Friday, 18 May 2012

Profit and Loss

For patients to have confidence in the doctors treating them, it is essential that each patient is certain that treatment recommendations given by their doctor, are made on the basis of an absolute absence of conflict of interest. Where a physician includes in their prescribed treatment, products which directly benefit a doctor financially, doubt must arise as to whether the doctor is prescribing the best option, or simply the most profitable one. Similarly when medical researchers move from involvement in scientific investigation to the provision of tests sold for profit, trust in the researchers’ motivations are likely to be lost on the part of those who are looking to the researchers for answers to serious medical problems – a circumstance aptly illustrated by the XMRV tests offered by the VIPdx/Redlabs(US) company under licence from the Whittemore Peterson Institute. 

Medical research is expensive and it is inevitable that research organisations will seek to protect their investments of time and money by lodging patents and by licensing products and methods. There is however a need for full transparency in such arrangements if there is not to be the suspicion that research has been constructed to promote the financial interests of the researchers, rather than to produce meaningful data.    

The relationship between VIPdx/Redlabs(US) and the Whittemore Peterson Institute had always suffered from a confusion and lack of transparency and this problem appears to extend to a European group of companies with which VIPdx/Redlabs(US) and the Whittemore Peterson Institute have connections.

The Suhadolnik Connection 

In 1998  Robert J.Suhadolnik , with  Daniel L Peterson , Paul R Cheney about, Susan E. Horvath, Nancy L Reichenbach, Karen O'Brien, Vincent Lombardi , Suzanne Welsch, Elizabeth G. Furr, Ramamurthy Charubala, and Wolfgang Pfleiderer produced a paper:  BiochemicalDysregulation of the 2-5A Synthetase/RNase L Antiviral Defense Pathway inChronic Fatigue Syndrome  Also in 1998 a business was incorporated in Belgium under the name of R.E.D Laboratories , the partners in which included Suhadolnik, Peterson, Charubala, Reichenbach and Pfleiderer. The current partner list comprises: 
Catherine Suzanne Armande Bisbal

Pascale Josse Florence de Becker

Isabelle Willie Luce Campine

Ramamurthy Charubala

Charles Vincent Taylor Herst

Bernard  Lebleu

Kenny de Meileir

Daniel  Peterson

Wolfgang Pfleiderer

Nancy L Reichenbach

Tamim Salezada

Robert J. Suhadolnik

Data from Coface Services

Red not R.E.D Laboratories

Although the two businesses have a similar name, there’s no public record of there being any corporate financial involvement between Redlabs(US) and R.E.D Laboratories. The ownership of Redlabs(US) is somewhat obsure being part of the Whittemore/Seeno corporate debacle , there is however a partner level connection between Redlabs(US) and R.E.D Laboratories, and that is via Charles Herst who according to a 2006 version of  Redlabs(US) website  was the company’s Laboratory Supervisor. Dr Herst parted company with Redlabs(US) in 2006, interestingly Dr Herst notes his involvement with Redlabs as dating from 1998 (being both President and Lab Director), which is sometime before the Nevada business register gives a date for incorporation of Redlabs, the business may therefore have operated under a different name and ownership prior to 2004, with possible closer links to R.E.D Laboratories than are currently evident. In 2006 Redlabs(US) listed as its Director of Operations, Vincent Lombardi, who is one of the listed authors of the 1998  Suhadolnik  paper, Lombardi was subsequently employed by the WPI and is now its Principle Investigator.

The Redlabs(US) website previously carried an ordering guide prepared by Dr Kenny de Meileir of R.E.D Laboratories. Dr de Meileir and Carine Muyldermans were the managers of a now revoked  Nevada registered company  called 8 Diamonds  the Registered Agent for which was Carli West Kinne, who is now the Senior Vice President and Legal Counsel of the Whittemore Peterson Institute and who has also served  as Registered Agent for many businesses in the Whittemore/Seeno owned corporate structure.  According to the European Society for ME, in 2010 R.E.D Laboratories(Belgium) entered into a licence agreement with the Whittemore Peterson Institute to provide the unvalidated WPI XMRV test, to European clients.

R.E.D Laboratories (Belgium) has two subsidiaries, a supplements supplier called Protea Nutraceuticals Ltd and product developer Protea Biopharma. Protea Nutraceuticals Ltd is listed by the Dutch Chamber of Commerce as being wholly owned by R.E.D Laboratories, with its Assignee being Marc Fremont, who is also listed as the Managing Director of Protea Biopharma (data Coface Serices) as well as being Chief Scientific Officer at R.E.D Laboratories. The listed address of Protea Nutraceuticals (Noordstraat 3, 4641SE Ossendrecht) is also that of Kalida B.V which is also a supplements business, the director of which, the Dutch Chamber of Commerce records as being Carine Jean Rosa de Meirleir-Muyldermans, who is apparently the spouse of Dr Kenny de Meileir. The domain listing of and records the registrant as being Peter van Oosterhout, whose email links to the website of an engineering company at the same Noordstraat 3 address. The Share, Posted and Paid-In capital of Protea Nutraceuticals Ltd is exactly the same as for Kalida – EUR 90,000, EUR 18,000, and EUR 18,000 respectively.

Listed as Managing Director alongside Marc Fremont at Protea Biopharma is Christian Roelant, who has published research with Kenny de Meileir and with de Meileir and Fremont, these research papers appear to underpin products marketed or planned to bemarketed by R.E.D Laboratories.

Bernard  Lebleu, Catherine Bisbal,  Pascale de Becker, Isabelle Campine have published with de Meileir A 37 kDa 2-5A binding protein as apotential biochemical marker for chronic fatigue syndrome, all the authors being listed as from Department of Human Physiology and Medicine, Vrije Universiteit Brussels. Lebleu, Bisbal and Tamim Salezada are elsewhere listed as being at  Université Montpellier.  Charles Herst is listed  as having 6 co publications with De Meileir and 3 with Marc Fremont who like Lebleu, Bisbal and Tamim Salezada is also listed as associated with Université Montpellier.   

