P-hacking in clinical trials and how incentives shape the distribution of results across phases.

Abstract:

:Clinical research should conform to high standards of ethical and scientific integrity, given that human lives are at stake. However, economic incentives can generate conflicts of interest for investigators, who may be inclined to withhold unfavorable results or even tamper with data in order to achieve desired outcomes. To shed light on the integrity of clinical trial results, this paper systematically analyzes the distribution of P values of primary outcomes for phase II and phase III drug trials reported to the ClinicalTrials.gov registry. First, we detect no bunching of results just above the classical 5% threshold for statistical significance. Second, a density-discontinuity test reveals an upward jump at the 5% threshold for phase III results by small industry sponsors. Third, we document a larger fraction of significant results in phase III compared to phase II. Linking trials across phases, we find that early favorable results increase the likelihood of continuing into the next phase. Once we take into account this selective continuation, we can explain almost completely the excess of significant results in phase III for trials conducted by large industry sponsors. For small industry sponsors, instead, part of the excess remains unexplained.

authors

Adda J,Decker C,Ottaviani M

doi

10.1073/pnas.1919906117

subject

Has Abstract

pub_date

2020-06-16 00:00:00

pages

13386-13392

issue

24

eissn

0027-8424

issn

1091-6490

pii

1919906117

journal_volume

117

pub_type

杂志文章
  • CASFISH: CRISPR/Cas9-mediated in situ labeling of genomic loci in fixed cells.

    abstract::Direct visualization of genomic loci in the 3D nucleus is important for understanding the spatial organization of the genome and its association with gene expression. Various DNA FISH methods have been developed in the past decades, all involving denaturing dsDNA and hybridizing fluorescent nucleic acid probes. Here w...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1515692112

    authors: Deng W,Shi X,Tjian R,Lionnet T,Singer RH

    更新日期:2015-09-22 00:00:00

  • Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.

    abstract::Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1708839115

    authors: Rawson S,Bisson C,Hurdiss DL,Fazal A,McPhillie MJ,Sedelnikova SE,Baker PJ,Rice DW,Muench SP

    更新日期:2018-02-20 00:00:00

  • Molecular cloning and sequence analysis of expansins--a highly conserved, multigene family of proteins that mediate cell wall extension in plants.

    abstract::Expansins are unusual proteins discovered by virtue of their ability to mediate cell wall extension in plants. We identified cDNA clones for two cucumber expansins on the basis of peptide sequences of proteins purified from cucumber hypocotyls. The expansin cDNAs encode related proteins with signal peptides predicted ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.92.20.9245

    authors: Shcherban TY,Shi J,Durachko DM,Guiltinan MJ,McQueen-Mason SJ,Shieh M,Cosgrove DJ

    更新日期:1995-09-26 00:00:00

  • A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system.

    abstract::The mitogen-activated kinase activating death domain protein (MADD) that is differentially expressed in neoplastic vs. normal cells (DENN) was identified as a substrate for c-Jun N-terminal kinase 3, the first demonstration of such an activity for this stress-activated kinase that is predominantly expressed in the bra...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.5.2586

    authors: Zhang Y,Zhou L,Miller CA

    更新日期:1998-03-03 00:00:00

  • Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity.

    abstract::Ciliary Neurotrophic Factor (CNTF) was first characterized as a trophic factor for motor neurons in the ciliary ganglion and spinal cord, leading to its evaluation in humans suffering from motor neuron disease. In these trials, CNTF caused unexpected and substantial weight loss, raising concerns that it might produce ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.061034298

    authors: Lambert PD,Anderson KD,Sleeman MW,Wong V,Tan J,Hijarunguru A,Corcoran TL,Murray JD,Thabet KE,Yancopoulos GD,Wiegand SJ

    更新日期:2001-04-10 00:00:00

  • An α/β-hydrolase fold protein in the biosynthesis of thiostrepton exhibits a dual activity for endopeptidyl hydrolysis and epoxide ring opening/macrocyclization.

    abstract::Thiostrepton (TSR), an archetypal bimacrocyclic thiopeptide antibiotic that arises from complex posttranslational modifications of a genetically encoded precursor peptide, possesses a quinaldic acid (QA) moiety within the side-ring system of a thiopeptide-characteristic framework. Focusing on selective engineering of ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1612607113

    authors: Zheng Q,Wang S,Duan P,Liao R,Chen D,Liu W

    更新日期:2016-12-13 00:00:00

  • DNA methyltransferase 3B regulates duration of neural crest production via repression of Sox10.

