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Choose a group sequential design. Randomize patients among the three arms, schedule interim analyses after prespecified amounts of information, and calculate the two Wald test statistics at each look. Prespecify efficacy boundaries and a futility rule; allow early stopping of an ineffective experimental arm or of the trial when sufficiently convincing efficacy evidence is obtained. Calibrate the boundaries for both repeated looks and the two shared-control comparisons so that the familywise error rate remains controlled. An alpha-spending function is one way to allocate the error probability across looks.

Two potential benefits are lower expected recruitment and shorter duration when a treatment is clearly effective or futile, and earlier identification of benefit or lack of benefit, reducing continued exposure to an ineffective experimental treatment. These benefits concern expected performance; the maximum sample size may still be required.

Two drawbacks are the extra operational work needed for rapid, reliable outcomes and confidential interim analyses, and more complicated inference: repeated testing requires adjusted boundaries, and ordinary fixed-sample effect estimates and confidence intervals can be misleading after data-dependent stopping. Continuing two comparisons against a shared control also requires care if an arm is stopped.

Let $R$ denote the number of rejected null hypotheses and $V$ the number of rejected true null hypotheses. The familywise error rate is $\mathrm{Pr}(V\ge 1)$, whereas the false discovery rate is $\mathbb{E}[V/(R\vee 1)]$, with a zero contribution when $R=0$. A valid true-null p-value satisfies $\mathrm{Pr}(p_i\le t)\le t$ for $0\le t\le 1$.

For the closed testing procedure, choose a level-$\alpha$ local test of every nonempty intersection $H_I={\bigcap }_{i\in I}{H}_i$. Reject $H_i$ only if every intersection containing it is rejected by its local test. If any true null hypothesis is rejected, the local test of $H_{I_0}$ must reject. Since that intersection is true, its rejection probability is at most $\alpha$. If $I_0$ is empty there can be no false rejection. This proves strong closed-testing control of the familywise error rate, under arbitrary dependence, provided each local test is valid under its whole intersection null.

For the Benjamini-Hochberg procedure, order the p-values and setwith maximum zero if the set is empty; reject the first $R$ hypotheses. To prove its false discovery rate bound, fix a true-null index $i$. Replace $p_i$ by zero and let $R_i$ be the modified rejection count. This is a function of the other p-values and satisfies $R_i\ge 1$.

The Benjamini-Hochberg leave-one-out identity isHere is its deterministic justification. If $i$ was rejected, lowering its value cannot decrease $R$, and leaves all ordered values of ranks greater than $R$ unchanged. No such rank can newly satisfy its threshold, so $R_i=R$. Conversely, if $R_i=r$ and $p_i\le \alpha r/m$, at least $r-1$ other values and $p_i$ are at most this threshold. Therefore the original procedure has $R\ge r$. Monotonicity under decreasing $p_i$ also gives $R\le R_i=r$, so $R=r$ and $i$ is rejected. This establishes the identity; harmless deterministic tie-breaking also covers the artificial zero introduced in the modified data.

The assumed independence makes $p_i$ independent of $R_i$. Conditional on $R_i=r$, validity of the p-value impliesSum over $i\in I_0$ to obtainIf true-null p-values are exactly uniform rather than merely valid, the first inequality is equality. No restriction on dependence among the false-null p-values is needed beyond their joint independence from the true-null values.

For the requested Simes inequality, apply this result to the $m_0$ true-null p-values alone, for $m_0>0$. Every rejection is now false, so $V=R$ and the false discovery rate is the probability of any rejection. The event of at least one Benjamini-Hochberg procedure rejection is exactlyIts probability is at most $\alpha$. This holds for $\alpha \in [0,1]$; with no true nulls the written minimum and division by $m_0$ are undefined and the error-control statement is instead vacuous.

The final step-up rule is the Hochberg procedure. Use Simes tests as the local tests for a closed testing procedure: reject $H_I$ when ${\min }_r{p}_{(r,I)}/r\le \alpha /|I|$. Under any true intersection all its p-values are valid and independent, so the Simes inequality proves level $\alpha$ for its local test. The implication supplied in the question says that whenever the Hochberg procedure rejects $H_{(i)}$, every intersection containing $(i)$ passes its local Simes test. Thus every such rejection is also a closed-testing rejection. ConsequentlyThe true-null independence assumption is essential to this particular proof of local-test validity; the arbitrary-dependence guarantee of closed testing does not create valid local tests automatically.