Transparency of researcher and treating physician interest 

Exploitation of research is of course the point of a company like R.E.D Laboratories, however it may be considered that there are legitimate questions about why a science based company would involve itself in the marketing of nutritional supplements, about the apparent lack of relevant statements of conflict of interest in published articles authored by the R.E.D Laboratories partners, and the potential conflicts of interest that Professor de Meirleir, or indeed Dr Peterson may potentially face in their prescribing practices when engaged in treating patients. Of course there may be no impropriety involved at all, but transparency is desirable. The  National (US)CFIDS Foundation has published a highly critical statement about Professor de Meirleir  . The criticism centres on Professor de Meirleir’s role as editor of TheJournal of Chronic Fatigue Syndrome and his delay in publishing research that the National (US) CFIDS Foundation considered was fundamental to progress in understanding CFS. The contention being that the delay was mediated by Professor de Meirleir’s wish to obtain patents on various aspects of the research.

The Journal of Chronic Fatigue Syndrome is no longer published and the research about which the National (US) CFIDS Foundation was concerned no appears to have been less promising than was first thought, however the issue of conflict of interest, where private business is involved remains an issue, and as the VIPdx/WPI XMRV testing issue demonstrates, transparency is vital if patients are to be able to make informed choices of where to medical advice and what interventions may indeed be justified, whether those interventions involve tests or claimed treatments.

Saturday, 18 February 2012

A Nasty Case of Infection

When Richard Dawkins developed the idea of the meme he considered them as behaving like free floating viruses infecting human cultures at will, the meme hypothesis is by no means universally accepted but it’s certainly an attractive explanation of human behaviour  in the face of the adoption of notions which patently offer no reasoned advantage to those individuals and groups who absorb these ‘memes’ and make them their own. A particularly virulent infection is sweeping through groups of people who are affected by M.E/CFS – the condition known as  antivax .

 A loss of Immunity 

The death knell of the XMRV hypothesis of M.E/CFS causation, tolled by accumulating evidence and culminating in the BWG study has caused a significant degree of cognitive dissonance  amongst a proportion of M.E/CFS affected people.  There has long been an element of collective concern about vaccination amongst M.E/CFS affected people because of reports of the illness having been initiated by a vaccination, or of vaccination having initiated a relapse, although these reports are rarely tested against the metric of  “correlation does not equal causation” .  Following the demise of XMRV however, there has been a definitive move to describe M.E/CFS as a vaccine induced illness and to link with antivax voices from the Wakefield  inspired “autism as vaccine damage” school of unthought.  Embracing the antivax position seems bizarre, both from a perspective in which M.E/CFS advocacy has long sought scientific and medical acceptance in the face of (at times undue) profound, scepticism, and from a perspective which advocates speculative treatment of M.E/CFS with drugs of significant toxicity. Being seen by the medical profession to be openly supportive of an antivax position can only reduce further, the already low regard that many medical professionals accord the validity of M.E/CFS as a definitive organic illness. It is in simple public relations terms, the equivalent of voluntarily stuffing one’s head in a toilet bowl, taking pictures and posting them on the Internet – a way to ensure perpetual derision. 

Why Oh Why Oh Why ? 

Apart from unalloyed desperation to fill the void of the lost hope of XMRV, why are M.E/CFS affected people willing to throw their lot in with an activist position such as antivax, that itself has so singularly failed to achieve any credibility amongst scientists and medics and indeed serves only to alienate all but scientific frauds or those determined to ply a trade unburdened by the demands of logic and scientific discipline   

Direct appeals to antivax authority are actually rare on the M.E/CFS dedicated forums, pro antivax positions are usually limited to quotes of approval for Wakefield and his supporters and allusions to ‘vaccine harm’. Somewhat typical is the defensive approach taken in the case of  Prof. John Walker-Smith who is currently seeking the support of the High Court in London in turning over his being struck of the medical register following an inquiry into his part in the Wakefield study . Walker-Smith is discussed on various M.E/CFS forums by some contributors as though he were a victim of an establishment conspiracy instead of someone found guilty of significant professional failings.

In a ‘break from the usual cover’ adopted by antivax sympathetic M.E/CFS affected people, Dr J. Deckoff-Jones , formerly of the Whittemore Peterson Institute and an advocate of antiretroviral treatment for the assumed (not XMRV) ‘retrovirus’ that is a supposed causative of M.E/CFS, has posted Blog entries which have included:

But then, introduce vaccines, and lots of them, from many different animal sources, plus killed vaccines containing adjuvants. Isn’t there a significant risk of unanticipated recombination events, not to mention persistent immune activation favoring virus?”


“Pretending it isn’t happening because the MMR vaccine doesn’t “cause” autism, is about as idiotic as saying that our disease isn’t retroviral in origin because XMRV was probably a contaminant.”

these comments  have brought approving responses and encouragement for Dr Deckoff-Jones.

There is perhaps some explication in Dr D-Js posts as to why antivax, might be an attractive position for some M.E/CFS affected people.  In the face of a sense of having been rejected by ‘main stream’ science, and being only of determined interest of psychiatry,  the notion of ‘outsider science offers both apparent safety and legitimacy (of a sort) , a place where the renegade scientist breaks with convention and achieves cures denied to a dispossessed patient population by a venal ‘establishment’. Antivax is attractive because it offers an alliance of the self described dispossessed.  The wish to belong 'somewhere' is a powerful motive but in the case of 'antivax',  if acted upon it will leave M.E/CFS perpetually locked into an ‘anti science’ association of outsiders, lacking any real purchase on either the administration of science or the realm of political oversight. It is a motive of emotion, that appears more suicidal than constructive, and raises a substantial question mark over the legitimacy of future M.E/CFS advocacy.     

Sunday, 29 January 2012

Good Science can't happen in Bad Institutions

When I started this blog it wasn’t with the intention of becoming slewed with the dubious nonsense of Mikovits’ XMRV non disease or the diabolically misbegotten organisational debacle of the Whittemore Peterson Institute. Scientific attention is thankfully moving on from XMRV and key funding agencies are breathing new life into M.E/CFS research, what is essential though is that the whole horrible story of the WPI needs to be told as a warning to the future. March will bring some edification via Mikovits’ appearance in Court on theft charges following a complaint by her former employer the Whittemore Peterson Institute.  Hopefully this case will elucidate why Mikovits felt compelled to commit acts which appear potentially criminal,  and also to expose whether there were indeed failings of science at the WPI. In the mean time the whole WPI edifice appears to be in a state of potential collapse.

Really, I mean, really, really – It was the money stupid !