    abstract::Neural crest stem cells arise within the central nervous system but then undergo an epithelial-to-mesenchymal transition to migrate away and contribute to the peripheral nervous system and craniofacial skeleton. Here we show that DNA methyltransferase 3B (DNMT3B) is responsible for the loss of competence of dorsal neu...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1318408111

    authors: Hu N,Strobl-Mazzulla PH,Simoes-Costa M,Sánchez-Vásquez E,Bronner ME

    更新日期:2014-12-16 00:00:00

  • Formation of benzene in the interstellar medium.

    abstract::Polycyclic aromatic hydrocarbons and related species have been suggested to play a key role in the astrochemical evolution of the interstellar medium, but the formation mechanism of even their simplest building block--the aromatic benzene molecule--has remained elusive for decades. Here we demonstrate in crossed molec...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1012468108

    authors: Jones BM,Zhang F,Kaiser RI,Jamal A,Mebel AM,Cordiner MA,Charnley SB

    更新日期:2011-01-11 00:00:00

  • Partial purification of an enzyme from Saccharomyces cerevisiae that cleaves Holliday junctions.

    abstract::An enzyme from Saccharomyces cerevisiae that cleaves Holliday junctions was partially purified approximately 500- to 1000-fold by DEAE-cellulose chromatography, gel filtration on Sephacryl S300, and chromatography on single-stranded DNA-cellulose. The partially purified enzyme did not have any detectable nuclease acti...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.82.21.7247

    authors: Symington LS,Kolodner R

    更新日期:1985-11-01 00:00:00

  • Multiple ligands for cytoadherence can be present simultaneously on the surface of Plasmodium falciparum-infected erythrocytes.

    abstract::A major virulence factor of Plasmodium falciparum is the adherence of parasitized erythrocytes to the wall of postcapillary venules via a specific interaction between parasite-derived erythrocyte surface ligands and receptors on endothelial cells. To study this phenomenon in vitro, we selected a parasite population th...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.91.23.10805

    authors: Chaiyaroj SC,Coppel RL,Novakovic S,Brown GV

    更新日期:1994-11-08 00:00:00

  • Poliovirus polypeptide precursors: expression in vitro and processing by exogenous 3C and 2A proteinases.

    abstract::Plasmids have been constructed to generate substrates for the study of proteinases 2A and 3C of poliovirus. They contain the P1 (capsomer precursor) region of the poliovirus genome or P1 and part of P2 (a nonstructural precursor), which can be transcribed and translated in vitro. A transcript containing the entire 5' ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.12.4002

    authors: Nicklin MJ,Kräusslich HG,Toyoda H,Dunn JJ,Wimmer E

    更新日期:1987-06-01 00:00:00

  • Contribution of phenotypic heterogeneity to adaptive antibiotic resistance.

    abstract::Antibiotic-resistant isolates of Salmonella enterica were selected on plates containing lethal concentrations of rifampicin, kanamycin, and nalidixic acid. The stability of the resistance phenotype was scored after nonselective growth. Rifampicin-resistant (Rif(r)) isolates were stable, suggesting that they had arisen...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1316084111

    authors: Sánchez-Romero MA,Casadesús J

    更新日期:2014-01-07 00:00:00

  • Antibody-dependent enhancement of influenza disease promoted by increase in hemagglutinin stem flexibility and virus fusion kinetics.

    abstract::Several next-generation (universal) influenza vaccines and broadly neutralizing antibodies (bNAbs) are in clinical development. Some of these mediate inhibitions of virus replication at the postentry stage or use Fc-dependent mechanisms. Nonneutralizing antibodies have the potential to mediate enhancement of viral inf...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1821317116

    authors: Winarski KL,Tang J,Klenow L,Lee J,Coyle EM,Manischewitz J,Turner HL,Takeda K,Ward AB,Golding H,Khurana S

    更新日期:2019-07-23 00:00:00

  • High-resolution optical imaging of functional brain architecture in the awake monkey.