Under the intended additional assumption of mutually independent, continuously calibrated null p-values, each test fails to reject with probability $0.95$. The familywise error rate is thereforeThere is a qualification to the printed use of “not correlated”: zero pairwise correlation coefficients do not generally imply mutual independence. A multivariate normal distribution with zero off-diagonal covariances does give independence, but an arbitrary biomarker distribution need not. The formula above requires independent rejection events, not just uncorrelated measurements.

The usual intuition for positively dependent tests is that they reject together, reducing the effective number of opportunities for a false positive. A rigorous sufficient assumption is positive association of random variables for the rejection indicators $I_1,\dots ,I_{10}$. Products of their non-rejection indicators are decreasing functions; association and induction giveThus under this stronger positive-dependence assumption the probability is no larger, and perfect dependence gives $0.05$ instead of $0.4013$. Strict inequality is not forced by every form of positive dependence.

Pairwise positive correlation coefficients alone, as printed, is insufficient. For a counterexample choose a vector of ten exchangeable random variables that are rejection indicators as follows: with probabilities $0.545,0.450,0.005$, respectively, reject none, reject one uniformly selected test, or reject all ten. Thenbut the familywise error rate is $0.455>1-0.95^{10}$. This can be realized with valid null p-values: conditional on the indicators, independently draw $p_i$ uniformly on $(0,0.05)$ if $I_i=1$ and on $(0.05,1)$ otherwise. Every $p_i$ is uniform on $(0,1)$, and $\mathrm{Cov}(p_i,p_j)=0.25\mathrm{Cov}(I_i,I_j)>0$. Taking biomarker statistics $X_i=1-p_i$ gives pairwise positively correlated null statistics with exactly these one-sided tests. Therefore the unconditional larger-or-smaller claim needs a specified dependence model.

Estimate the signal by one-dimensional total variation denoising, which penalizes adjacent differences rather than the constant level:This is a fused Lasso objective. Its L1 norm penalty makes many adjacent differences exactly zero, producing a piecewise-constant fit. For change-point detection, estimate the locations by $\hat{S}=\{i:{\hat{\mu }}_i\ne {\hat{\mu }}_{i+1}\}$. The tuning parameter controls the strength of the penalty; it can be chosen, for example, using a validation criterion appropriate to the noise model.

For a general family of elementary nulls $H_1,\dots ,H_m$, the closed testing procedure forms every nonempty intersection $H_B={\bigcap }_{j\in B}{H}_j$ and gives it a local test of level $\alpha$. Reject $H_j$ precisely when all intersections with $j\in B$ are locally rejected. This gives strong control of the familywise error rate: let $T_0$ be the indices of the true elementary nulls. If $T_0$ is empty there is no false rejection. Otherwise, rejecting any $H_j$ with $j\in T_0$ requires rejection of the true intersection $H_{T_0}$. Its local test has rejection probability at most $\alpha$, henceThis proof of closed-testing control of the familywise error rate needs no independence of the tests.

For the interval procedure, a true tested interval is contained in one maximal constant block $B\in \mathcal{T}$. If $I\subseteq B$, the intervals over which $p_B$ takes its maximum are a subset of those used for $p_I$, so $p_I\ge p_B$. Therefore rejection of a true $I$ forces rejection of its containing block. Conversely, a rejected block is itself a rejected true null.

There is a small indexing issue in the PDF: its testing family excludes singleton intervals, while $\mathcal{T}$ may contain singleton blocks. Put ${\mathcal{T}}_{\ast }=\{B\in \mathcal{T}:|B|\ge 2\}$. Every true tested interval lies in one of these blocks, so the exact statement, using only hypotheses defined in the paper, isSingleton blocks contain no eligible tested interval and can be ignored. Equivalently, one may define their nulls as never rejected.

For each $B\in {\mathcal{T}}_{\ast }$, the term $J=B$ occurs in the maximum defining $p_B$, giving $p_B\ge n{q}_B/|B|$. A valid p-value is a super-uniform random variable under its null, so for $0\le \alpha \le 1$,The union bound and disjointness of the constant blocks now giveThis establishes weighted interval testing for a piecewise-constant mean even when the interval p-values are dependent. Values $p_I>1$ do not affect rejection at levels at most one.

A procedure controls the familywise error rate at level $\alpha$ when, for every configuration of true nulls $I$,Let $i_{\ast }=\min I$. The step-down procedure can reject any true null only if it reaches and rejects $H_{i_{\ast }}$, which requires $p_{i_{\ast }}\le \alpha$. Since a valid p-value under its null satisfies $\mathbb{P}(p_{i_{\ast }}\le \alpha )\le \alpha$, the procedure controls FWER without any assumption on dependence among the p-values.