Lets just recap – the Whittemore Peterson Institute is a non profit organisation, its funds have either come from public donation, large individual donations, or Government Grant; the only public records of large single donations are those from the Whittemore family via the Whittemore Family Trust. From the creation of the WPI its president has been Annette Whittemore who has also held the unpaid position of CEO; the Board of WPI has had up to five members but on occasion that has been down to just two, with Annette Whittemore the only constant presence. All other Board members have been close associates of the Whittemore family. I’ve written previously about how this lack of breadth of Board representation is problematic in that it exposes both the members and the organisation to concerns about lack of broad perspective and issues of conflict of interest. Such concerns now appear substantiated because Annette Whittmore along with her husband has been named in a Lawsuit that implicates the Whittemores in a multimillion dollar, multifaceted fraud to which the WPI itself is linked.

You think it couldn’t get worse ? Think again   

The most interesting aspect of the claims against Harvey Whittemore is that not merely has he defrauded his business partners, but that he has acknowledged this as fact and that the case now only comes to Court because he has failed to fully recompense those he has defrauded despite having previously promised to do so. However the Whittemores are contesting the allegations, describing them as entirely false.

It is beyond the scope of this blog to cover all the intricacies of the 41 page legal suit, in simple terms however the complaint is that: Harvey Whittemore, in part, and in cooperation with Annette Whittemore and up to ten as yet unidentified individuals and ten as yet unidentified corporations plus a limited partnership called The Lakeshore House Limited, is alleged to have defrauded his partners in three companies, Wingfield Nevada  Holdings Company LLC (Wingfield), Tuffy Ranch Properties LLC and The Foothills at Wingfield LLC.  

The Document of Complaint lodged with the Court provides an impressive depth of detail and scope of the alleged misconduct by the Defendants, an item of particular interest to M.E/CFS affected people is a mention of Redlabs, the company that marketed the  XMRV test licensed by WPI. Redlabs is not recorded as being a particular focus of any fraudulent activity but the Plaintiffs do claim that in 2004 Harvey and Annette Whittemore, via their The Lakeshore House Limited partnership sold 50% of several businesses including Redlabs to one of two companies owned by Thomas Seeno. The remaining interests in these companies held by The Lakeshore House Limited partnership together with Mr Seeno’s previously purchased interests were then, in 2005, transferred to either the Wingfield Nevada Holdings Company LLC or The Foothills at Wingfield LLC. From 2005 Redlabs was therefore wholly owned by Wingfield, its registration in the name of Harvey Whittemore  being in accord with Whittemore being the manager (but not sole owner) of Wingfield .  An important aspect of the complaint against Harvey Whittemore is that he withheld information from his business partners, it is therefore appropriate to ask, whether his partners were aware of the License agreement with the WPI for the XMRV tests, whether they considered sale of the non FDA approved tests to be ethical business and whether they considered the $226,652  paid to the WPI in licensing fees in 2010, to be justified ?   Further questions will no doubt be asked by the Plaintiffs in respect of how the operational activities of the Redlabs (operating as VIPdx) commercial business was seemingly transferred to the benefit of the WPI, via creation of UNEVX as a for profit corporation owned by the WPI.

Don’t Mix Business with Charity  

Aside from the ‘for profit’ Redlabs/VIPdx company, the Document of Complaint against Whittemore and others, lists amongst numerous charges of alleged fraud, a number of incidences which directly involve the Whittemore Peterson Institute. These are:

  • Diversion and donations of assets and equipment from a Wingfield called Wild West Sound Company Inc. (renamed – Western Electronics Inc.) to (amongst others) the WPI. 
  • Diversion of funds disguised as donations to WPI.
  • Improper and abusive use of Wingfield personnel for WPI purposes.
  • Harvey Whittemore caused aircraft leasing costs of over $2 million to accrue to Wingfield accounts in support of private use made by him and Annette Whittemore and others, including travel related to WPI activities which it is claimed alone amounts to $346,546 remains unreimbursed. 
  • Annette and Harvey Whittemore directed employees of Wingfield to work on WPI at Wingfield’s expense, it is specifically alleged that Annette Whittemore represented herself as having management authority at Wingfield.
  • A 'PR' Agency retained by Wingfield was directed to do work for the WPI without any recompense being paid to Wingfield.  It I claimed that Wingfield’s Director of Marketing Angelina Wyss-Gordon [Angelina Gordon] who at the same time was the WPI Director of Marketing and Events, instructed the Agency that all work carried for WPI should be charged to Wingfield.
  • Harvey Whittemore permitted Annette Whittemore to charge compensation and other employee expenses of the WPI to Wingfield.
  • Specifically Annette Whittemore caused 75% of Dr J.Mikovits’ salary ($185k) to be charged to Wingfield as was the $42,000 relocation expenses paid to Dr Mikovits.
  • Currently unnumerated expenses of other WPI staff and consultants were paid for by Wingfield.
  • A Wingfield owned company, the Redhawk Golf Course and Entertainment facility was used at the direction of Harvey and Annette Whittemore for fundraising events for the WPI for which fees were not paid, the costs are claimed to exceed $157,000.
  • Harvey Whittemore solicited grants and donations from businesses dealing with Wingfield, which were of benefit to the WPI, but which were undeclared to the owners of Wingfield, to their detriment.
Should any of these claims be true then huge embarrassment would be attached to the WPI, and by association, the wider cause of M.E/CFS research. 

Fall Out 

The Plaintiffs are seeking a court hearing in front of jury, in addition copies of the documents are with the Nevada police and it seems highly likely that criminal investigations will now follow, such  investigation would necessarily involve the WPI as an institution. While apportionment of criminal blame or civil liability remain to be properly tested, it is abundantly clear that the management structure of the WPI leaves it profoundly exposed, and there must be serious questions about it’s long term future despite it having been recipient of  millions of dollars in public funding in the last 4 years. The positions of both Annette Whittemore and  Angelina Wyss-Gordon are to be tested in public if a trial goes ahead, but it would seem likely that all those who have served on the WPI board since WPI was first set up will be called upon to give evidence to investigatory authorities – and those may be multiple. The position of  Carli West Kinne , current Vice President and long term General Council at WPI would seem to be potentially quite difficult given her listing as Registered Agent for many Whittemore ventures, including Wingfield, as well as the Whittemore Family Trust. 

Other investigatory authorities seem likely to have a great interest in the Wingfield case, some of what is alleged would seem to have Federal relevance, and in respect of the WPI there are aspects which are likely of concern to the IRS in respect of WPI’s annual returns. For example should the WPI have declared costs for fundraising or airfares, and those costs have not been paid then a false declaration has been made. And questions then arise as to what has happened to the unaccounted funds. The role of Federal Grant giving agencies must also be in question – was there due diligence to ensure that WPI was fit and proper recipient ? 

