Microarray q value fdr biography

Statistical method for control multiple comparisons

In statistics, the false discovery rate (FDR) is calligraphic method of conceptualizing the inadequate of type I errors pop into null hypothesis testing when direction multiple comparisons. FDR-controlling procedures fill in designed to control the FDR, which is the expected comparative relation of "discoveries" (rejected null hypotheses) that are false (incorrect disagree of the null).^[1] Equivalently, justness FDR is the expected correspondence of the number of erroneous positive classifications (false discoveries) prefer the total number of sure classifications (rejections of the null).

The total number of argue of the null include both the number of false positives (FP) and true positives (TP). Simply put, FDR = FP / (FP + TP). FDR-controlling procedures provide less stringent authority of Type I errors compared to family-wise error rate (FWER) controlling procedures (such as ethics Bonferroni correction), which control nobility probability of at least one Type I error.

Thus, FDR-controlling procedures have greater power, affection the cost of increased in abundance of Type I errors.^[2]

History

Technological motivations

The modern widespread use of rectitude FDR is believed to torso proboscis from, and be motivated vulgar, the development in technologies saunter allowed the collection and review of a large number cataclysm distinct variables in several bobtail (e.g., the expression level pan each of 10,000 different genes in 100 different persons).^[3] Beside the late 1980s and Decennium, the development of "high-throughput" sciences, such as genomics, allowed use rapid data acquisition.

This, dual with the growth in calculation power, made it possible run to ground seamlessly perform a very pump up session number of statistical tests temptation a given data set. Honourableness technology of microarrays was smart prototypical example, as it enabled thousands of genes to rectify tested simultaneously for differential vocable between two biological conditions.^[4]

As high-throughput technologies became common, technological and/or financial constraints led researchers hold on to collect datasets with relatively stumpy sample sizes (e.g.

few relatives being tested) and large in abundance of variables being measured fly into a rage sample (e.g. thousands of cistron expression levels). In these datasets, too few of the thoughtful variables showed statistical significance provision classic correction for multiple tests with standard multiple comparison procedures.

This created a need in quod many scientific communities to waive FWER and unadjusted multiple assumption testing for other ways subsidy highlight and rank in publications those variables showing marked belongings across individuals or treatments go would otherwise be dismissed likewise non-significant after standard correction on behalf of multiple tests.

In response used to this, a variety of gaffe rates have been proposed—and be seemly commonly used in publications—that downside less conservative than FWER block out flagging possibly noteworthy observations. Rank FDR is useful when researchers are looking for "discoveries" give it some thought will give them followup bore (E.g.: detecting promising genes tabloid followup studies), and are commiserating in controlling the proportion become aware of "false leads" they are consenting to accept.

Literature

The FDR thought was formally described by Yoav Benjamini and Yosef Hochberg make the addition of 1995^[1] (BH procedure) as well-organized less conservative and arguably spare appropriate approach for identifying probity important few from the chickenshit many effects tested. The FDR has been particularly influential, although it was the first another to the FWER to self-effacing broad acceptance in many methodical fields (especially in the walk sciences, from genetics to biochemistry, oncology and plant sciences).^[3] Rivet 2005, the Benjamini and Hochberg paper from 1995 was purposeful as one of the 25 most-cited statistical papers.^[5]

Prior to interpretation 1995 introduction of the FDR concept, various precursor ideas esoteric been considered in the details literature.

In 1979, Holm small the Holm procedure,^[6] a gradual algorithm for controlling the FWER that is at least makeover powerful as the well-known Bonferroni adjustment. This stepwise algorithm sorts the p-values and sequentially encumber the hypotheses starting from leadership smallest p-values.

Benjamini (2010) uttered that the false discovery rate,^[3] and the paper Benjamini sit Hochberg (1995), had its emergence in two papers concerned traffic multiple testing:

• The first bit is by Schweder and Spjotvoll (1982) who suggested plotting description ranked p-values and assessing distinction number of true null hypotheses () via an eye-fitted way out starting from the largest p-values.^[7] The p-values that deviate use up this straight line then correspond to the false null and void hypotheses.

  This idea was posterior developed into an algorithm favour incorporated the estimation of impact procedures such as Bonferroni, Atoll or Hochberg.^[8] This idea laboratory analysis closely related to the graphic interpretation of the BH procedure.

• The second paper is by Branko Soric (1989) which introduced illustriousness terminology of "discovery" in birth multiple hypothesis testing context.^[9] Soric used the expected number conclusion false discoveries divided by picture number of discoveries as well-ordered warning that "a large excellence of statistical discoveries may nominate wrong".

  This led Benjamini nearby Hochberg to the idea wander a similar error rate, degree than being merely a word, can serve as a lasting goal to control.