    abstract::Optical imaging of the functional architecture of cortex, based on intrinsic signals, is a useful tool for the study of the development, organization, and function of the living mammalian brain. This relatively noninvasive technique is based on small activity-dependent changes of the optical properties of cortex. Thus...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.24.11559

    authors: Grinvald A,Frostig RD,Siegel RM,Bartfeld E

    更新日期:1991-12-15 00:00:00

  • Configuration Interaction in the Calculation of Oscillatory and Rotatory Intensities of Nonplanar pi-Electronic Systems.

    abstract::The interaction of configurations, including all possible singly excited configurations, is incorporated into the calculation of oscillatory and rotatory intensities of simple nonplanar pi-electronic systems such as skewed butadiene and acrolein. The results are discussed in terms of the reliability of the (self-consi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.67.4.1727

    authors: Cheong KK,Oshita A,Caldwell DJ,Eyring H

    更新日期:1970-12-01 00:00:00

  • Full-length CD4 electroinserted in the erythrocyte membrane as a long-lived inhibitor of infection by human immunodeficiency virus.

    abstract::Recombinant full-length CD4 expressed in Spodoptera frugiperda 9 cells with the baculovirus system was electroinserted in erythrocyte (RBC) membranes. Of the inserted CD4, 70% was "correctly" oriented as shown by fluorescence quenching experiments with fluorescein-labeled CD4. The inserted CD4 displayed the same epito...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.10.4409

    authors: Zeira M,Tosi PF,Mouneimne Y,Lazarte J,Sneed L,Volsky DJ,Nicolau C

    更新日期:1991-05-15 00:00:00

  • Algal ancestor of land plants was preadapted for symbiosis.

    abstract::Colonization of land by plants was a major transition on Earth, but the developmental and genetic innovations required for this transition remain unknown. Physiological studies and the fossil record strongly suggest that the ability of the first land plants to form symbiotic associations with beneficial fungi was one ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1515426112

    authors: Delaux PM,Radhakrishnan GV,Jayaraman D,Cheema J,Malbreil M,Volkening JD,Sekimoto H,Nishiyama T,Melkonian M,Pokorny L,Rothfels CJ,Sederoff HW,Stevenson DW,Surek B,Zhang Y,Sussman MR,Dunand C,Morris RJ,Roux C,Wong GK

    更新日期:2015-10-27 00:00:00

  • Natal dispersal driven by environmental conditions interacting across the annual cycle of a migratory songbird.

    abstract::Natal dispersal, the process through which immature individuals permanently depart their natal area in search of new sites, is integral to the ecology and evolution of animals. Insights about the underlying causes of natal dispersal arise mainly from research on species whose short dispersal distances or restricted di...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0710732105

    authors: Studds CE,Kyser TK,Marra PP

    更新日期:2008-02-26 00:00:00

  • Differential regulation of S-region hypermutation and class-switch recombination by noncanonical functions of uracil DNA glycosylase.

    abstract::Activation-induced cytidine deaminase (AID) is essential to class-switch recombination (CSR) and somatic hypermutation (SHM) in both V region SHM and S region SHM (s-SHM). Uracil DNA glycosylase (UNG), a member of the base excision repair (BER) complex, is required for CSR. Strikingly, however, UNG deficiency causes a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1402391111

    authors: Yousif AS,Stanlie A,Mondal S,Honjo T,Begum NA

    更新日期:2014-03-18 00:00:00

  • The timing of phasic transmitter release is Ca2+-dependent and lacks a direct influence of presynaptic membrane potential.

    abstract::Ca2+ influx through voltage-gated Ca2+ channels and the resulting elevation of intracellular Ca2+ concentration, [Ca2+]i, triggers transmitter release in nerve terminals. However, it is controversial whether in addition to the opening of Ca2+ channels, membrane potential directly affects transmitter release. Here, we ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2433276100

    authors: Felmy F,Neher E,Schneggenburger R

    更新日期:2003-12-09 00:00:00

  • In vitro synthesis of RNA that contains polyadenylate by virion-associated RNA polymerase of vesicular stomatitis virus.

    abstract::The RNA synthesized in vitro by the virion-associated RNA-instructed RNA polymerase of purified vesicular stomatitis virus contains polyadenylate sequences. These have been demonstrated by their partial resistance to pancreatic and T(1) ribonucleases and their capacity to bind to poly(U) filters and oligo(dT)-cellulos...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.70.12.3566

    authors: Banerjee AK,Rhodes DP

    更新日期:1973-12-01 00:00:00

  • A single dose of doxorubicin-functionalized bow-tie dendrimer cures mice bearing C-26 colon carcinomas.