XMRV was a disastrous association for M.E/CFS in terms of research credibility – the associated publicity has in fact been played well by a few effective advocacy organisations and the harm that could have resulted has been largely mitigated. The possible implosion of the WPI, a consequent association with illegality and with it a loss of credibility for M.E/CFS fundraising and advocacy would be a further blow that M.E/CFS affected people should not have to endure. How organisations are structured matters – good intentions are not enough, nor are smiling lobbyists with promises of donations beyond dreams the stuff of long term research stability.  M.E/CFS affected people and their advocacy organisations must ensure that in future support is only given where sound institutional practices are demonstrated and guaranteed by external measures.

Thursday, 8 December 2011

Myth, Money and Self Delusion

As both science and accountancy begins to inform those who invested heavily in the XMRV hypothesis of disease causation, a presentation of what cash actually bought the WPI lab coat drama alive, seems in order.

No free lunches at the privately funded research table.

Surprisingly there are still articles being written that continue to sow confusion over the foundational finances of the Whittemore Peterson Institute.  An important part of the mythology that describes the Whittemore family as saviours of M.E/CFS research  and which has been much repeated by enthusiasts of the HGRV (formerly XMRV) hypothesis of M.E/CFS causation, is the proposition that the Whittemore family gave $5 million to the WPI. No such donation was ever made. What is the case, as written on this Blog in February 2011, is that via the Whittemore Family Foundation, something over $1 million was contributed by Annette and Harvey Whittemore  University of Nevada as contribution to the building of the University’s Center for Molecular Medicine .

The WPI has accommodation within the CMM building, the basis for this occupancy arrangement is not on public record, although it may be relevant that the WPI donated $100,000 to UofN in 2009.  The total cost of the CMM building project was $77million, $16 million of which was met by Nevada tax payers, the balance being met by University of Nevada financial bonds, together with sums donated by the Whittemore family. Total transfers from the Whittemore Family Foundation to the University of Nevada in the years 2007-2009 amounted to  $1,571,168, matched to a number of stated budgetary purposes.

Mo’ Money 

Funding of the WPI, and the meeting of costs of  administration and research can be broken down into three main categories, income gained from fundraising activities, funds donated by the Whittemore family, and Federal Research Grants.  In 2010/11 a number of Social Network supported grants were also received by the WPI. 

Although WPI was created in 2006, its first year of  operating was in 2007, when its stated income and was: 
  • Income: 2007 
Public support                              $37,083

Government Grant                       $400,00

Bank Interest                                 $1,106

In 2008 WPI’s declared income significantly increased due to additional grant income and a transfer of $540,172 from an entity called the Nevada CFS Foundation (subsequently Neuro-Immune Research Institute), of which Annette Whittemore was listed as President. The source of  the NCFSF’s income 2006-2008 was fundraising together with donations from the Whittemore Family Foundation totalling $214,000. The NCFSF contribution was accounted as part of WPI’s 2008 publicly supported funds
  • Income: 2008

Fundraising Events                      $514,685

Public support                              $739,345

Government Grant                       $600,000

Bank Interest                                   $8,314

In 2009 WPI declared reduced income from both fundraising events and public support. The Whittemore Family Trust gifted $100,000 to the WPI in 2009, coincidentally the same amount gifted by the WPI to the University of Nevada.
  •  Income: 2009
Fundraising Events                      $324,720

Public support                              $287,204

Government Grant                       $600,000

Bank Interest                                   $7,635

Where’s My Grant ?

The WPI has chosen not to account separately for the various Federal sources of its grant funding, it is not required to do so, however it is good practice for Institutions to be explicit about what funds they have received for what purpose. There is often difficulty in relating grant income to annual accounts because grant periods frequently cut across accounting years. The US Government does helpfully list grants given, by Recipient, in the case of the WPI six grants are currently listed .

In 2008 WPI received $189,667 from the HRSA   under award number C76HF09846.  transaction date 07-11-2008 . 

In 2009 a further $565,290 was paid under the award number with an award date of  09-09-2009.

Also in 2009 the WPI received the first annual payment of a multi year award from the National Institute of Allergy and Infectious Diseases(NIAID) under award number R01AI078234 , the payment amount being $335,000 with a transaction date of 24-SEP-2009.

The total amount of Federal Grant awarded to the WPI  in 2008/2009  was £1,089,957 which accords reasonably well with the $1,200,000 declared by the WPI , however the declared sum of $400,000 for 2007 does not appear to relate to any Federal award. There is however the matter of $2,000,000 appropriated by the Nevada State legislature for:

“the use of the Institute for Neuro-Immune Disease[sic] “the construction  of, and furnishings, and equipment for, a facility relating to  the research and treatment of neuro-immune disorders.”

It seems likely that of the $1.6 million declared by the WPI as being ‘received’ Government Grants in the years 2007 - 2009, something in the region of $500,000 came from the Nevada State legislature.

The NIAID R01AI078234 award was matched with $311,316 from the same source in 2010, and a further $302,866 was due in September 2011. In total,  US Federal sources list in excess of $1.7 million having been paid or due to the WPI between 2008 and 2011. The WPI 2010 accounts are not currently available but it is clear that WPI, far from being supported independently of Government as claimed by some commentators, has been heavily dependent on Government funding.

Good People Cost

One aspect of WPI finances that stands out rather strongly is it’s burgeoning wage bill. From just $146,373 in 2007, salaries rose to $354,803 in 2008 and $545,748 in 2009.  Dr Mikovits was paid  $146,154 in 2008 and $185,000 in 2009, an amount which substantially above comparable norms and a surprisingly large amount given the size of the institution. 

* Account information of all US non profit organisations, including for the WPI and WFF, is available from Guidestar in the form of .pdf versions of Form 990 tax returns. The most recent three year’s return are available without cost although registration may be required.

