deplete and product re-anneals in competition with the primers, amplification slows and stops — which is why quantitative PCR measures the cycle at which signal crosses a threshold rather than the amount of product at the end

Worked example

30 cycles at 100% amplification efficiency
Per-cycle multiplier = 1 + 1.00 = 2, so fold = 2³⁰ = 1,073,741,824, about 1.07 × 10⁹
Now drop the efficiency to 80% and change nothing else. The multiplier is 1.8, and 1.8³⁰ = 45,517,160, about 4.55 × 10⁷
The ratio is 1.07 × 10⁹ ÷ 4.55 × 10⁷ = 23.6. A 20 percentage point efficiency deficit costs a factor of nearly 24 in yield over the same 30 cycles
Extend both to 35 cycles and the gap widens further: 2³⁵ is 34,359,738,368 against 1.8³⁵ of 860,077,682, a ratio of just under 40. The same deficit, more cycles, a bigger penalty — that is what an exponent does
The practically important range is subtler. At 95% efficiency, 30 cycles gives 502,386,940 — less than half the yield at 100%, from a 5 percentage point difference that would be easy to miss on a standard curve
This is the assumption the ΔΔCt method makes when it uses a base of 2: that both the target and the reference assay amplify at exactly 100%. Where they do not, the base is wrong for both and the error compounds with the size of the ΔΔCt
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Yield over 30 cycles at different efficiencies

EfficiencyPer-cycle multiplierFold amplificationRelative to 100%
100%2.001,073,741,8241
95%1.95502,386,940about 1/2
90%1.90230,466,618about 1/5
85%1.85103,550,417about 1/10
80%1.8045,517,160about 1/24
70%1.708,193,466about 1/131
Efficiency differences that look small on a standard curve are not small in yield. A 5 percentage point deficit halves the product over thirty cycles; a 10 point deficit costs a factor of five. This is why an efficiency figure is validated rather than assumed, and why the MIQE guidelines ask for it to be published.

Yield at 100% efficiency by cycle number

CyclesFold amplification
101,024
201,048,576
2533,554,432
301,073,741,824
3534,359,738,368
401,099,511,627,776
Every ten cycles is about a thousandfold, and 3.32 cycles is tenfold — the same relationship that makes a standard curve slope of −3.32 correspond to 100% efficiency. The later rows are arithmetic rather than chemistry: no real reaction is still amplifying exponentially at cycle 40.

What an exponent does to a small deficit

The polymerase chain reaction is described by one of the simplest growth models there is. If a fraction E of the template molecules present at the start of a cycle are successfully copied during it, then the quantity is multiplied by (1 + E) each cycle, and after n cycles it has been multiplied by (1 + E) raised to the power n. At perfect efficiency, E = 1, the multiplier is 2 and thirty cycles give 2³⁰ — a little over a thousand million fold. That is the number that makes the technique work: a handful of starting molecules becomes a detectable quantity.

The interesting behaviour is in what happens when E is not 1. At 80% efficiency the multiplier is 1.8 rather than 2, which sounds like a modest shortfall. Over thirty cycles it is not: 1.8³⁰ is about 4.6 × 10⁷ against 1.07 × 10⁹, a factor of nearly 24. Extend both to thirty-five cycles and the same deficit costs a factor of 40. A per-cycle difference of ten per cent becomes an order-of-magnitude difference in yield, because the exponent applies it again and again — and the penalty grows with the number of cycles, not just with the size of the deficit.

The range that matters in practice is narrower and less obvious. At 95% efficiency, thirty cycles gives a little under half the yield of a 100% assay. Five percentage points, and half the product. An assay at 95% or even 90% produces plenty of material and a perfectly convincing amplification curve, so nothing about its appearance announces the deficit. That is exactly why efficiency has to be measured from a standard curve rather than inferred from a reaction that worked, and why the MIQE guidelines ask for the efficiency figure to be published: without it, a quantitative result cannot be evaluated by anyone else.

The quantitative consequence is specific. The ΔΔCt shortcut computes relative expression as 2 raised to the negative ΔΔCt, and the 2 in that expression is precisely the assumption that E = 1 exactly, for the target assay and the reference assay alike. Where an assay runs at 90%, its true base is 1.9, and because the term is exponentiated the error compounds with the size of the ΔΔCt rather than staying a fixed percentage. This page quantifies that assumption; the efficiency calculator measures the quantity it needs; and where the measured efficiencies are not close to 100% and to each other, the Pfaffl method takes them as explicit inputs instead. One caveat applies to everything above: exponential growth describes the early and middle cycles only. Reagents deplete, product re-anneals in competition with the primers, polymerase activity falls, and a real reaction plateaus — which is why quantification reads the cycle at which signal crosses a threshold during the exponential phase and never the amount of product at the end.

Frequently asked questions

How do you calculate fold amplification in PCR?

Fold amplification = (1 + E)^n, where E is the efficiency as a fraction and n the number of cycles. At 100% efficiency (E = 1) over 30 cycles that is 2³⁰ = 1,073,741,824. At 80% efficiency the multiplier is 1.8 and the same 30 cycles give about 4.55 × 10⁷.

How much does low PCR efficiency reduce yield?

Far more than the efficiency figure suggests, because the deficit compounds. Over 30 cycles, 95% efficiency gives about half the yield of 100%, 90% about a fifth, and 80% about a twenty-fourth. Over 35 cycles the 80% penalty widens to about a fortieth.

Why does qPCR efficiency have to be measured rather than assumed?

Because an inefficient assay still looks like a working one. An assay at 90% efficiency produces abundant product and a clean curve, but yields a fifth of what a 100% assay would over 30 cycles — and any quantification assuming doubling gets the wrong answer. Efficiency comes from a standard curve.

What does the 2 in 2^-ΔΔCt assume?

That one cycle doubles the product, for both the target and the reference assay — that is, that both run at exactly 100% efficiency. This page quantifies what that assumption costs when it is wrong: at 90% the true base is 1.9, and the error compounds with the size of the ΔΔCt.

Can amplification efficiency exceed 100%?

Not really. An apparent efficiency above 100% usually means primer-dimer or non-specific product contributing signal, an inhibitor being diluted out along the standard curve and lifting its low points, or a pipetting error in the dilution series. Investigate it rather than reporting it.

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References

  1. Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611–622.
  2. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods. 2001;25(4):402–408.
  3. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001;29(9):e45.
  4. Svec D, Tichopad A, Novosadova V, Pfaffl MW, Kubista M. How good is a PCR efficiency estimate: recommendations for precise and robust qPCR efficiency assessments. Biomol Detect Quantif. 2015;3:9–16.

Not medical advice. For healthcare professionals and education. Reference intervals vary by laboratory and assay — always use your own laboratory's. Never base a dose or a treatment decision on this page alone. Full disclaimer at calcengines.com/disclaimer/