    abstract::The antitumor effect of doxorubicin (DOX) conjugated to a biodegradable dendrimer was evaluated in mice bearing C-26 colon carcinomas. An asymmetric biodegradable polyester dendrimer containing 8-10 wt % DOX was prepared. The design of the dendrimer carrier optimized blood circulation time through size and molecular a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0607705103

    authors: Lee CC,Gillies ER,Fox ME,Guillaudeu SJ,Fréchet JM,Dy EE,Szoka FC

    更新日期:2006-11-07 00:00:00

  • Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism.

    abstract::Myosin-binding protein C (MyBP-C) is an accessory protein of striated muscle thick filaments and a modulator of cardiac muscle contraction. Defects in the cardiac isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- and fibronectin-like domains and a cMyBP-C-specific motif. In vitro studies show that in addi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1316001111

    authors: Mun JY,Previs MJ,Yu HY,Gulick J,Tobacman LS,Beck Previs S,Robbins J,Warshaw DM,Craig R

    更新日期:2014-02-11 00:00:00

  • Allometric scaling of plant life history.

    abstract::Plant mortality and birth rates are critical components of plant life history affecting the stability of plant populations and the ecosystems they form. Although allometric theory predicts that both plant birth and mortality rates should be size-dependent, this prediction has not yet been tested across plants ranging ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0703476104

    authors: Marbà N,Duarte CM,Agustí S

    更新日期:2007-10-02 00:00:00

  • VIPER is a genetically encoded peptide tag for fluorescence and electron microscopy.

    abstract::Many discoveries in cell biology rely on making specific proteins visible within their native cellular environment. There are various genetically encoded tags, such as fluorescent proteins, developed for fluorescence microscopy (FM). However, there are almost no genetically encoded tags that enable cellular proteins t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1808626115

    authors: Doh JK,White JD,Zane HK,Chang YH,López CS,Enns CA,Beatty KE

    更新日期:2018-12-18 00:00:00

  • Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules.

    abstract::Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer's. Here, we report on a direct force me...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1513172112

    authors: Chung PJ,Choi MC,Miller HP,Feinstein HE,Raviv U,Li Y,Wilson L,Feinstein SC,Safinya CR

    更新日期:2015-11-24 00:00:00

  • Long-chain fatty acids activate calcium channels in ventricular myocytes.

    abstract::Nonesterified fatty acids accumulate at sites of tissue injury and necrosis. In cardiac tissue the concentrations of oleic acid, arachidonic acid, leukotrienes, and other fatty acids increase greatly during ischemia due to receptor or nonreceptor-mediated activation of phospholipases and/or diminished reacylation. In ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.14.6452

    authors: Huang JM,Xian H,Bacaner M

    更新日期:1992-07-15 00:00:00

  • The subtilisin E gene of Bacillus subtilis is transcribed from a sigma 37 promoter in vivo.

    abstract::A cloned Bacillus subtilis gene (sprE) expressed only during the stationary growth phase is shown to encode the subtilisin E protease, an enzyme associated with sporulation. We have determined the DNA sequence of the sprE promoter region and the promoter-proximal half of the structural gene. The sprE gene codes for a ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.81.4.1184

    authors: Wong SL,Price CW,Goldfarb DS,Doi RH

    更新日期:1984-02-01 00:00:00

  • Partitioning of atmospherically relevant ions between bulk water and the water/vapor interface.

    abstract::Recently, surface-sensitive spectroscopy data and molecular dynamics simulations have generated intense interest in the distribution of electrolyte ions between bulk water and the air/water interface. A partitioning model for cations and anions developed for biopolymer surface is extended here to interpret the effects...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0606256103

    authors: Pegram LM,Record MT Jr

    更新日期:2006-09-26 00:00:00

  • In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras-effector interaction.

    abstract::Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets s...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1217730110

    authors: Shima F,Yoshikawa Y,Ye M,Araki M,Matsumoto S,Liao J,Hu L,Sugimoto T,Ijiri Y,Takeda A,Nishiyama Y,Sato C,Muraoka S,Tamura A,Osoda T,Tsuda K,Miyakawa T,Fukunishi H,Shimada J,Kumasaka T,Yamamoto M,Kataoka T

    更新日期:2013-05-14 00:00:00