Wednesday, 23 November 2011

Chronicle of an Embarrassment Foretold

10 months ago I wrote on an internet forum, something that has shown to be prescient:

Progress in science frequently involves two diametrically opposing principles; there's competition between researchers - and there is co-operation between researchers, very often both principles apply to involved research groups at the same time. For this to work, all the participants have to have a degree of confidence in the basis on which each group is working. Where confidence is lacking then a particular laboratory or even a whole institution will be avoided by others working in the field, this will have effects of unwillingness to take on replication, confirmation or validation studies, of unwillingness to peer review and ultimately reduce confidence on the part of publishers. Mikovits and WPI have only themselves to blame if other researchers do not take them seriously, the comments on the ERV blog do represent serious issues for WPI even if the posters are not themselves established researchers the attitudes expressed are likely to be widely held in the medical research field. Mikovits and Whittemore may be happy to wrap themselves up in a Wakefieldesque flag, championing some mythical disease causation - but that will do nothing to advance the cause of M.E/CFS research, in fact it will probably have a highly negative effect because M.E/CFS will once again be associated with 'crank' pseudoscience in the minds of many researchers.

Sadly the damage is already done, and I'm sure that as with Wakefield's followers who refuse to accept the antivax agenda is nonsense, that long after XMRV has been consigned to 'minor interest' status, there will be those invoking mass conspiracy for the research leading nowhere. As Mikovits said - "a negative result doesn't mean you are not [XMRV] positive" - yeah right, just keep buying the tests, we'll get you a positive result eventually !?! What serious scientist would want to associate themselves with that kind of madness, it's a career killer at the very least for anyone committed
to objective investigation.

Shortly after writing those two paragraphs  I completed “Creating a Research base isn’t like buying a Football Team” for this blog and thereafter rather lost momentum in writing about what was looking ever more like a train wreck in slow motion.  For the intervening period the headline M.E/CFS story has been entirely subsumed into the XMRV and WPI charade and while the wreck has been evolving there’s been little to write about other than what was clearly going to be an unpleasant transfer of momentum as the Mikovits/Whittemore skytrain achieved negative motion. Not that I predicted the nature of the collapse, but given the florid nature of the WPI Götterdämmerung, a summary of events might be now worthy of record. 

Too good to be true 

In 2009 the magazine Science published a study Detectionof an Infectious Retrovirus, XMRV, in Blood Cells of Patients with ChronicFatigue Syndrome authored by researchers associated with the Whittemore Peterson Institute.  The study was contentious for a number of reasons, not least of which was that it appeared to offer evidence of a single infective agency common to a large percentage of individuals diagnosed with M.E/CFS, such a position is problematic given the diverse presentation of patients falling within the M.E/CFS ambit. The Science article also raised urgent concern amongst Blood Donation Authorities because it appeared to suggest that a XMRV was a potential pathogen that could be communicated via blood donation – numerous studies were initiated to address these concerns necessitating application of large amounts of research funding. Some 38 studies were carried out, yet none provided any support for the WPI study, Science Magazine took the unusual step of issuing an Editorial ‘expression of concern’ and subsequently part of the article was retracted at the request of two of the co-authors.    

No further publication was offered from the WPI until May 2011 and even then this new article  offered no elucidation of the issues of developing concern regarding the 2009 article, despite the new article being predicated on the testing regime used in the 2009 study. The May 2011 article claimed to identify an inflammatory signature specific to XMRV positively tested M.E/CFS sufferers, however as the XMRV test had never been independently validated it is unclear whether the signature was either XMRV or M.E/CFS specific.

At the end of September 2011, doctoral student Abbie Smith, a consistent critic of the WPI XMRV work, published via the ERV blog  a telling critique of the use of  the contradictory usage of data by Dr Judy Mikovits, the senior researcher at WPI .  The material presented in the ERV blog was soon picked up by other researchers and attracted the attention of sciencejournalists .  The credibility of both WPI as an institution, and Mikovits as individual researcher seemed to be impugned and a mature response in defence of their relative positions from both would have been expected by most observers of science. What happened instead only served to bring further opprobrium upon the WPI and Dr Mikovits.

When science fails, there’s always religion

 In January of 2011 I wrote a blog entry entitled  Saints and demons in the Cult of The Chronically Fatigued where I highlighted what I saw as a deeply unhealthy sanctification by some M.E/CFS affected people of  Dr Mikovits, Annette Whittemore and Andrea Whittemore. I subsequently wrote about what I saw as the inherent failings of the WPI, particularly the role played in the organisation by Annette Whittemore:  Creating a Research base isn’t like buying a Football Team .  While the intemperate adulation exercised by some M.E/CFS affected people and the internal failings of the WPI were not causally linked,  together these two elements created a toxic brew in which the inevitable ‘failure to launch’, and consequent breakdown of professional relationships, produced in turn a cognitive dissonance amongst the formerly adulatory claque.  The ‘patient population'  to which both Dr Mikovits and Annette Whittemore made effusive appeals for support, has now become enthralled to a near religious hysteria in which demonisation and martyristic conspiracy are being invoked to explain ‘the Downfall’. While other ‘devils’ in the M.E/CFS firmament have faded from the excited view of ‘advocates’, a new ‘demoness de jour’ has been revealed in all her evil . Once perceived as a fragrant deity of all that was light in the enshadowed world of M.E/CFS research,  Annette Whittemore confirmed her allegiance  to the Dark Side (© G.Lucas)  by sacking Dr J.Mikovits from the employ of the WPI.

For a researcher to part company with an institution under less than happy circumstances is not exactly a rare occurrence – differences of research direction, management styles or simply clashing egos underly many researcher relocations. However these 'separations of the ways' usually occur with little public pronouncement, and in most cases decorum is the order of the day. This however is not the way with WPI and Mikovits. Within hours of Mikovits being told she was surplus to requirements, a variety of Internet Blogs and Forums were alight with tales of the immoderate way in which Annette Whittemore verbally terminated Mikovits’ employment and the stage was set for an unseemly outplaying of an embarrassing drama.

It’s the money stupid

 The Mikovits/Whittemore split generated especial anxiety amongst those who claim M.E/CFS affectedness and who are strongly wedded to the belief that M.E/CFS is a retroviral disease. The WPI with Mikovits at its helm has been the sole institution to have given the ‘M.E/CFS = retrovirus’ proposition any credence. The expulsion of Mikovits saw ' believers' rapidly invoking conspiracy (evil forces ‘getting at’ the WPI) theories together with expressions for the fear of martyrdom (both figurative and literal) of Dr Mikovits. A key part of the narrative soon emerged  - the question of who would continue to enjoy the Federal Research funds that had been awarded for a further two years.  It appeared, via proxy Blogs, that Mikovits was claiming the grant award was to her in person, while this was contested by the WPI. The contention by Mikovits was particularly strange because there is long established  precedent,  that the research contract is between funder and Institution. Nevertheless Mikovits’ supporters promoted the meme that only Mikovits could be trusted to continue the work on putative retroviruses, which Mikovits called HGRVs - Human Gamma Retroviruses, and on that basis Mikovits and not WPI was the rightful recipient of the funds. 