A distribution $P$ has the global Markov property for a directed acyclic graph $G$ when every D-separation statement $A{\perp }_{G}B\mid C$ implies the corresponding conditional independence $Z_A\perp \perp Z_B\mid Z_C$ under $P$.

If $G\in \mathcal{S}$ has nonadjacent vertices $j,k$, choose a topological ordering. Suppose $j$ precedes $k$. Then $j$ is a non-descendant and non-parent of $k$, so the directed local Markov property givesThe reversed ordering case is analogous. HenceUse the intersection-union test: reject $H_0$ exactly when $p_S\le \alpha$ for every $S$. Under $H_0$, at least one $H_{S_{\ast }}$ is true, soThis is nontrivial because it rejects whenever every tested conditional independence is rejected.

The familywise error rate isThe Bonferroni correction rejects $H_i$ when $p_i\le \alpha /m$. Since a valid p-value is super-uniform under its null, the union bound givesNo independence assumption is needed.

For the closed testing procedure, form the intersection hypothesis $H_I={\bigcap }_{i\in I}{H}_i$ for every nonempty $I\subseteq \{1,\dots ,m\}$ and choose a level-$\alpha$ local test for each $H_I$. Reject $H_i$ exactly when every $H_I$ with $i\in I$ is rejected by its local test. If any true $H_i$ is rejected, then the intersection $H_{I_0}$ of all true nulls is rejected. Since its local test has significance level $\alpha$,This is the closed-testing control of the familywise error rate.

Write $W={\sum }_{j=1}^m{w}_j$. Procedure (A) is the Weighted Bonferroni correction: it rejects $H_i$ when $p_i\le \alpha w_i/W$. Therefore

Procedure (B) is the Weighted Holm step-down procedure. Let $k$ be the first rank in the ordering $q_{(1)}<\cdots <q_{(m)}$ whose hypothesis is a true null, and put $W_0={\sum }_{i\in I_0}{w}_i$. If any true null is rejected, the procedure reaches step $k$ andbecause every true null remains among ranks $k,\dots ,m$. Henceand another union bound gives FWER at most $\alpha$.

At step $k$, procedure (B) divides by the total weight still under consideration, which is no larger than $W$. Its critical values therefore increase as hypotheses are rejected. Moreover, if procedure (A) would reject a hypothesis, every earlier ordered $q$ also passes the initial threshold, so procedure (B) reaches and rejects it. Thus (B) contains every rejection of (A) and can make strictly more rejections while retaining the same strong FWER control.

Let $I_0=B^c$ and $m_0=|I_0|$. Each $q_j$ with $j\in I_0$ is a valid p-value by the argument in part c. If the Holm step-down procedure selects any index from $I_0$, let $r$ be the rank of the first such index. All $r-1$ earlier selections belong to $B$, soSelection through rank $r$ impliesConsequentlyThus the procedure controls the familywise error rate without requiring independence among the p-values.

Under the intersection null, every rejection is false, so the false-discovery proportion is $1_{\{R>0\}}$ and its expectation is the familywise error rate. Because the p-values are independent and exactly uniform, every super-uniform inequality in part (b) is an equality. Here $|I_0|=m$, and thereforeEquivalently, the order-statistic identity in the hint gives the same equality by induction on $m$.

A random vector $X$ is positively associated if $\mathrm{Cov}(f(X),g(X))\ge 0$ for every pair of coordinatewise nondecreasing bounded functions $f,g$. The same inequality holds when both are nonincreasing, by negating them. Repeatedly applying it to products of nonnegative increasing indicators gives $\mathbb{P}({\bigcap }_i{E}_i)\ge {\prod }_i\mathbb{P}(E_i)$ for increasing events; the same is true for decreasing events. Thus associated rejection indicators have familywise error rate no greater than independent indicators with the same marginals. Pairwise positive correlation coefficients alone do not give this stronger property. The classical definition is in Esary, Proschan and Walkup (1967).

For positive deterministic weights $w_i$, the weighted Bonferroni correction rejects $H_i$ whenThe union bound over the true nulls controls the familywise error rate without an independence assumption.

Given valid p-values $q_J$ for constancy on intervals of length at least two, reject $I$ when ${\max }_{J\supseteq I}n{q}_J/|J|\le \alpha$. Every rejected true interval forces rejection of its maximal constant block. A union bound over the non-singleton maximal blocks gives familywise error rate at most $\alpha$, since their lengths sum to at most $n$. Singleton blocks have no tested interval in this formulation.