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My Apple Predictions. 2012 edition

Last year I published a list Apple predictions and I will post a complete score card. However, some of my predictions can not be judged until Apple announces its first quarter results on January 24th. I will however provide my 2012 predictions now.

iPad
The iPad 3 will be announced February 28th and released March 16th. The iPad 3 will include a Retina Display with a resolution of 2048×1536. The case will largely look like the current iPad but Apple will introduce colors (again) like the iPod Nano and possibly patterns like the old Flower Power and Blue Dalmatian iMacs.

The cellular equipped iPad 3 will come with LTE radios in addition to the 3g and 2g radios they currently have. The large battery capacity of the iPad will make this luxury a possibility even though the iPhone 5 will lag behind with 3g.

The iPad 3 will also have the new quad-core A6 processor and get the same battery life as the current iPad except when using the LTE radio.

The memory options will remain16, 32, and 64 gb. This will be the last iOS device to include the 30 pin dock connector. The iPad 3 will get Siri. Prices will remain the same.

The current iPad 2 will continue as a discount model to fight the Kindle Fire and what-ever 7 inch piece of crap Eric Schmidt is talking about. The iPad 2 will only be available in 16 gb, but will still be available with WiFi or WiFi +cellular. The iPad 2 will be priced at $349 for the WiFi version and $479 for the WiFi +cellular

In addition to Verizon and AT&T, Sprint will get both iPads. Sprint will introduce a discounted price that bundles the wireless internet for your phone and iPad in order to solidify its position as the bargain wireless plan.

Last year I estimated cumulative sales of 65 million iPads (total of 2010 and 2011 iPad sales). Barring a total sales frenzy over this past Christmas I’m was a wee bit optimistic, with cumulative sales coming in closer to 54 million (that assumes iPad sales of 14 million in the Christmas quarter, 90% more than last Christmas, and 30% more than previous quarter). I am going to predict sales of 60 million iPads in 2012.

iPhone
The iPhone 5 will be introduced in September and go on sale two weeks later. The message of the design is durability. Apple will use the same nano-coating that Motorola used on the RAZR to make it more water repellant. Apple will brand this with a unique name and claim it to be a major breakthrough.

Continuing with the theme of durability, Apple will abandon the 30-pin dock connector and seal the entire body of the phone. All data connections will need to be done wirelessly. A new MagSafe-like connector will be introduced for charging. Additionally the iPhone will lose the glass back, and it will be replaced with an aluminum one like on the iPad.

NFC will be added to go along with an  electronic wallet system called iCash. This will be linked to your iTunes account.

The phone will be slightly thinner than the iPhone 4, but will largely have the same form factor. There will not be a tear-drop shaped design. The screen size remains 3.5 inches. Like the iPad 3, it will be released in multiple colors. The rear camera gets better, the device gets thinner, the phone receives the quad core A6. 

With the introduction of the iPhone 5, the iPhone 4S is only offered with 16 gb and moves down to $99. The 8 gb iPhone 4 becomes the free offering in developed countries and the 3GS soldiers on as the price leader in emerging economies.

Last year I predicted Apple would sell 65 million iPhones. As of September 1, Apple has sold 56 million and analysts are expecting 30 million in the Christmas quarter, for a total of 86 million iPhones. So I blew that. 86 million represents an increase of 181% over 2010, which was an 189% increase over 2009 which was an increase of 183% over 2008. I’m going to guess that iPhone sales continue this incredible streak and grow by 180% in 2012 so that is 154 million. My official guess is 160 million iPhones in 2012 (that seems totally insane given that Apple has cumulative sales of 146 million iPhones as of September 2011).
Data from Asymco. 
iPods
After a stale year with no changes besides a white iPod touch the iPod line gets a significant revision.
In October, a month after the iPhone announcement, Apple will unveil the new iPod lineup. It’s tag line will be something like “Something big. Something small.” The iPod Nano is the something small. It adopts iOS and becomes the smallest general purpose computer. Like the iPhone it will lose the 30-pin doc connector while gaining WiFi and bluetooth. Apple will open the Nano to a specialized corner of the App with simple single function apps that incorporate voice control and feedback. The Nano will also gain a front and rear facing camera. Yes I know this is exactly what I predicted a year ago, but in the grand-tradition of Apple prognostication, I wasn’t wrong, just a year too early.
The iPod touch goes big. It gains a 4 or 4.5 inch screen and is marketed as a game machine and Kindle competitor. It bumps up to the A5 processor and remains just as thin as the current device. The front face gains multiple colors but the back remains polished stainless steel. It also loses the 30-pin dock connector. All of those sightings of a teardrop shaped, 4-inch screened iPhone 5 from last summer were actually early proto-types of the 2012 iPod Touch. 
Apple offers an iPod Touch with a cellular radio for the first time, just like in the iPad. The data rates are also identical to the iPad. No LTE option. Prices: 
  • 8 gb   WiFi $229 
  • 32 gb WiFi $329        WiFi + Cellular $399 
  • 64 gb WiFi $429        WiFi + Cellular $499 