The final act of this increasing soapy drama was opened by the WPI when it further spiced the narrative with a claim about missing lab materials, something which was to lead to an absurdist peak of  drama – Dr Mikovits being arrested and held in jail prison on charges of theft and conspiracy.  The drama was thus complete, not only is ‘conspiracy’ implied, not only has there been betrayal by a close ally, but martyrdom has occurred. M.E/CFS as a religion finally has the objectification of suffering, not merely by the serried ranks of the poorly masses but it now has its own ‘truth bringer’ brought low by those who would follow 12 pieces of silver (actually $1 million in research funds) and who would sell out the truth to render under Caesar that which belongs to posterity. 

Never Ending Story

Mikovits seems likely to face a full criminal trial in due course, given the content of affidavits published in respect of the Civil case that the WPI has brought against Mikovits. The affidavits published on the WPI website attest to theft of research materials from the WPI by a PhD student acting at Mikovits’ behest.  A criminal trial whether or not it results in conviction, will only further cement Mikovits in the role of martyr in the eyes of her unthinking supporters  and full canonical Wakefieldisation appears entrained. The myths of HGRVs will be stitched irrevocably to Mikovits’ beatification and the believers will be wholly immune to any reasoned argument over the failings of Mikovits work.  M.E/CFS research has now has to face up to a future in which all intelligent debate is perpetually dogged by a crank fringe who in the manner of the anti-vaccination movement’s entryism into ASD advocacy, parasitises every open discussion on the epidemiology and aetiology of M.E/CFS.

No ‘get out of jail free’ card 

Mikovits’ travails, whatever her culpability or innocence in criminal matters must not distract from full examination of the apparent egregious systemic failures of the WPI. Mikovits, Lombardi as lead scientists and Annette Whittemore  as the de facto senior manager have at the very least to answer the many questions that M.E/CFS affected people have about the research, testing procedures and finances of the WPI. Mikovits is reported to have claimed at a conference in September,  shortly before her contract with WPI was terminated, that the VIPdx laboratory, which had been providing tests for XMRV under licence to the WPI,  would not continue XMRV-testing because the test had not been shown to be reproducible.  Mikovits statement appears to have prompted a response from  Dr Lombardi .  Lombardi’s statement notwithstanding, patients who in total paid in the region of $1 million to VIPdx for these worthless tests, the results of which confirmed for many that they had a retrovirus for which there was no known treatment, deserve elucidation of:

·       Why the WPI felt confident in issuing the test licence before independent validation had been achieved ?

·       What income accrued to the WPI from the licence agreement ?

·       What profit was made by VIPdx on the processing of XMRV tests ?

·       What financial benefit, if any accrued to Mikovits, Lombardi, members of the board of the WPI or there surrogates, from the operation of VIPdx ?

·       In the light of the VIPdx statement that  The interpretation of the XMRV test results, as with all laboratory tests, is the responsibility of the ordering physician.” What records were kept by WPI/VIPdx of the ordering physician ?

VIPdx operated as private company and there is no legal obligation on VIPdx to make its financial circumstances public, however WPI is a public trust which has operated under claims of acting in the interests of patients. The WPI has a moral obligation to provide transparency , it should not and must not hide behind any wrong doing that may be proved on the part of its employees.

Thursday, 17 February 2011

Creating a Research base isn’t like buying a Football Team

The beginnings of the WPI seem to make it inevitable that controversy would dog whatever research product the Institute would lay claim to.

All but the largest scientific Institutions, are by their very nature, forced to focus on narrow fields of enquiry, this in the main is not a handicap to progress and scientists are in the most part accepting of research briefs limited by funding availability and an individual institution’s statement of purpose. Science requires that objectivity of endeavour be paramount, limited research briefs in general actually serve the cause of objectivity, however where there is an institutional presumption of ‘value’ of research product, then objectivity will almost certainly be lost. Of course in the field of medical research many institutions have strategic ambitions, for example Cancer Research UK which funds research in both its own and other facilities, seeks to understand and ultimately cure cancer  but such a strategic ambition can not be allowed to impact upon the science of an individual project.

The reality of medical research is that the vast majority of investigations will produce either no conclusive evidence to support treatment, or will positively identify unrewarding avenues and only rarely will ‘breakthrough’ results be achieved. In such a context it is vital that all research evidence, whether or not leading to treatments or cures, is accepted by the research institution as valid science; the alternative is that the institution itself becomes partial and research evidence is validated only in terms of its ‘breakthrough’ status. When that happens the entire institution moves from being an agency of science to being an agency of propaganda.

How research institutions maintain scientific integrity is a matter of much debate and there is perhaps no absolute model of how impartiality can be ensured within internal validation of outcomes, however there are some aspects of institutional management that could be seen as representing ‘best practice’. Clear separation of roles within the management and oversight structures would seem to be essential, so that while the institution may have advocacy, research and income generation priorities, these potentially competing  aspects have necessarily to be pursued within expressly separated contexts. Without this separation, role confusion within both management and executive structures is inevitable and there is a very great danger that scientific integrity will be compromised by financial or advocacy demands.

The Whitmore Peterson Institute states its goals as:
  • To facilitate and advance patient care
  • Research the pathophysiology of neuro-immune diseases such as ME/CFS, fibromyalgia, atypical MS, and autism
  • Develop therapeutics, diagnostics and prevention strategies for this spectrum of diseases
  • To advance and support medical education and physician training
At first reading this may seem an entirely reasonable strategy for a medical institute but the line “Research the pathophysiology of neuro-immune diseases such as ME/CFS, fibromyalgia, atypical MS, and autism” bears closer consideration. What in fact does this apparently authoritative statement actually mean ?

Pathophysiology is a part of the medical lexicon, meaning the functional changes associated with or resulting from disease or injury, so it seems that the intent of the Institute is clear, but difficulties quickly arise when considering “neuro-immune diseases”. Tellingly entering this phrase into a web browser brings as the first result  - the Whittemore Peterson Institute website which provides the information, without any other reference that:

The spectrum of neuro-immune diseases including: Myalgic Encephalomyelitis (ME/CFS), Atypical MS, Fibromyalgia and Gulf War Syndrome, share common abnormalities in the innate immune response, which result in chronic immune activation and immune deficiency.