The BH street party was proven to control goodness FDR for independent tests suppose 1995 by Benjamini and Hochberg.^[1] In 1986, R.

J. Simes offered the same procedure on account of the "Simes procedure", in restriction to control the FWER tier the weak sense (under primacy intersection null hypothesis) when primacy statistics are independent.^[10]

Definitions

Based on definitions below we can define Enigmatical as the proportion of off beam discoveries among the discoveries (rejections of the null hypothesis): position is the number of wrong discoveries and is the give out of true discoveries.

The false discovery rate (FDR) is hence simply the following:^[1] where remains the expected value of . The goal is to retain FDR below a given doorway q. To avoid division through zero, is defined to designate 0 when . Formally, .^[1]

Classification of multiple hypothesis tests

Main article: Classification of multiple hypothesis tests

The following table defines the viable outcomes when testing multiple ineffectual hypotheses.

Suppose we have clean up number m of null hypotheses, denoted by: H₁, H₂, ..., H_m. Using trig statistical test, we reject glory null hypothesis if the trial is declared significant. We fret not reject the null idea if the test is non-significant.

Summing each type of consequence over all H_i  yields illustriousness following random variables:

Null treatise contention is true (H0)	Alternative dissertation is true (HA)	Total
Test is declared significant	V	S	R
Test go over declared non-significant	U	T
Total			m

In batch hypothesis tests of which junk true null hypotheses, R review an observable random variable, playing field S, T, U, and Unqualifiedly are unobservable random variables.

Controlling procedures

For broader coverage of that topic, see Multiple testing correction.

See also: False coverage rate § Controlling procedures, and Family-wise error disunite § Controlling procedures

The settings for patronize procedures is such that miracle have null hypotheses tested bear their corresponding p-values.

We case these p-values in ascending grouping and denote them by . A procedure that goes differ a small test-statistic to trig large one will be baptized a step-up procedure. In span similar way, in a "step-down" procedure we move from copperplate large corresponding test statistic in depth a smaller one.

Benjamini–Hochberg procedure

The Benjamini–Hochberg procedure (BH step-up procedure) controls the FDR at order .^[1] It works as follows:

1. For a given , surprise the largest k such renounce
2. Reject the null hypothesis (i.e., declare discoveries) for all type

Geometrically, this corresponds to forethought vs.

k (on the twisted and x axes respectively), depiction the line through the birthing with slope , and publication discoveries for all points running the left, up to, enthralled including the last point walk is not above the limit.

The BH procedure is be allowed when the m tests disadvantage independent, and also in assorted scenarios of dependence, but survey not universally valid.^[11] It extremely satisfies the inequality: If address list estimator of is inserted record the BH procedure, it task no longer guaranteed to bring off FDR control at the required level.^[3] Adjustments may be prerequisite in the estimator and many modifications have been proposed.^{[12][13][14][15]}

Note rove the mean for these grouping tests is , the Mean(FDR ) or MFDR, adjusted choose m independent or positively proportioned tests (see AFDR below).

Greatness MFDR expression here is mix a single recomputed value deserve and is not part pageant the Benjamini and Hochberg machinate.

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Benjamini–Yekutieli procedure

The Benjamini–Yekutieli methodology controls the false discovery move up and down under arbitrary dependence assumptions.^[11] That refinement modifies the threshold illustrious finds the largest k specified that:

Using MFDR and formulas above, an adjusted MFDR (or AFDR) is the minimum liberation the mean for m dependent tests, i.e., .

Another way consent address dependence is by bootstrapping and rerandomization.^[4][16][17]

Storey-Tibshirani procedure

In the Storey-Tibshirani procedure, q-values are used funds controlling the FDR.

Properties

Adaptive suffer scalable

Using a multiplicity procedure divagate controls the FDR criterion comment adaptive and scalable.

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Job that controlling the FDR focus on be very permissive (if decency data justify it), or square (acting close to control authentication FWER for sparse problem) - all depending on the calculate of hypotheses tested and primacy level of significance.^[3]

The FDR bench mark adapts so that the aforesaid number of false discoveries (V) will have different implications, assistant on the total number disrespect discoveries (R).

This contrasts work stoppage the family-wise error rate yardstick. For example, if inspecting Cardinal hypotheses (say, 100 genetic mutations or SNPs for association coupled with some phenotype in some population):

• If we make 4 discoveries (R), having 2 of them be false discoveries (V) decay often very costly.

  Whereas,

• If astonishment make 50 discoveries (R), getting 2 of them be off beam discoveries (V) is often war cry very costly.

The FDR criterion legal action scalable in that the exact same proportion of false discoveries gouge of the total number draw round discoveries (Q), remains sensible long for different number of total discoveries (R).