iOS
iOS 6 is announced at WWDC in June and roles out to all iOS devices in September a week before the introduction of the iPhone 5. The marque feature of iOS6 is Siri which becomes available on the iPhone 4, iPod 4th Generation and all three iPads. Siri leaves beta and opens up to allow limited third party software access to new voice and speech APIs. TV shows and movies get the iCloud experience and can be downloaded repeatedly. FaceTime over 3g.
Macintosh
The big story of 2011 is the repositioning of the MacBook Pro line. After the MacBook Air displaced the MacBook in 2011, it will set its sights on the iconic MacBook Pro. The MacBook Pro 13 inch will disappear entirely. The 15 and 17 inch will remain.
The Macbook Air line will add a 15 inch model. The MacBook Airs will begin to offer a cellular modem option.

MacPro will get updated without fanfare in March. Despite much handwringing, this will not be the final update of the tower mac which continues to serve a small, but influential, sliver of the Macintosh family. 
Apple will introduce a cloud back up service which will move Time Machine from a spare drive on your desk to one of Apple’s data centers. This will be a pay-to-play service: one year of back-up will be provided with new machines and it will be $100 per year after that.

Throughout 2012 there is not a peep about the next version of OS X.

Apple TV

Apple introduces a revamped Apple TV at WWDC and it goes on sale in September. It remains the little iOS box that is currently sold with a bigger processor and a new version of the OS and Siri. An iOS device running iOS 6 will be required to act as the microphone for Siri. It will also gain the ability to add apps from the iTunes App Store. The Apple TV Set will also be introduced in June for a September or October role out. The Apple TV set (iPanel?) will not offer any significant feature beyond the Apple TV. However, it will come bundled with a 7 inch iPad to act as a remote control, game controller and auxiliary screen. Additionally, any iPhone, iPad and iPod running iOS will be able to duplicate the functions of this uber-remote.

Apple

Apple will spill some of their massive war chest to lock-up exclusive content deals. This will include sports, movies and original content. They will continue to purchase small engineering-focussed companies but no other major merger.

Tim Cook will remain the CEO and there will be a steady trickle of VPs leaving the company for other CEO positions. Names that will stay include Cook, Cue, Ive and Schiller. Forstall, Mansfield are among the Veeps who may move on.

A lot of companies might try to entice the architect of the iPhone to be their top guy and with a young Tim Cook (born 1960) secure as CEO, an ambitious Forstall might make the jump. Can you imagine Scott Forstall being tapped to replace Ballmer at Microsoft?

With the release of the new Apple TV the stock will be seriously goosed. I expect a 52-week high of $667 and the stock to close 2012 at $605.
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Coffee + MacBook Air = No posts for awhile

I spilled an entire cup of coffee on my laptop.

Dead laptop.

Last back-up, 7 weeks old.

Lost blogging momentum.

I have a pile of half written posts and should be out of the funk soon.

I have also purchased a dropbox account and will not be caught with two-month old back-ups again. That’s a pretty good new years resolution, though better would be to not spill cups of coffee into my laptop.

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AASK: a cautionary tale for bardoxolone?

Robert Leversee had some questions regarding my presentation on diabetic nephropathy. You can see his concerns in the comments after the post. he was specifically concerned about this slide.

Robert felt it minimized the GFR gains found with bardoxolone. What is not clear from the deck is that 56 weeks, represents the GFR one month after stopping the drug. In the lecture, I pointed out that patients that were on bardoxolone all had a higher GFR than at baseline, while patients randomized to placebo had a lower GFR.

As a reminder, the primary end-point of the study was the change in GFR at 24 weeks and that was dramatic.

The reason I included the slide showing the 56 week data was my concern that bardoxolone may be pulling a creatinine slight of hand. My personal concern is that the changes in GFR are due to simple hemodynamic changes like were seen with amlodipine in AASK.

AASK was a trial of hypertension therapy in African Americans with a renal end-point rather than a cardiovascular end-point that are more common in hypertension trials. The trial is a two by three design with two blood pressure targets (MAP 102-107 vs <92) and three blood pressure medications (amlodipine, ramipril, metoprolol).