 The term Neuroimmune Mechanisms has been used in reference to Alzheimer Disease Pathogenesis, inflamatory diesease and more generally with consideration of health and disease function which yields the description:

A novel scientific discipline that examines the complex interdependence of the neural, endocrine and immune systems in health and disease has emerged in recent years. In health, the neuroimmunoregulatory network is fundamental to host defence and to the transfer of immunity to offspring; the network also plays important roles in intestinal physiology and in tissue regeneration, healing and reproduction.

The term Neuroimmunology has been in use since the 1980s and there is a Journal dedicated to this field of study. , while the term Neuro-Immune Interactions has been used in relation to studies of Multiple sclerosis  and neuroimmunomodulation has been used in relation to psychiatric illness  Despite these technical uses of terms which are of apparent close, or even cognate meaning with “neuro-immune” there appears to be little in medical reference sources which assist in elucidating what the WPI might mean by “neuro-immune diseases”. This lack of elucidation is compounded by the list of conditions that WPI considers to be neuro-immune in character yet which appear to have no established commonality, or in one case even an agreed medical classification. Atypical MS has no authoritative designation that is separate from the accepted spectra of Multiple Sclerosis while the identification of the developmental disorder Autism (ASD) as an immunity mediated condition appears eccentric to say the least. WPI’s additional reference to Gulf War Syndrome adds further doubt as to the underlying science of the WPI conception of “neuro-immune diseases” given the lack of any evidence of a single causative agent of the now widely recognised spectra of illnesses  affecting Gulf War veterans.  Further there is no apparent data to support the WPI claim that these disparate conditions “share common abnormalities in the innate immune response, which result in chronic immune activation and immune deficiency.” Bizarrely, considering it is much vaunted by WPI, the hypothesis that persistent XMRV infection is the cause of CFS would militate against abnormal innate immune response having a role in CFS, given that ‘normal’ immune response would be sufficient to explain the CFS symptomology in the face of persistent infection.

What any of this may actually mean is impossible to divine, but WPI seems irrevocably confused, either by its own publicity, or by the state of science in the very fields in which WPI seeks to undertake research; certainly it raises many questions about how the Institute arrived at this state.

The Whittemore Peterson Institute is a Private philanthropic foundation with tax exempt status . Since the creation of WPI its President has been Annette Whittemore who is listed as the Institute’s founder and the Whittemore Family Foundation (which shares the same registration address as WPI) donated a total of $309,000 to WPI in the years 2007-2009. WPI also received $540,572 from the Neuro Immune Research Foundation when it closed in 2008; Annette Whittemore was President of NIRF.  In addition to Annette Whittemore, the Board of WPI has only had two consistent members since its foundation, its Secretary Peggy Sullivan and its Director of Government & Public Affairs, Michael D. Hillerby;  Hillerby is a business associate of Harvey Whittemore, Annette Whittemore’s husband.  Annette and Harvey Whittemore are benefactors of the University of Nevada, and were closely involved in the development of the Center for Molecular Medicine  within which the WPI is housed. The Whittemores pledged $5 million to the building of the $77 million Centre although only a little over $1 million of this pledge was actually drawn down by the project managers.

The motivation of the Whittemores seems more than simple philanthropy, and although the various PR material promoting WPI appears explicit  in expounding the history of the Whittemore family’s concern with Chronic Fatigue Syndrome, this doesn’t explain the focus on neuro-immune diseases rather than just the CFS/M.E that affected Andrea Whittemore.  In the 2009 WPI annual statement to the IRS Annette Whittemore states that she works 40 hours per week (unpaid) in her role as WPI President, clearly a profound level of commitment, given that the Executive Director (Judy Mikovits) receives $185,000 for a 45 hour week. The role of President and Executive Director of WPI are closely linked, with Annette Whittemore and Judy Mikovits regularly attending conferences in both the US and Europe, and on at least one occasion Whitmore has shared in the presentation of scientific material.

Clearly to understand the nature of the Whittemore Peterson Institute, some account has to be taken of the role of Annette Whittemore, not simply as a parent seeking a Lorenzo’s Oil , or as a disinterested philanthropist distributing personal wealth, but as someone with a particular perspective on disease.  An indication how Whittemore’s own perspective has been shaped comes for her WPI bio: Annette Whittemore graduated from the University of Nevada with a BS Ed in Elementary and Special Education. Teaching children who had neuro-cognitive deficits, like those found in autism, ADD, and learning disabilities, provided her with a unique experience to later use in her pursuit of answers to her daughter's serious illness. It is difficult not to see the speculative neuro-immune disease designation as being a reflection of Annette Whittemore’s personal conception of disease processes rather than a result of a deliberative scientifically informed process.

And what if the Founder of (to give it it’s full title) the Whittemore Peterson Institute for Neuro-immune Disease has provided the Institute’s primary perspective,  does that actually matter ?  From a scientific perspective it is a matter of overwhelming importance. The basis of any scientific institution must be the capacity to address all questions, devoid of prior assumptions which are not supported by scientific certainty. WPI has not set itself the challenge of testing the validity of “neuro-immune” as a disease catergorisation, nor is it presenting hypotheses of  “neuro-immune” processes that may be tested, instead the very existence of the organisation is a statement that neuro-immune disease is an established fact, and that it is a ‘known’ that:  ME/CFS, Atypical MS, Fibromyalgia, Gulf War Syndrome and Autism are neuro-immune diseases. The research context provided by such an ‘a priori’ position must inevitably generate expectations of ‘proof’ that confirm the Institution’s pre stated position; irrespective of the quality of any research, such a context seems doomed to promote exceptional researcher bias, something which is both unnecessary and unjustifiable.    