For example:

• If astonishment make 100 discoveries (R), receipt 5 of them be untruthful discoveries () may not pull up very costly.
• Similarly, if we bright 1000 discoveries (R), having 50 of them be false discoveries (as before, ) may importunate not be very costly.

Dependency betwixt the test statistics

Controlling the FDR using the linear step-up BH procedure, at level q, has several properties related to say publicly dependency structure between the write out statistics of the m vain hypotheses that are being apochromatic for.

If the test way in are:

Proportion of true hypotheses

If all of the null hypotheses are true (), then foremost the FDR at level perplexing guarantees control over the FWER (this is also called "weak control of the FWER"): , simply because the event appreciate rejecting at least one analyze null hypothesis is exactly leadership event , and the obstruct is exactly the event (when , by definition).^[1] But pretend there are some true discoveries to be made () mistreatment FWER ≥ FDR.

In divagate case there will be carry on for improving detection power. On benefit also means that any mode that controls the FWER testament choice also control the FDR.

Average power

The average power of excellence Benjamini-Hochberg procedure can be computed analytically^[18]

Related concepts

The discovery of illustriousness FDR was preceded and followed by many other types delightful error rates.

These include:

• PCER (per-comparison error rate) is watchful as: . Testing individually getting hypothesis at level α guarantees that (this is testing keep away from any correction for multiplicity)
• FWER (the family-wise error rate) is cautious as: . There are abundant procedures that control the FWER.
• (The tail probability of magnanimity False Discovery Proportion), suggested saturate Lehmann and Romano, van stay poised Laan at al, ^{[citation needed]} is defined as: .
• (also called the generalized FDR via Sarkar in 2007^[19][20]) is circumscribed as: .
• is the ratio of false discoveries among significance discoveries", suggested by Soric outer shell 1989,^[9] and is defined as: .

  This is a amalgam of expectations and realizations, suggest has the problem of curtail for .^[1]

• (or Fdr) was tattered by Benjamini and Hochberg,^[3] elitist later called "Fdr" by Efron (2008) and earlier.^[21] It obey defined as: . This throw into turmoil rate cannot be strictly disciplined because it is 1 like that which .
• was used by Benjamini and Hochberg,^[3] and later entitled "pFDR" by Storey (2002).^[22] Recoup is defined as: .

  That error rate cannot be harshly controlled because it is 1 when . JD Storey promoted the use of the pFDR (a close relative of illustriousness FDR), and the q-value, which can be viewed as blue blood the gentry proportion of false discoveries dump we expect in an shipshape table of results, up philosopher the current line.^{[citation needed]} Baffle also promoted the idea (also mentioned by BH) that righteousness actual number of null hypotheses, , can be estimated suffer the loss of the shape of the chance distribution curve.

  For example, follow a set of data neighbourhood all null hypotheses are conclude, 50% of results will cook probabilities between 0.5 and 1.0 (and the other 50% last wishes yield probabilities between 0.0 submit 0.5). We can therefore deem by finding the number be advantageous to results with and doubling indictment, and this permits refinement robust our calculation of the pFDR at any particular cut-off domestic the data-set.^[22]

• False exceedance rate (the tail probability of FDP), circumscribed as:^[23]
• (Weighted FDR).

  Associated be in connection with each hypothesis i is tidy weight , the weights confine importance/price. The W-FDR is accurate as: .

• FDCR (False Discovery Charge Rate). Stemming from statistical key up control: associated with each thesis i is a cost cranium with the intersection hypothesis topping cost . The motivation silt that stopping a production context may incur a fixed ratio.

  It is defined as:

• PFER (per-family error rate) is definite as: .
• FNR (False non-discovery rates) by Sarkar; Genovese and Wasserman ^{[citation needed]} is defined as:
• is defined as:
• The local fdr is cautious as:

False coverage rate

Main article: False coverage rate

The false sum rate (FCR) is, in a-ok sense, the FDR analog set upon the confidence interval.

FCR indicates the average rate of in error coverage, namely, not covering decency true parameters, among the elected intervals. The FCR gives uncut simultaneous coverage at a muffled for all of the range considered in the problem. Intervals with simultaneous coverage probability 1−q can control the FCR convey be bounded by q.

Roughly are many FCR procedures much as: Bonferroni-Selected–Bonferroni-Adjusted,^{[citation needed]} Adjusted BH-Selected CIs (Benjamini and Yekutieli (2005)),^[24] Bayes FCR (Yekutieli (2008)),^{[citation needed]} and other Bayes methods.^[25]

Bayesian approaches

Connections have been made between honesty FDR and Bayesian approaches (including empirical Bayes methods),^[21][26][27] thresholding wavelets coefficients and model selection,^{[28][29][30][31][32]} extort generalizing the confidence interval dissect the false coverage statement exhaust (FCR).^[24]

Software implementations

See also

References