The data is difficult to interpret because the amlodipine caused an acute hemodynamic-related bump in the GFR, but after 12 months the loss of GFR in the amlodipine group was faster than with ramipril. The study designers designated co-primary end points, a total change in GFR and a chronic change in GFR that ignored the initial 3 months.

Ramipril was superior to amlodipine in the chronic phase but not in the total change in GFR. Though this ambiguity was not represented in the conclusions of the trial:

The fact that amlodipine improved renal function for one year makes me nervous about the one year duration of the bardoxolone study. Thankfully BEACON is in full swing enrolling patients so a definitive answer is just ahead.
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Brilliant little video on exercise

My pithy little push for exercise is that it is the closest thing we have found to the fountain of youth. That it doesn’t mater what disease you look at, increasing you exercise or fitness is associated with better outcomes.

Love this video.

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Less medicine, better care

Thought provoking article at Zocalo Public Square by Ken Murray a family practice doctor who writes that he was so frustrated with futile end-of-life care he suspended his hospital practice.

Of course, doctors don’t want to die; they want to live. But they know enough about modern medicine to know its limits. And they know enough about death to know what all people fear most: dying in pain, and dying alone.

The essay feels right but relies on anecdote rather than data to support the central premise that doctors are more likely to to use hospice and palliative care to have gentler passing.

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Diabetic nephropathy

I was invited to do grand-rounds at St John and was given no guidance on selecting my topic. I recently received a phone call from a long-time family friend, this man had literally changed my diapers, and he asked me to help a relative get bardoxolone. My group is participating in Beacon (the current phase II trial for bardoxolone) and though I am not one of the investigators I assured him that we would evaluate his friend. I couldn’t guarantee he would get study drug rather than placebo or even qualify for the trial.

The whole event shocked me. I had no idea that the results of the Bardoxolone study had slipped beyond the geek fringes of nephrology. It reminded me of a story that Judah Folkman told. He came to Indiana University to collect an award and give a lecture, shortly after a NYTimes profile. In that front page story James Watson (yes that James Watson) said Folkman would cure cancer in two years.

Judah told the story that he was getting phone calls from strangers and friends asking for his miracle cure and was heart broken because he had nothing to offer them. At that stage his drug was only for mice.

That’s Judah and me following the afore mentioned lecture in 1999.

Getting that call from my friend gave me the same sort of Folkman moment. I never thought people would be calling me trying to get experimental therpy. So I decided to talk about Bardoxolone.

As I started my research I became concerned that patients randomized to bardoxolone developed increased albumniuria.

Some patients tripled their albuminuria! The drug increased GFR, but the increased albuminuria could not be fully accounted for by the improved function.
ASN Kidney Week fell 10 days prior to my Grand Rounds so I planned on grabbing some good ideas at the meeting. On Friday I went to Kidney Disease in Type 2 Diabetes: New Insights. There were four lectures. The last two were homeruns.
Dr. Bruce Perkins was perfect for my talk. He spoke of how albuminuria is not a great surrogate end-point for diabteic nephropathy studies. Bad outcomes often follow a reduction in proteinuria.
I used my iPhone to record the audio and took pictures of each slide with my Nikon (this was before I learned that ASN did not want attendees taking pics of the lectures. WTF). When I got home I grabbed the best thoughts from his lecture and made it the cornerstone of my talk on diabetic nephropathy, bardoxolone, and a more modern view of albuminuria.
Thanks Dr. Perkins.

The lecture was a little light, I finished in 45 minutes and used some filler from my Diabetic Nephropathy 2009 lecture. Before I use the lecture again I would add some of the points from Andrew Bomback’s excellent lecture, “RAAS Blockade: More is better? Yes. No. It depends.”

Here is my PowerPoint (58mb) and PDF (51mb).
Note to self: the Helvetica Neue UltraLight, didn’t project so well.

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We’ve got one! Finding a functional adrenal adenoma

A year ago, a slender, 40 year old, white female presented to my clinic with new onset elevated blood pressure. The hypertension was discovered during a routine visit for a minor injury. The family practitioner refused to believe the vitals and kept having the patient return for follow-up visits before resigning himself to the diagnosis. Surprisingly, this otherwise healthy woman, was resistant to multiple medications. He began to suspect a more sinister diagnosis and initiated a work-up for secondary hypertension and referred her to me.

The initial work-up showed a aldosterone of 16 but the renin was not done. She also had modestly elevated metanephrines, but not high enough to suggest a pheochromacytoma. Her blood pressure typically ran 140-160/100 with labetalol 100 mg bid, but she admitted to being forgetful regarding her medications.

One of the findings that stood out for me was the hypokalemia on the initial labs

We repeated the renin-aldo ratio and did a EKG. Unfortunately she had LVH. For me, this ruled out white coat syndrome. The demonstration of end-organ damage also helped the patient see that this condition was “real” and after that she was compliant with the medical therapy.