Friday, 14 January 2011

Saints and demons in the Cult of The Chronically Fatigued

You can't convince a believer of anything; for their belief is not based on evidence, it's based on a deep seated need to believe. Carl Sagan 
Cultism seems an inherent human behaviour, probably an evolutionary adaptation selected for as a group cohesion process in the development of the language and culture of our homonin ancestors. Cultism frequently has harmful effects when encountered on a broad social scale but it is likely to be an inevitable group response where the group is experiencing, or (perceives that it is experiencing) external stress. Having an illness which is effectively ‘undiagnosable’, which causes individuals significant social dislocation, which has limited social and scientific acceptance and which leaves the individual feeling permanently ‘crap’, is as an effective a source of individual stress as one could want. Multiply that individual stress amongst a group defined on the basis of a shared experience of that stress and the conditions for a group psychology founded on a sense of external oppression appears ready made. Of course this doesn’t mean that CFS = cult, merely that some people affected by CFS, which may include carers as well as those who are ill, will find a degree of safety in adopting a cultified mindset. This ‘safety’ default position can also be seen in anti vaccination groups, groups of parents of developmentally challenged children and groups advocating exclusive adoption of non scientifically validated medicine and it is notable that across internet forums there is a degree of interchange between these various groups.

Shame the Devils

Cults and cultic thinking are not phenomena which are exclusively religious in character, neither are these phenomena dependant upon the presence of a charismatic founder/originator but there is a very strong propensity for cultic thinking to drive the process of ingroup  bonding by identification of a personified outgroup ‘demon’ and a personified ingroup ‘saint’. Indeed these personifications may multiply into a veritable pantheon of  white hat and black hat wearers, however in the cultified thinking found within the CFS forums there are only two major demon figures, notably one male and one female.  The senior devil, and veritable prince of lies according to the liturgy of his CFS detractors is psychiatrist  Professor Simon Wessely . The demonstration of Wessley’s commitment to the dark side was his co-authorship of a paper on the use of CBT as a treatment for CFS which demonstrated high levels of positive outcomes. CBT is considered by some of those affected by CFS/M.E to be inimical to good illness management and some even claim it is substantially injurious to CFS sufferers. There is a commonly repeated meme that Wessely specifically chose a predominantly psychiatric model of CFS to load his CBT study so as to get a ‘positive’ result.  Ironically not only did Wessley and his colleagues reference their patient recruitment terms to recommendations from a US expert conference which noted the need to exclude psychiatric diagnoses ( It was viewed as essential for the investigator to screen for psychiatric disorder using a combination of self-report instruments followed by at least one structured interview to identify patients who should be excluded from studies or considered as a separate subgroup in data analysis)  as well as to a UK expert conference where psychiatrists were in a minority, but in any case both these recruitment references were superseded by reclassifications by the CDC  and the DOH . The reclassifications rendered the Wessley et al study of CBT largely inapplicable to succeeding patient populations, so even were that study to have been anything other than scientifically sound, it was largely redundant even by the time it was published in 1997 given the CDC adoption of Fukuda et al in 1994. Nevertheless Wessely is code for evil in CFS cultism, and by association, so is psychiatry, all psychiatrists and any treatment they may recommend for CFS.

More recently recruited to be an object of vilification by cultic thinking CFS affected individuals, is Dr Esther Crawley,  Dr Crawley has doubly damned herself, firstly merely by following the guidelines of the National Institute for Health in treating CFS patients, and subsequently by proposing a study involving (in this author’s inexpert opinion, the decidedly un-scientific) Lightening Process© .  Normally a scientist like Crawley could have expected support from the science orientated MEA but even the MEA was drawn to seek a review of the ethics of the less than appositely named SMILE study. Crawley has now been cleared to go ahead with SMILE but her role as cultic hate figure  is assuredly permanent.  

Angels in the Firmament

The early heroes of CFS research have passed on , additionally the disease has never attracted the sort of media whore … cough er ..  celebrity campaigner, to whom the hordes have flocked adoringly and CFS in recent years has especially been a cause in need of a Joan of Arc to publicly suffer vicariously for the afflicted. The cultic inclined of those affected by CFS have found a trinity of Joans in the guise of Dr Judy Mikovits and Annette and Andrea Whittemore . No doubt admirable people these three individuals are now treated as personae mirabilis wholly beyond criticism, as also is the product of their sphere of creation   – the XMRV organism and its supposed role in causation of CFS.

 XMRV has ticked all the boxes for those affected by CFS and who are looking for a miracle, although the nature of the miracle has turned out to be something of a surprise. While the tenuous link between XMRV and CFS offers the hope of a ‘cure’, far more of the enthusiasm of the cultically inclined has been directed toward XMRV’s potential to accord social acceptance. Within the CFS forums the aspect of social acceptance has been mediated via a discourse which favourably compares HIV with XMRV and there is a repetition of statements to the effect that CFS sufferers are worse off than those affected with HIV !  The sheer scale of the dislocation between the perceived status of HIV affected people and the actual reality of living with that disease almost suggests a kind of collective dissociative thinking on the part of some CFS groups, it’s as if herpes suffers were seeking the public and scientific ‘acceptance’ accorded to small pox victims. 

In the way of many cultic phenomena, the force of reasoned external critique has only served to re-inforce the saintly status of the Whittemore Institute, its Director,  its pre-eminent ‘person of treatment’ its President  and its ‘discovery’ . Every scientific paper that casts doubt on the definitive role of XMRV in CFS is explained away in terms of incompetence on the part of naysayers, contempt on the part of authority and conspiracy on the part of – well everyone from the massed ranks of psychiatry led by the evil Wessely (see above)  to Big Pharma wanting to defend profits from ineffective drugs prescribed to lifetime sufferers of CFS. The dubious positions taken by the WPI – marketing of XMRV tests to desperate CFS sufferers before any test validation has been achieved, ownership of the testing laboratory by the husband of the WPI president, Mikovits sharing a platform with disgraced and apparently medically fraudulent researcher Andrew Wakefield , the WPI President allying the WPI to an anti CBT agenda - only serve to elevate the WPI as the only true voice of the CFS ‘dispossessed’.

No matter what contrary evidence may arise, there is now no hope that the WPI ‘followers’ will be dissuaded that XMRV is the cause of their disease, every challenge to WPI or its science will be treated as an undeserved attack motivated by jealousy or competing financial and  professional interests. The demands for anti viral treatments will grow, pointless testing will take place, patients given positive test results will feel the need for treatment and when conscientious doctors refuse to prescribe dangerous and inappropriate medication, those patients will go to unscrupulous doctors happy to prescribe whatever the patient demands, merely for the consult fee. Mikovits and WPI could do much to rectify the situation – Mikovits could start being positive about all the science of XMRV, instead of perpetually defending her own work, and WPI should withdraw its anti CBT stance given that, no matter how inadequate, CBT based treatments are proven effective in helping CFS sufferers to at least to maintain a level of functionality.