The repeat Aldo was only 3 with a fully suppressed renin at 0.15. This is an aldosterone-renin ratio (ARR) of 20, however, I was taught a low total aldosterone ruled this diagnosis out. In other words, one needs an elevated aldosterone, not just a suppressed renin to make the diagnosis of primary hyperaldosteonism. This always made sense to me but the Endocrine Society states that this is not always true and questions the requirement for a high aldosterone:

Against a formal cutoff level for aldosterone are the findings of several studies. In one study, seated plasma aldosterone levels were less than 15 ng/dl in 36% of 74 patients diagnosed with PA after screening positive by ARR defined as more than 30 and showing failure of aldosterone to suppress during fludrocortisone suppression testing (FST), and in four of 21 patients found by AVS to have unilateral, surgically correctable PA.

Her potassium remained low at 3.1 despite potassium supplementation. She was breast feeding at the time so we did not use an ACEi or ARB and were successfully treating her blood pressure with a combination of nifedipine XL and labetalol.

The low aldosterone appeared to rule-out primary hyperaldo but with the unexplained hypokalemia I ordered a third ARR and hit pay-dirt

An ARR of close to 300 with a sky-high aldosterone of 29. Remember, when you calculate the aldosterone-renin ratio make sure the units are correct:
  • aldosterone in nanograms per deciliter
  • renin measured as plasma renin activity (PRA) in nanograms per milliliter per hour
With a positive ARR, the endocrine society recommends a confirmatory test. There are four recommended tests, all of which are variations on attempts to suppress endogenous aldosterone via sodium loading or fludrocortisone suppression. I did not do this. I feel that the critical diagnosis to make is the functional adenoma that is surgically curative. Whether the patient has bilateral hyperplasia or simply aldosterone driven hypertension that doesn’t meet the criteria for primary aldosterone is not important to me because I’m going to treat both of those conditions identically, with spironolactone or eplerenone.

So we proceeded with the work-up for a functional adenoma and sent her for a CT scan. We found a 1 x 2 cm left adrenal mass.

Here is where it gets tricky. This sounds like a functional adenoma, however functional adrenal adenomas are rare diagnosis, and even in the presence of documented hyperaldosteronism, non-functional incidentalomas are too common (0.35-5%) to assure that a CT finding of an adrenal mass represents a functional adenoma. Following a CT scan, you can neither rule-out nor rule-in the diagnosis of a surgically correctible functional adenoma. Patients still need to get adrenal vein sampling. Here is the experience from University of Texas Southwestern:

Twenty patients had unilateral CT abnormalities, and 14 (70%) of them lateralized to the same side (concordant). Of the remaining 6 patients with unilateral CT abnormalities (3 left and 3 right), 1 patient each lateralized to the opposite side and 2 patients each had bilateral hypersecretion. Only 5 of 15 patients (33%) with bilateral CT abnormalities showed concordant bilateral aldosterone hypersecretion. The other 10 patients (67%) demonstrated unilateral hypersecretion. Of the 5 patients with normal-appearing adrenal glands on CT, 1 patient each lateralized to 1 side, and the other 3 patients had bilateral hypersecretion.

The authors did not provide a 2×2 table to determine sensitivity or specificity (insert rant regarding surgical literature here) so I put one together. This is how I interpreted the data above:

  • Positive test: 20 with unilateral findings, 14 true positives and 6 false positives (I considered the CT scan identifying the wrong affected adrenal as being a fail)
  • Negative test: 15 patients with bilateral findings, 5 were true negatives and 10 were false negatives
  • Negative test: 5 patients with normal adrenals, 2 lateralized, false negatives and 3 true negatives
The two-way table looks like this:
What? You’re still using Epocrates’ medical
calculator? Don’t be a tool, get a tool, MedCalc
It should be apparent that a CT scan looks truly terrible at diagnosing a functional adenoma. A negative predictive value of only 40%. Ughh! Note: these numbers assume the adrenal vein sampling is a valid gold-standard.

We sent her for adrenal vein sampling to see if the aldosterone secretion lateralizes. It did with a 20-fold increase in aldosterone on the left side. Because aldosterone levels can be unreliable due to dilution and technique, it is recommended that an adjusted aldosterone (aldo/cotisol) exceed the contralateral adrenal by three fold. In our case, it was 10-fold.

She went for an laparoscopic left adrenalectomy and is now normotensive off all medications.

The endocrine society had published consensus recommendations on screening, diagnosis and treatment of primary hyperaldosteronism. I love it when important articles are available in PDF for free.